SNPMiner Trials by Shray Alag


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Report for Mutation I148M

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 5 clinical trials

Clinical Trials


1 Effects of Overfeeding Followed by Weight Loss on Liver Fat Content and Adipose Tissue Inflammation

A. BACKGROUND Accumulation of fat in the liver due to non-alcoholic causes (NAFLD) is associated with hepatic insulin resistance, which impairs the ability of insulin to inhibit the production of glucose and VLDL . This leads to increases in serum glucose, insulin and triglyceride concentrations as well as hyperinsulinemia. Recent epidemiologic studies have shown that a major reason for the metabolic syndrome as well as the accompanying increased risk of cardiovascular disease and type 2 diabetes is overconsumption of simple sugars. The investigators have recently shown that overeating simple sugars (1000 extra calories/day, "CANDY" diet) increases liver fat content by 30% within 3 weeks (4), and recapitulates features of the metabolic syndrome such as hypertriglyceridemia and a low HDL cholesterol concentration. The fatty acids in intrahepatocellular triglycerides may originate from peripheral lipolysis, de novo lipogenesis, uptake of chylomicron remnants by the liver and from hepatic uptake of fatty acids released during intravascular hydrolysis of triglyceride-rich lipoproteins (the spillover pathway). A classic study using stable isotope methodology by the group of Elisabeth Parks showed that in subjects with NAFLD, the excess intrahepatocellular triglycerides originate from peripheral lipolysis and de novo lipogenesis. It is well-established that ingestion of a high carbohydrate as compared to high fat diet stimulates de novo lipogenesis in humans. Meta-analyses comparing isocaloric high fat and high carbohydrate diets have shown that high carbohydrate but not high fat diets increase increase serum triglycerides and lower HDL cholesterol. Since hypertriglyceridemia results from overproduction of VLDL from the liver, these data suggest the composition of the diet influences hepatic lipid metabolism. Whether this is because overfeeding fat leads to preferential deposition of fat in adipose tissue while high carbohydrate diets induce a relative greater increase in liver fat is unknown. There are no previous studies comparing effects of chronic overfeeding of fat as compared to carbohydrate on liver fat or and the sources of intrahepatic fatty acids. A common polymorphism in PNPLA3 at rs738409 (adiponutrin) gene is associated with a markedly increase liver fat content. This finding has been replicated in at least 20 studies across the world. The investigators have shown that PNPLA3 is regulated by the carbohydrate response element binding protein 1. Mice overexpressing the human I148M PNPLA3 variant in the liver exhibit an increase in liver triglycerides and cholesteryl esters on a high sucrose but not high fat diet. These data suggest that overfeeding a high carbohydrate as compared to a high fat diet may increase liver fat more in subjects carrying the I148M allele than in non-carriers. B. HYPOTHESIS The investigators hypothesize that overfeeding a high fat as compared to an isocaloric high carbohydrate diet influences the source of intrahepatocellular triglycerides. During a high fat diet, relatively more of intrahepatocellular triglycerides originate from peripheral lipolysis and less from DNL than during a high carbohydrate diet in the face of a similar increase in liver fat. It is also possible given the lack of previous overfeeding data comparing 2 different overfeeding diets that the high fat diet induces a smaller increase in liver fat than a high carbohydrate diet even in the face of an identical increase in caloric intake because a greater fraction of ingested fat is channeled to adipose tissue than the liver. The investigators also hypothesize that liver fat may increase more in carriers than non-carriers of the I148M variant in PNPLA3 during a high carbohydrate than a high fat diet. C. SPECIFIC AIMS The investigators wish to randomize, using the method of minimization (considers baseline age, BMI, gender, liver fat, PNPLA3 genotype) 40 non-diabetic subjects with NAFLD as determined by the non-invasive score developed in our laboratory or previous knowledge of liver fat content based on MRS to overeat either a high carbohydrate or high fat diet (1000 extra calories per day) for 3 weeks. Before and after the overfeeding diets, will measure liver fat content by 1H-MRS and the rate of adipose tissue lipolysis using doubly labeled water (DDW) and [1,1,2,3,3-2H5] glycerol as described in detail below. The investigators also wish to characterize glucose, insulin, fatty acid and triacylglyceride profiles before and while on the experimental diet. An adipose tissue biopsy is taken to determine whether expression of genes involved in lipogenesis or lipolysis, or those involved in adipose tissue inflammation change in response to overfeeding, and for measurement of LPL activity. After overfeeding, both groups will undergo weight loss to restore normal weight as described in our recent study. The metabolic study is repeated after weight loss.

NCT02133144 NAFLD Behavioral: overeating fat Behavioral: overeating carbohydrate
MeSH:Inflammation Weight Loss
HPO:Decreased body weight Weight loss

The investigators have shown that PNPLA3 is regulated by the carbohydrate response element binding protein 1. Mice overexpressing the human I148M PNPLA3 variant in the liver exhibit an increase in liver triglycerides and cholesteryl esters on a high sucrose but not high fat diet. --- I148M ---

These data suggest that overfeeding a high carbohydrate as compared to a high fat diet may increase liver fat more in subjects carrying the I148M allele than in non-carriers. --- I148M ---

The investigators also hypothesize that liver fat may increase more in carriers than non-carriers of the I148M variant in PNPLA3 during a high carbohydrate than a high fat diet. --- I148M ---

Primary Outcomes

Measure: Liver fat content (1H-MRS) and intra-abdominal and subcutaneous fat (MRI)

Time: 3 weeks

Description: the rate of DNL and adipose tissue lipolysis is measured using doubly labeled water (DDW) and [1,1,2,3,3-2H5] glycerol

Measure: De novo lipogenesis (DNL) and measurement of lipolysis

Time: 3 weeks

Secondary Outcomes

Description: Laboratory tests including fasting glucose, insulin, C-peptide, liver enzymes, total, LDL and HDL cholesterol and TG concentrations PNPLA3 genotyping is performed also

Measure: Analytical procedures

Time: 3 weeks

Other Outcomes

Description: Needle biopsies of abdominal subcutaneus tissue will be taken for subsequent isolation of RNA for measurements of gene expression (by quantitative PCR). Fat cell size is also measured.

Measure: Biopsies and analysis of subcutaneus adipose tissue

Time: 3 weeks

Description: Indirect calorimetry is the method by which metabolic rate is estimated from measurements of oxygen (O2) consumption and carbon dioxide (CO2) production.

Measure: Indirect calorimetry

Time: 3 week

2 Body Composition and Metabolic Manifestations of Insulin Resistance in Adolescents With Polycystic Ovary Syndrome: Ectopic Fat Deposition and Metabolic Markers: Intervention and Follow-up Portion

This project, "A double-blind placebo-controlled randomized clinical trial assessing the efficacy of metformin for hepatic fat in adolescents and young adults with polycystic ovary syndrome", proposes exploring the use of novel and noninvasive methodologies in an at-risk adolescent and young adult population with polycystic ovary syndrome (PCOS) who may gain long-term health benefits from early detection and treatment of non-alcoholic fatty liver disease (NAFLD). PCOS is a common condition that frequently presents in adolescence and young adulthood and is defined by elevated androgens (male hormones) in the blood leading to 1. hirsutism and acne and 2. menstrual abnormalities or amenorrhea. Affected individuals are at increased risk of developing insulin resistance (a precursor of diabetes), NAFLD and lipid (cholesterol) abnormalities.These features are all associated with the metabolic syndrome, a rising major public health concern. Recently, an association between PCOS and NAFLD has been noted but has only been superficially studied in the adolescent and young adult population. The susceptibility of certain PCOS patients to developing NAFLD is theorized to be due to having underlying insulin resistance, elevated androgen levels, and a genetic predisposition. Metformin is an insulin sensitizing medication widely used to treat type 2 diabetes mellitus that may have beneficial effects on insulin resistance-related conditions including PCOS and NAFLD. Although widely used in PCOS, its effect on NAFLD in this group has not been previously studied. The primary aims of this proposal are: 1) To determine whether PCOS with liver fat >/=4.8% treated with metformin for six months will have a decline in percentage liver fat compared to a placebo group. 2) To measure the association of the PNPLA3 I148M allele with NAFLD in PCOS at baseline (n=40). 2b) To measure the association of percentage liver fat with biomarkers of NAFLD, dyslipidemia, insulin resistance and body composition at baseline (n=40) and after a placebo-controlled intervention with metformin in PCOS with liver fat >4.8% (n=20). The goal of this research proposal is to explore the use of novel and noninvasive technologies in a young and at risk population. Dr. Sopher hopes to use the results of this research to lay the groundwork for the prevention and treatment of NAFLD and other metabolic disorders in adolescents and young adults with PCOS and to prevent lifelong morbidity associated with PCOS.

NCT02500147 Polycystic Ovary Syndrome Non-Alcoholic Fatty Liver Disease Metabolic Syndrome Drug: Metformin Drug: Placebo
MeSH:Polycystic Ovary Syndrome Liver Diseases Fatty Liver Non-alcoholic Fatty Liver Disease Metabolic Syndrome Syndrome
HPO:Abnormality of the liver Decreased liver function Elevated hepatic transaminase Hepatic steatosis Polycystic ovaries

2) To measure the association of the PNPLA3 I148M allele with NAFLD in PCOS at baseline (n=40). --- I148M ---

The proportion of PCOS subjects with the high risk I148M PNPLA3 allele in the PCOS groups with elevated and normal liver fat will be compared using a chi-squared or Fisher's Exact test.. --- I148M ---

Other IR indices that will be evaluated are whole body insulin sensitivity (WBIS) and insulin area under the curve; 6) Genetic evaluation: A blood sample for the PNPLA3 I148M allele (baseline only). --- I148M ---

Primary Outcomes

Description: To compare percentage liver fat by magnetic resonance spectroscopy in the metformin group and placebo group to baseline and between the groups in order to determine if metformin is efficacious for reducing liver fat compared to placebo in adolescents and young women with Polycystic Ovary Syndrome (PCOS)

Measure: Difference in percentage liver fat between Metformin arm and Placebo arm in adolescents and young adults with PCOS and with elevated percentage liver fat (>/=4.8%)

Time: 6 months

Secondary Outcomes

Description: The proportion of PCOS subjects with the high risk I148M PNPLA3 allele in the PCOS groups with elevated and normal liver fat will be compared using a chi-squared or Fisher's Exact test.

Measure: Proportion of PCOS subjects with the PNPLA3 allele comparing those with elevated percentage liver fat (>/=4.8%) and those with normal percentage liver fat (<4.8%) by magnetic resonance spectroscopy

Time: 6 months

Description: The association of percent liver fat with insulin resistance as measured by HOMA-IR will be measured by correlation/regression. Change in HOMA-IR with change in percent liver fat following metformin will be assessed using multiple regression analysis.

Measure: The association of percentage liver fat by magnetic resonance spectroscopy with insulin resistance as measured by HOMA-IR in adolescents with PCOS

Time: 6 months

Description: The association of percent liver fat with triglycerides will be measured by correlation/regression. Change in triglycerides with change in percent liver fat following metformin will be assessed using multiple regression analysis.

Measure: The association of percentage liver fat with triglycerides

Time: 6 months

Description: The association of percent liver fat with visceral adipose tissue will be measured by correlation/regression. Change in visceral adipose tissue with change in percent liver fat following metformin will be assessed using multiple regression analysis.

Measure: The association of percentage liver fat with visceral adipose tissue

Time: 6 months

Description: The association of percent liver fat with total body adipose tissue will be measured by correlation/regression. Change in total body adipose tissue with change in percent liver fat following metformin will be assessed using multiple regression analysis.

Measure: The association of percentage liver fat with total body adipose tissue

Time: 6 months

Description: The association of percent liver fat with pancreatic polypeptide will be measured by correlation/regression. Change in pancreatic polypeptide with change in percent liver fat following metformin will be assessed using multiple regression analysis.

Measure: The association of percentage liver fat with pancreatic polypeptide

Time: 6 months

Description: The association of percent liver fat with M30 will be measured by correlation/regression. Change in M30 with change in percent liver fat following metformin will be assessed using multiple regression analysis.

Measure: The association of percentage liver fat with M30, a hepatic apoptosis marker

Time: 6 months

3 Genetic Regulation of Lipid Pathways Contributing to Non-alcoholic Fatty Liver and Atherogenic Dyslipidemia

The aims of the study are: 1. To investigate if carriers of apolipoprotein (apo) CIII loss-of-function (LOF) mutations produce less apo-CIII that results in reduction of large very low-density lipoprotein (VLDL) particle secretion as compared to non-carriers of these variants and compare the results with carriers of apo-CIII gain-of-function (GOF) to elucidate the role of apo-CIII in hepatic lipid metabolism. 2. To study if carriers of the TM6SF2 E167K and PNLPLA3 I148M mutations produce less large VLDL particles to transport fat out of the liver as compared to non-carriers. 3. To test whether the specific mutations in the apo-CIII, TM6SF2 and PNLPLA3 genes are reflected in changes of liver de novo lipogenesis (DNL), liver fat, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), plasma lipid and apolipoprotein kinetics and fasting concentrations in carriers of the TM6SF2 E167K and PNLPLA3 I148M mutations as compared to non-carriers. 4. To study the effects of APOE, angiopoietin (ANGPTL3 and ANGPTL8) or endothelial lipase (LIPG) genotypes on liver fat metabolism, lipid and apolipoprotein metabolism and lipid phenotypes.

NCT04209816 Non-alcoholic Fatty Liver Atherogenic Dyslipidemia Insulin Resistance Diagnostic Test: Lipoprotein kinetics
MeSH:Fatty Liver Non-alcoholic Fatty Liver Disease Insulin Resistance Dyslipidemias
HPO:Abnormal circulating lipid concentration Hepatic steatosis Insulin resistance

2. To study if carriers of the TM6SF2 E167K and PNLPLA3 I148M mutations produce less large VLDL particles to transport fat out of the liver as compared to non-carriers. --- E167K --- --- I148M ---

3. To test whether the specific mutations in the apo-CIII, TM6SF2 and PNLPLA3 genes are reflected in changes of liver de novo lipogenesis (DNL), liver fat, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), plasma lipid and apolipoprotein kinetics and fasting concentrations in carriers of the TM6SF2 E167K and PNLPLA3 I148M mutations as compared to non-carriers. --- E167K --- --- I148M ---

Inclusion Criteria: - persons who have provided written consent - apo-CIII loss-of-function mutation (heterozygous) or apo-CIII gain-of-function mutations (heterozygous) or TM6SF2 E167K mutation (homozygous) or PNLPLA3 I148M or apoE or LIPG or ANGPTL3 or ANGPTL8 LOF and GOF variants. --- E167K --- --- I148M ---

m² at inclusion Exclusion Criteria: - Patients with Type 1 and 2 diabetes, BMI > 40 kg/m2, - ApoE2/2 phenotype, thyrotropin concentration outside normal range, - Lipid-lowering drugs - Blood pressure >160 mmHg systolic and/or > 105 diastolic mmHg - Liver failure or abnormal liver function tests >3 x upper limit of normal - Intestinal disease - Pregnancy, breastfeeding - Patients with volume depletion Inclusion Criteria: - persons who have provided written consent - apo-CIII loss-of-function mutation (heterozygous) or apo-CIII gain-of-function mutations (heterozygous) or TM6SF2 E167K mutation (homozygous) or PNLPLA3 I148M or apoE or LIPG or ANGPTL3 or ANGPTL8 LOF and GOF variants. --- E167K --- --- I148M ---

Primary Outcomes

Description: Production rate, mg/day

Measure: Difference in the rate of production of VLDL Apo B

Time: Baseline

Description: Production rate, mg/kg/day

Measure: Difference in the rate of production of VLDL Triglycerides

Time: Baseline

Description: Production rate, mg/kg/day

Measure: Difference in the rate of production of VLDL ApoC-III and apoE

Time: Baseline

Description: Rate of disappearance, pools/day

Measure: Difference in the Fractional Catabolic Rate of VLDL Apo B

Time: Baseline

Description: Rate of disappearance, pools/day

Measure: Difference in the Fractional Catabolic Rate of VLDL Triglycerides

Time: Baseline

Description: Rate of disappearance, pools/day

Measure: Difference in the Fractional Catabolic Rate of VLDL ApoC-III and apoE

Time: Baseline

Description: Measure of newly synthesized triglycerides in VLDL, μmol/l

Measure: Difference in de novo lipogenesis

Time: Baseline

Description: Percentage of liver fat measured with magnetic resonance spectroscopy

Measure: Difference in liver fat

Time: Baseline

Description: Remnant lipoproteins and lipoprotein fraction composition, mg/L

Measure: Difference in atherogenic dyslipidemia

Time: Baseline

Description: Calculated Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)

Measure: Difference in insulin resistance

Time: Baseline

Description: ApoA, mg/dl

Measure: Difference in apoprotein A concentration

Time: Baseline

Description: ApoB, mg/dl

Measure: Difference in apoprotein B concentration

Time: Baseline

Description: ApoC, mg/dl

Measure: Difference in apoprotein C concentration

Time: Baseline

Description: ApoE, mg/dl

Measure: Difference in apoprotein E concentration

Time: Baseline

Description: Rate of turnover, pools/day

Measure: Difference in the rate of production and Fractional Catabolic Rate of intermediate-density Apo B

Time: Baseline

Description: Rate of turnover, pools/day

Measure: Difference in the rate of production and Fractional Catabolic Rate of low-density lipoprotein Apo B

Time: Baseline

Description: Measured lipoprotein lipase activity, mU/ml

Measure: Lipolytic activity

Time: Baseline

Description: Measured hepatic lipase activity, mU/ml

Measure: Hepatic lipase activity

Time: Baseline

4 A Phase 2, Randomised, Placebo Controlled Study to Evaluate the Efficacy, Tolerability and Safety of Metabolic Cofactor Supplementation in Obese Subjects With Non-Alcoholic Fatty Liver Disease (NAFLD)

This short-term, randomized, placebo-controlled, investigator-initiated trial aims to establish metabolic improvements in NAFLD subjects by dietary supplementation with cofactors N-acetylcysteine, L-carnitine tartrate, nicotinamide riboside and serine. Concomitant use of pivotal metabolic cofactors via simultaneous dietary supplementation will stimulate three different pathways to enhance hepatic β-oxidation and this study's hypothesis is that this will result in decreased amount of fat in the liver.

NCT04330326 Non-alcoholic Fatty Liver Disease (NAFLD) Drug: Metabolic Cofactor Supplementation Drug: Sorbitol
MeSH:Liver Diseases Fatty Liver Non-alcoholic Fatty Liver Disease
HPO:Abnormality of the liver Decreased liver function Elevated hepatic transaminase Hepatic steatosis

heart failure, documented coronary artery disease, valvular heart disease) - Patients with active bronchial asthma - Patients with phenylketonuria (contraindicated for NAC) - Patients with histamine intolerance - Clinically significant TSH level outside the normal range (0.04-6 mU/L) - Known allergy for substances used in the study - Concomitant medication use: 1. Lipid-lowering drugs within 3 months 2. Oral antidiabetics given for insulin resistance of obesity (metformin, liraglutide etc.) within 3 months 3. Thiazide diuretics with a dose >25 mg/d 4. Postmenopausal estrogen therapy 5. Any medication acting on nuclear hormone receptors or inducing Cytochromes P450 (CYPs) 6. Self-administration of dietary supplements such as any vitamins, omega-3 products, or plant stanol/sterol products within 1 month 7. Treatment with medications known to cause fatty liver disease such as atypical neuroleptics, tetracycline, methotrexate or tamoxifen 8. Use of an antimicrobial agent in the 4 weeks preceding randomization - Active smokers consuming >10 cigarettes/day - Alcohol consumption over 192 grams for men and 128 grams for women per week - Patients considered as inappropriate for this study for any reason (patients unable to undergo MRI study, noncompliance etc.) - Subjects with Patatin-like phospholipase domain-containing protein 3( PNPLA3) I148M (homozygous for I148M) - Women who are pregnant, are planning pregnancy, or who are breast-feeding - Women of childbearing potential not protected by effective birth control method - Active participation in another clinical study Inclusion Criteria: - Men and women (18-70 years old) - Body mass index >27kg/m2 - Triglyceride levels ≤354 mg/dl and LDL chol ≤175 mg/dl - No history of medication use for hepatic steatosis - Increased liver fat (>5.5%) --- I148M ---

heart failure, documented coronary artery disease, valvular heart disease) - Patients with active bronchial asthma - Patients with phenylketonuria (contraindicated for NAC) - Patients with histamine intolerance - Clinically significant TSH level outside the normal range (0.04-6 mU/L) - Known allergy for substances used in the study - Concomitant medication use: 1. Lipid-lowering drugs within 3 months 2. Oral antidiabetics given for insulin resistance of obesity (metformin, liraglutide etc.) within 3 months 3. Thiazide diuretics with a dose >25 mg/d 4. Postmenopausal estrogen therapy 5. Any medication acting on nuclear hormone receptors or inducing Cytochromes P450 (CYPs) 6. Self-administration of dietary supplements such as any vitamins, omega-3 products, or plant stanol/sterol products within 1 month 7. Treatment with medications known to cause fatty liver disease such as atypical neuroleptics, tetracycline, methotrexate or tamoxifen 8. Use of an antimicrobial agent in the 4 weeks preceding randomization - Active smokers consuming >10 cigarettes/day - Alcohol consumption over 192 grams for men and 128 grams for women per week - Patients considered as inappropriate for this study for any reason (patients unable to undergo MRI study, noncompliance etc.) - Subjects with Patatin-like phospholipase domain-containing protein 3( PNPLA3) I148M (homozygous for I148M) - Women who are pregnant, are planning pregnancy, or who are breast-feeding - Women of childbearing potential not protected by effective birth control method - Active participation in another clinical study Inclusion Criteria: - Men and women (18-70 years old) - Body mass index >27kg/m2 - Triglyceride levels ≤354 mg/dl and LDL chol ≤175 mg/dl - No history of medication use for hepatic steatosis - Increased liver fat (>5.5%) --- I148M --- --- I148M ---

heart failure, documented coronary artery disease, valvular heart disease) - Patients with active bronchial asthma - Patients with phenylketonuria (contraindicated for NAC) - Patients with histamine intolerance - Clinically significant TSH level outside the normal range (0.04-6 mU/L) - Known allergy for substances used in the study - Concomitant medication use: 1. Lipid-lowering drugs within 3 months 2. Oral antidiabetics given for insulin resistance of obesity (metformin, liraglutide etc.) within 3 months 3. Thiazide diuretics with a dose >25 mg/d 4. Postmenopausal estrogen therapy 5. Any medication acting on nuclear hormone receptors or inducing Cytochromes P450 (CYPs) 6. Self-administration of dietary supplements such as any vitamins, omega-3 products, or plant stanol/sterol products within 1 month 7. Treatment with medications known to cause fatty liver disease such as atypical neuroleptics, tetracycline, methotrexate or tamoxifen 8. Use of an antimicrobial agent in the 4 weeks preceding randomization - Active smokers consuming >10 cigarettes/day - Alcohol consumption over 192 grams for men and 128 grams for women per week - Patients considered as inappropriate for this study for any reason (patients unable to undergo MRI study, noncompliance etc.) - Subjects with Patatin-like phospholipase domain-containing protein 3( PNPLA3) I148M (homozygous for I148M) - Women who are pregnant, are planning pregnancy, or who are breast-feeding - Women of childbearing potential not protected by effective birth control method - Active participation in another clinical study Non-alcoholic Fatty Liver Disease (NAFLD) Liver Diseases Fatty Liver Non-alcoholic Fatty Liver Disease In this study, investigators aim to lower liver fat content in obese patients with NAFLD by increasing the hepatic levels of pivotal metabolic cofactors via simultaneous dietary supplementation of serine, L-carnitine, N-acetylcysteine (NAC) and nicotinamide riboside (NR). --- I148M ---

heart failure, documented coronary artery disease, valvular heart disease) - Patients with active bronchial asthma - Patients with phenylketonuria (contraindicated for NAC) - Patients with histamine intolerance - Clinically significant TSH level outside the normal range (0.04-6 mU/L) - Known allergy for substances used in the study - Concomitant medication use: 1. Lipid-lowering drugs within 3 months 2. Oral antidiabetics given for insulin resistance of obesity (metformin, liraglutide etc.) within 3 months 3. Thiazide diuretics with a dose >25 mg/d 4. Postmenopausal estrogen therapy 5. Any medication acting on nuclear hormone receptors or inducing Cytochromes P450 (CYPs) 6. Self-administration of dietary supplements such as any vitamins, omega-3 products, or plant stanol/sterol products within 1 month 7. Treatment with medications known to cause fatty liver disease such as atypical neuroleptics, tetracycline, methotrexate or tamoxifen 8. Use of an antimicrobial agent in the 4 weeks preceding randomization - Active smokers consuming >10 cigarettes/day - Alcohol consumption over 192 grams for men and 128 grams for women per week - Patients considered as inappropriate for this study for any reason (patients unable to undergo MRI study, noncompliance etc.) - Subjects with Patatin-like phospholipase domain-containing protein 3( PNPLA3) I148M (homozygous for I148M) - Women who are pregnant, are planning pregnancy, or who are breast-feeding - Women of childbearing potential not protected by effective birth control method - Active participation in another clinical study Non-alcoholic Fatty Liver Disease (NAFLD) Liver Diseases Fatty Liver Non-alcoholic Fatty Liver Disease In this study, investigators aim to lower liver fat content in obese patients with NAFLD by increasing the hepatic levels of pivotal metabolic cofactors via simultaneous dietary supplementation of serine, L-carnitine, N-acetylcysteine (NAC) and nicotinamide riboside (NR). --- I148M --- --- I148M ---

Primary Outcomes

Description: The change in liver fat content as well as subcutaneous abdominal and intra-abdominal fat content between the placebo and cofactor treatment arms in NAFLD patients from baseline to 2 weeks, 6 weeks and 10 weeks.

Measure: Magnetic Resonance Spectroscopy (MRS) Measurement

Time: 2 weeks, 6 weeks and 10 weeks

Secondary Outcomes

Description: Body weight will be measured at every visit to evaluate safety of metabolic cofactor supplementation.

Measure: Change in body weight from baseline

Time: 10 weeks

Description: Change in heart rate will be measured at every visit to evaluate safety of metabolic cofactor supplementation.

Measure: ECG Measurement

Time: 10 weeks

Description: Systolic and Diastolic Blood Pressure will be measured at every visit to evaluate safety of metabolic cofactor supplementation.

Measure: Change in Blood Pressure from baseline

Time: 10 weeks

Description: Waist and hip circumference will be measured at every visit to evaluate safety of metabolic cofactor supplementation.

Measure: Change in waist and hip circumference from baseline

Time: 10 weeks

Description: Complete blood count includes number of blood cells. Complete blood count test will be performed to measure possible toxic effects of the metabolic cofactor supplementation on hematological system.

Measure: Change of complete blood count (number of blood cells) from baseline

Time: 10 weeks

Description: Complete blood count includes concentration of hemoglobin. Complete blood count test will be performed to measure possible toxic effects of the metabolic cofactor supplementation on hematological system.

Measure: Change of complete blood count (hemoglobin) from baseline

Time: 10 weeks

Description: Kidney function tests (creatinine, urea, uric acid) will be performed to measure possible toxic effects of the metabolic cofactor supplementation on kidney function.

Measure: Changes in kidney function tests (creatinine, urea, uric acid) from baseline

Time: 10 weeks

Description: Kidney function tests (sodium, potassium) will be performed to measure possible toxic effects of the metabolic cofactor supplementation on kidney function.

Measure: Changes in kidney function tests (sodium, potassium) from baseline

Time: 10 weeks

Description: Liver function tests (ALT, AST, GGT, ALP) will be performed to measure possible toxic effects of the metabolic cofactor supplementation on liver function.

Measure: Changes in liver function tests [Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Gamma-glutamyl transferase (GGT), Alkaline phosphatase (ALP)] from baseline

Time: 10 weeks

Description: Liver function tests (Total Bilirubin, Albumin) will be performed to measure possible toxic effects of the metabolic cofactor supplementation on liver function.

Measure: Changes in liver function tests (Total Bilirubin, and Albumin) from baseline

Time: 10 weeks

Description: Creatinine kinase (CK) level will be evaluated to measure possible toxic effects of the metabolic cofactor supplementation.

Measure: Changes in creatinine kinase (CK) level from baseline

Time: 10 weeks

Description: Blood lipid levels (total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C)) will be evaluated to measure possible toxic effects of the metabolic cofactor supplementation.

Measure: Changes in blood lipid levels (total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C)) from baseline

Time: 2 weeks, 6 weeks and 10 weeks

Description: Blood glucose levels will be evaluated to measure possible toxic effects of the metabolic cofactor supplementation.

Measure: Changes in blood glucose levels from baseline

Time: 10 weeks

Description: Blood insulin level will be evaluated to measure possible toxic effects of the metabolic cofactor supplementation.

Measure: Change in blood insulin level from baseline

Time: 10 weeks

Description: Thyroid-stimulating hormone (TSH) level will be evaluated to measure possible toxic effects of the metabolic cofactor supplementation.

Measure: Change in thyroid-stimulating hormone (TSH) level from baseline

Time: 10 weeks

Description: The change in gut microbiota between the placebo and the treatment arms in NAFLD patients. Feces and saliva samples will be collected to assess changes in gut microbiota. Instructions on specimen collection will be given during the first visit. Microbiota will be assessed using shot-gun metagenomic techniques.

Measure: Microbiota analysis

Time: 2 weeks, 6 weeks and 10 weeks

Description: This process aiming to monitoring of adverse events of metabolic cofactor supplementation. Adverse events and serious adverse events will be monitored continuously and all adverse events that occur at any time during the study will be reported in Case Report Forms. Any symptoms of intestinal discomfort or other side effects will be carefully recorded and all study subjects will be informed to contact (by phone or text message) the investigators immediately if they experience any symptoms of discomfort or any side effects during the intervention period.

Measure: Monitoring of adverse events

Time: 10 weeks

5 A Phase 1, Double Blind, Randomised, Placebo-controlled, Multi-centre, Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZD2693 in Patients With Non-alcoholic Steatohepatitis (NASH) With Fibrosis Stage 1-3 and Homozygous for the PNPLA3 148M Risk Allele

This study is intended to investigate the safety and tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of AZD2693, following subcutaneous (SC) administration of multiple ascending doses in patients with Non-alcoholic Steatohepatitis (NASH) with fibrosis Stage 1 to 3 and homozygous for the PNPLA3 148M risk allele.

NCT04483947 Non-alcoholic Steatohepatitis (NASH) Drug: AZD2693 Other: Placebo
MeSH:Fatty Liver Non-alcoholic Fatty Liver Disease
HPO:Hepatic steatosis

- Provision of signed, written, and dated informed consent for mandatory Genetic PNPLA3 I148M determination genetic/biomarker, for inclusion or exclusion in the clinical trial. --- I148M ---

- Mandatory PNPLA3 Genetic Biomarker and Companion Diagnostic Development Sample: - The participant will be excluded from the study if consent for the PNPLA I148M Genetic Biomarker Samples is not given. --- I148M ---

- The mandatory consent will include assessment of PNPLA3 I148M status as well as additional genotyping of gene variants associated with PNPLA3 expression. --- I148M ---

Primary Outcomes

Description: Safety and tolerability will be evaluated in terms of number of subjects with adverse events and/or abnormal values of vital signs and/or clinical laboratory and/or electrocardiogram and/or renal assessments and/or blood assessments.

Measure: Number of participants with adverse events

Time: Up to 36 weeks (From Screening to Final Visit)

Secondary Outcomes

Description: The effect of AZD2693 on changes in LFC using magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) compared to placebo will be assessed. Samples will be taken under fasting conditions (10 h) in the morning at the same time (±1.5-2 h) during the day before lunch.

Measure: Absolute change from baseline to Week 8 and Week 12 in liver fat content (LFC)

Time: Baseline (Day 1), Week 8, Week 12

Description: The effect of AZD2693 on changes in LFC using magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) compared to placebo will be assessed. Samples will be taken under fasting conditions (10 h) in the morning at the same time (±1.5-2 h) during the day before lunch.

Measure: Percent change from baseline to Week 8 and Week 12 in liver fat content (LFC)

Time: Baseline (Day 1), Week 8, Week 12

Description: The effect of AZD2693 on circulating markers of hepatic inflammation compared to placebo will be assessed.

Measure: Absolute change from baseline in Alanine Aminotransferase

Time: Up to 36 weeks (From Screening to Final Visit)

Description: The effect of AZD2693 on circulating markers of hepatic inflammation compared to placebo will be assessed.

Measure: Percent change from baseline in Alanine Aminotransferase

Time: Up to 36 weeks (From Screening to Final Visit)

Description: The effect of AZD2693 on circulating markers of hepatic inflammation compared to placebo will be assessed.

Measure: Absolute change from baseline in Aspartate Aminotransferase

Time: Up to 36 weeks (From Screening to Final Visit)

Description: The effect of AZD2693 on circulating markers of hepatic inflammation compared to placebo will be assessed.

Measure: Percent change from baseline in Aspartate Aminotransferase

Time: Up to 36 weeks (From Screening to Final Visit)

Description: The effect of AZD2693 on circulating markers of hepatic inflammation compared to placebo will be assessed.

Measure: Absolute change from baseline in Gamma Glutamyl Transferase

Time: Up to 36 weeks (From Screening to Final Visit)

Description: The effect of AZD2693 on circulating markers of hepatic inflammation compared to placebo will be assessed.

Measure: Percent change from baseline in Gamma Glutamyl Transferase

Time: Up to 36 weeks (From Screening to Final Visit)

Description: The effect of AZD2693 on circulating markers of hepatic inflammation compared to placebo will be assessed. ELF score: <7.7: no or mild fibrosis, ≥7.7 to <9.8: moderate fibrosis, ≥9.8 to <11.3: severe fibrosis, and ≥11.3: cirrhosis. A negative change from baseline indicates decreased fibrosis.

Measure: Absolute change from baseline in Enhanced Liver Fibrosis (ELF) score

Time: Up to 36 weeks (From Screening to Final Visit)

Description: The effect of AZD2693 on circulating markers of hepatic inflammation compared to placebo will be assessed. ELF score: <7.7: no or mild fibrosis, ≥7.7 to <9.8: moderate fibrosis, ≥9.8 to <11.3: severe fibrosis, and ≥11.3: cirrhosis. A negative change from baseline indicates decreased fibrosis.

Measure: Percent change from baseline in ELF score

Time: Up to 36 weeks (From Screening to Final Visit)

Description: The effect of AZD2693 on cholesteryl ester 16:1/16:0 compared to placebo will be assessed.

Measure: Absolute change from baseline in plasma cholesteryl ester 16:1/16:0 ratio.

Time: Days 1, 29, 50, and 78

Description: The effect of AZD2693 on cholesteryl ester 16:1/16:0 compared to placebo will be assessed.

Measure: Percent change from baseline in plasma cholesteryl ester 16:1/16:0 ratio.

Time: Days 1, 29, 50, and 78

Description: The effect of AZD2693 on disease-specific biomarkers compared to placebo will be assessed.

Measure: Absolute change from baseline in disease-specific biomarkers

Time: Days 1, 29, 50, and 78

Description: The effect of AZD2693 on disease-specific biomarkers compared to placebo will be assessed.

Measure: Percentage change from baseline in disease-specific biomarkers

Time: Days 1, 29, 50, and 78

Description: To characterise effects of AZD2693 on lipid handling compared to placebo.

Measure: Absolute change from baseline β-Hydroxybutyrate and lipid profile

Time: Days 1, 29, 50, and 78

Description: To characterise effects of AZD2693 on lipid handling compared to placebo

Measure: Percent change from baseline β-Hydroxybutyrate and lipid profile

Time: Days 1, 29, 50, and 78

Description: Single dose PK parameters for AZD2693 and AZD2693 full-length antisense oligonucleotides (ASOs) will be derived from plasma concentrations

Measure: Maximum observed plasma drug concentration (Cmax)

Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.

Description: Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Time to reach maximum observed plasma concentration (tmax)

Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.

Description: Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Terminal elimination rate constant, estimated by log-linear least-squares regression of the terminal part of the concentration-time curve (λz)

Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.

Description: Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Apparent terminal elimination half-life associated with the terminal slope (λz) of the semi-logarithmic concentration-time curve, estimated as (ln2)/λz (t½λz)

Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.

Description: Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Area under the plasma concentration-time curve from time zero to 48 hours after dosing (AUC(0-48h))

Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.

Description: Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length antisense oligonucleotides (ASOs) will be derived from plasma concentrations

Measure: Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration (AUClast)

Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.

Description: Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Area under the concentration-time curve from time zero extrapolated to infinity. AUC is estimated by AUClast + Clast/λz where Clast is the last observed quantifiable concentration (AUC)

Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.

Description: Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Apparent total body clearance of drug from plasma after extravascular administration calculated as Dose/AUC (CL/F)

Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.

Description: Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length antisense oligonucleotides (ASOs) will be derived from plasma concentrations

Measure: Mean residence time (MRT)

Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.

Description: Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Time delay between drug administration and the first observed concentration in plasma (tlag)

Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.

Description: Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Apparent volume of distribution for parent drug at terminal phase (extravascular administration), estimated by dividing the apparent clearance (CL/F) by λz (Vz/F)

Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.

Description: Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Area under the plasma concentration-time curve from time zero to time of last quantifiable analyte concentration divided by the dose administered (AUClast/D)

Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.

Description: Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUC/D)

Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.

Description: Single dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Observed maximum plasma concentration divided by the dose administered (Cmax/D)

Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.

Description: Single and multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Time of the last quantifiable concentration (tlast)

Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.

Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Maximum observed plasma drug concentration at steady state (Cssmax)

Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.

Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Minimum observed drug concentration at steady state (Cssmin)

Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.

Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Time to reach maximum observed plasma concentration at steady state (tssmax)

Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.

Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Area under the concentration-time curve in the dose interval (AUCss)

Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.

Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Apparent total body clearance of drug from plasma after extravascular administration calculated as Dose/AUCss (CLss/F)

Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.

Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUCss/D)

Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.

Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Observed maximum plasma concentration divided by the dose administered (Cssmax/D)

Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.

Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Accumulation ratio based on Cmax (RacCmax)

Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.

Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Accumulation ratio based on AUC (RacAUC)

Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.

Description: Multiple dose PK parameters for AZD2693 and AZD2693 full-length ASOs will be derived from plasma concentrations

Measure: Temporal change parameter in systemic exposure (TCP)

Time: First dose: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 8 and 29 (pre-Dose 2). Last dose (Day 57): pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 hours post-dose and at Days 64, 78, 92, and 106.

Description: Urine PK parameters for AZD2693 full-length ASOs will be derived from the urine data

Measure: Amount of analyte excreted into the urine from time t1 to t2 (Ae(t1-t2))

Time: Pre-dose and 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose.

Description: Urine PK parameters for AZD2693 full-length ASOs will be derived from the urine data

Measure: Cumulative amount of analyte excreted from time zero through the last sampling interval (Ae(0-last))

Time: Pre-dose and 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose.

Description: Urine PK parameters for AZD2693 full-length ASOs will be derived from the urine data

Measure: Fraction of dose excreted unchanged into the urine from time t1 to t2 (fe(t1-t2))

Time: Pre-dose and 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose.

Description: Urine PK parameters for AZD2693 full-length ASOs will be derived from the urine data

Measure: Cumulative fraction (%) of dose excreted unchanged into the urine from time zero to the last measured time point (fe(0-last))

Time: Pre-dose and 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose.

Description: Urine PK parameters for AZD2693 full-length ASOs will be derived from the urine data

Measure: Renal clearance of drug from plasma, estimated by dividing Ae(0-t) by AUC(0-t) where the 0-t interval is the same for both Ae and AUC (CLR)

Time: Pre-dose and 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose.


HPO Nodes


HP:0001392: Abnormality of the liver
Genes 1412
PLIN1 CTBP1 CASR BCS1L GLB1 GDF2 SDCCAG8 TCIRG1 MICOS13 RAG1 INSR IFT172 TSC2 CDIN1 IL17F BLNK KCNAB2 FAN1 PHKA2 ARHGAP31 SGSH TSFM STK11 KCNN4 RNASEH2C EPCAM GPC3 RRAS2 OSTM1 CASP10 CC2D2A PDGFRA BRIP1 MOGS SFTPC ASAH1 NDUFAF1 BOLA3 GPR35 LIPE MED25 RAG2 TYMP TTC37 KCNH1 LTBP3 MTRR RNASEH2A PEX1 WDR35 CC2D2A PIEZO1 RHAG TTC7A GPC3 MLH3 FAH NDUFS3 MSH2 AUH IL6 POLG2 ATP7A ALDH7A1 SRD5A3 TRIM32 AXIN1 TCF4 AP1B1 ALG8 RUNX1 SERPINA1 SLC7A7 INS GBA ICOS SETBP1 CFI ALAS2 MYBPC3 SLC35A2 SLC37A4 MRPS16 RPGRIP1 DLD BSCL2 IFT43 PKLR GBA KCNH1 TRNW MRAS PEX12 CIDEC SLX4 PCCA PALB2 PEX10 DHFR OCLN PFKM CASK GLB1 ACADVL COX8A BBS4 TREX1 STX11 AGA POU6F2 ABCG8 TBX19 DAXX HGSNAT CEP290 LIPA MARS1 LRP5 BCS1L SLC25A20 FCGR2A PSMB8 FANCA ARSA CLCN7 MST1 PEX12 TRAPPC11 NCF4 NDUFS6 ARSB CFTR LYST RAG1 TPP2 NBAS FOXF1 UROD F5 ARSA AP1S1 XRCC2 TMEM67 ITCH WDR19 OFD1 UGT1A1 B2M WT1 PDGFRB HYMAI TRAPPC11 UNC13D SRD5A3 SRP54 AGPAT2 TNNI3 TINF2 RHAG HSD17B4 DCLRE1C HSD3B7 NPHP1 ACAT1 ABCA1 PMM2 GTF2IRD1 ND5 IFT80 COG8 UFD1 LETM1 SLC26A4 NDUFS8 NDUFAF3 FANCB SP110 TMEM126B HNRNPA2B1 NPC1 GPIHBP1 DPM3 TSHR RFXANK ICOS LPIN2 FANCM CD3D GPC1 SNX10 LDLR JAK2 ERCC6 POU1F1 COX6B1 TMEM199 PCCA CPT1A LHX4 GPC4 HNF1A HBB GANAB PKHD1 XRCC4 KRT8 TET2 COX14 ATP7B HFE SUMF1 OFD1 DGUOK CD3E ALG13 EXTL3 NCF1 PIK3CA CLIP2 COG6 COMT DCDC2 WDPCP SLC4A1 HLA-DRB1 DPM3 SLC5A5 RMRP GLIS3 PEX26 KCNN4 PLEKHM1 DCDC2 DIS3L2 PEX12 LBR RAB27A TRMT5 NDUFS2 PKLR SMAD4 CALR NDUFV1 APC CFH PEX5 TFAM NEU1 NOTCH1 DMPK DUOX2 HIRA DKC1 BRCA1 ADAR UQCRC2 STEAP3 PCK1 PEX19 IFIH1 DOLK CPLX1 MRPL3 MSH6 PMS1 CTSA APC PKD1 STK11 DYNC2I2 PRSS1 ACADM HBB IGLL1 SOS1 LCAT COG6 STX1A HMGCS2 RNF43 TERT G6PD NSD2 CYTB FBP1 C8ORF37 MKS1 BRCA2 IL2RB PEX2 SLC22A5 TP53 HMGCL MAD2L2 PAX4 IQCB1 WDR19 TMEM67 C11ORF95 FOXP3 IL12RB1 ABCG8 BCS1L TRNL1 PRKCD SLC4A1 TALDO1 HNF1A RAF1 MSH6 TANGO2 ADAMTS13 DYNC2H1 ABCA1 BTK RFXANK ND3 PEX13 C1S NEK1 HK1 TERC NDUFB3 ND6 HBB RPS20 CDKN1C AGA TERC H19 FGA RIT1 PYGL NCF1 CR2 IL2RA MYC ACAD9 MKS1 SLC7A7 CAVIN1 KCNQ1 NFKB2 CLDN1 PEPD MMUT GCK ALG8 PRKCD CTC1 IFT122 PMM2 KRT6A NSMCE2 CDKN2B PALB2 EPB42 NDUFS7 PEX16 SCNN1B HAVCR2 HBA2 ASAH1 RNU4ATAC DHCR7 KMT2E KIT TREX1 SPTB AMACR IL17RC PSAP NAB2 SC5D APC IFT172 DMD EIF2AK3 RECQL4 NGLY1 PEX16 NPHP3 PMS2 PIGM A2ML1 POLG TACO1 LYRM4 SETBP1 CASR ALMS1 ATRX TBX19 GUSB CCDC28B ND3 SLCO2A1 EPB41 CPT2 APOE RNU4ATAC SDHD VHL GCDH B3GLCT CDKN1B PRDM16 BBS5 C4B NEUROG3 ARSA SEC63 HYOU1 NHP2 TNFRSF11A SDHC PRKCSH UROS ATPAF2 PEX13 MSH2 PSAP HESX1 COG4 ALDOB RREB1 DDRGK1 CD40LG IFT140 PEX11B ND1 HNF1B SLC39A8 NPHP3 LMNA CFTR COX10 C1QBP AKR1D1 SMPD1 RFT1 LHX3 PEX3 PC NAGA TMEM216 MMUT BTNL2 ABCG8 TRIM37 SLC25A1 POMC MEN1 USP18 PSAP PEX19 FBN1 NDUFS1 PEX1 TNFRSF13C PDGFB ALG9 LIG4 MKS1 GALNS GBA NAGLU COA8 LMNA MAN2B1 CTSC HMGCL KCNJ11 ANK1 TARS2 TGFBR2 DYNC2I1 KRAS TINF2 FLT1 SLC30A10 SP110 GPD1 SMPD1 ACADL NHLRC2 TRMU HADHA HNF4A FAS PKD1 FANCD2 TPI1 TMEM165 PTPRC TCIRG1 ZIC3 COX10 POLG ADA ABCB4 DMPK PEX2 SEMA4A COG2 POLG2 BAZ1B EXTL3 CYP7B1 ABCD3 UQCRB PCSK9 KRT8 NDUFS4 CTLA4 ASXL1 WT1 LRP5 WDPCP DYNC2LI1 ATP7A EARS2 ASS1 GYPC GCGR GBA MPL CDKN1A DUOXA2 TRIM28 GP1BB CTNNB1 CYP7B1 TGFB1 COA8 HPD CLPB PIK3CA EFL1 BBS12 SBDS CAVIN1 MVK ICOS PAX8 PYGL RAD51 GALT NPHP4 SFTPA2 JAG1 MMUT KIT PEX11B BSCL2 SLCO1B3 FAH PSMB9 SLC17A5 IDUA TRNS1 NFKB1 IFT27 GBA TPO INPP5E STAT1 SDCCAG8 BMPR1A TET2 RAG2 HLA-DRB1 HADHB APC XIAP POLG GNPTAB ESCO2 MS4A1 TTC21B SLC30A10 NAGA ATM NDUFA6 MIF AIRE SEC23B BBS7 UQCRFS1 MPV17 NPHP3 MEFV STXBP2 CBS AKT2 RFX5 CEP164 HMOX1 FH APC GBA RAD51C ACSF3 DIS3L2 KRAS NDUFS4 BTNL2 DNAJC19 LMNA SH2D1A HBA2 ABCB11 ALG1 NDUFA1 TBX1 CHD7 SLC25A15 BBS1 NDUFA11 CD96 ALG9 IL12A TNFRSF13B CD28 MLH1 MPC1 RPGRIP1L JAM3 IL7R LZTR1 APPL1 MECP2 IL2RG PRPS1 CIDEC TG PHKG2 DDOST BBS1 POU1F1 ND4 CNTNAP2 WDR19 PARN EOGT TSC1 TRIM37 PEX10 HMBS CTCF C8ORF37 PRKAR1A NPHP1 SPTA1 GPI DLD KRT18 VCP HELLPAR TRNK FASLG TSHR DYNC2I2 GATA6 GABRD ADK SLC20A2 PIEZO1 AGPAT2 PEX10 PEX6 AKT2 CTLA4 COG4 GALT NDUFB9 CSPP1 PHKA2 HBB ITK RNASEH2A KIF20A CBS SUMF1 APOA1 HLA-DRB1 TRNV MPI CD27 UGT1A1 DPAGT1 SLC25A19 CLCN7 CD46 TNFSF12 PSAP RRAS PLPBP IFT172 WDR19 SLC4A1 LACC1 PDGFRL IFIH1 TRHR GALE TNFSF15 APC NDUFS7 PRKCD PNPLA2 TGFB1 IDUA EFL1 NOS3 LIPA NUBPL SNX14 NHP2 DYNC2LI1 CCDC47 LIMK1 LBR CPT2 PDX1 PSAP HNF1A CPOX FANCL EPB42 TERT CD79A SURF1 SLC22A5 LYZ IL36RN ATP11C ND2 KLF11 COG7 LIG4 ARL6 ELN APOA1 CTSK SPTB RELA DPM2 PRKAR1A ERBB3 PCCB CEP55 TJP2 GBE1 RRM2B ABCC2 UGT1A1 CD81 ATP6V1B2 ZAP70 WRAP53 ADA2 MYRF MRPL44 HAMP EPB41 FGFRL1 KLF1 PHKB CLCA4 SAA1 HADH CP BTK ABCB4 ALG2 TERT NDUFV2 TNNT2 PRKCSH HBG2 ERCC8 PHKG2 PEX6 SPINK1 ACVRL1 TNFSF11 IFT172 ATP8B1 LIPE TNFRSF13B PALLD HLA-B CDKN2A MPV17 FADD GCLC CTLA4 NLRP3 KRT18 NDUFB11 CYBC1 PRSS2 VPS33A CA2 HSD3B7 UGT1A1 MYD88 DOCK6 PEX1 AGL GYS2 DZIP1L MAN2B1 GPC4 TIMMDC1 NDUFAF8 NDUFB10 CLDN1 IL21R TMEM70 FASLG ASL PLAGL1 SMAD4 CYP7A1 LMNA CORIN SLC40A1 AP3D1 PEX1 AGGF1 RPGRIP1L LARS1 NOD2 ARVCF DLL4 BPGM RAG2 KIAA0586 INVS COG1 H19-ICR B9D1 FOXRED1 LRPPRC TGFB1 INPPL1 SKI TNFSF11 XIAP RBPJ VPS33B XPR1 HBG1 ABHD5 UBR1 TRIM28 NDUFAF4 FOS IL2RG NR1H4 HFE F5 CLCN7 FAS GNPTAB RNASEH2B GBA IGF2 TRAF3IP1 PPARG RFXAP UBE2T DHDDS MET GLRX5 VPS45 ATP8B1 APOE ANK1 PEX1 PEX16 PPARG SOS2 SLC2A1 TMEM216 ARSA HADHA CDKN2C NAGS PEX11B PEX6 PCCB TTC21B PEX14 PEX5 MYH9 CAV1 ATP8B1 SPIB PRF1 PEX19 RFC2 ERCC4 IL2RG REST MMAA PEX12 KRT16 CLCN7 NCF2 BBS10 SRP54 IDUA MCCC1 STEAP3 STN1 NSD2 ERCC4 ACOX1 PCK2 BBS9 SDHA LMNA GALK1 NLRP1 SCNN1G BBS2 TCIRG1 PEX6 XK BCS1L CASR SLC25A15 FUCA1 SKIV2L GLB1 JMJD1C COA3 G6PC FERMT3 GNAS HBB STAT6 NEUROD1 LZTFL1 PEX5 TNFRSF13C SCYL1 PKD2 SPTB UCP2 TRIP13 PSAP DNAJB11 BRCA2 NELFA SLC25A13 TBX1 CTRC JAK3 CTNNB1 MYPN IDS SBDS LMNA ITCH BRCA1 PCSK1 CSPP1 WDR35 CCDC115 DPM1 CYBB IDUA HOXD13 TCTN2 CR2 GAA FECH ALMS1 ETFDH JAK2 CARS2 BMP2 ELN GNMT HJV PNPLA6 MKKS AHCY SMPD1 NDUFAF2 COX15 PLEKHM1 GATA6 KCNQ1OT1 LMNB2 RNU4ATAC RMRP ABCB4 DDRGK1 PIK3C2A CAV1 RNASEH2C TMEM67 POLR3A CPT2 IL17RA SF3B1 TRNW TBX1 CPT1A HNF4A MMEL1 DCLRE1C PSMB4 JAK2 CIITA TET2 ARL6 POMC ALG6 TRAF3IP1 PIGS CEP290 STOX1 COX20 IRF5 TMEM67 USP9X INTU GBA NGLY1 MFN2 SPECC1L SEC24C BSCL2 TRMU IARS1 CTNS PEX3 COG2 FAS SLC2A1 H19-ICR TMEM107 HAMP SAR1B FGFR2 HADHB HNF1B PEX2 TRMT10C XYLT1 SLC25A4 FLNC SON TNFRSF1B GPC3 ACADM RAG1 TNFRSF1B CEP120 TTC8 FANCE GBA CYBA CBL UGT1A1 SDHB TERT NPHP3 SCO1 NDUFAF5 HNRNPA1 NOTCH2 MET TMEM67 SPTB PGM1 G6PC3 PEX19 SLC25A13 NOP10 MPI IFT80 SEC63 RFWD3 PDGFRA SPRTN TRNE IGF2R SCNN1A ALG11 CD19 PPARG WDR35 TREX1 PARS2 CPT2 SLC39A4 HADHA LHX1 HBB IGHM TTC7A PET100 ABCA1 HNF4A CPA1 GNE SLC29A3 INSR COG8 HADH RFT1 PEX26 SCARB2 HFE DYNC2I1 GNS APOB PEX5 ACVRL1 SLC25A20 CD19 RRM2B TUFM BSCL2 DCTN4 ABCB11 PEX10 BLK BLVRA CYC1 FANCF HNF1B SAMHD1 PEX26 IFT140 AKR1D1 FGFR2 CFTR CC2D2A BRCA2 MAN2B1 ACOX1 NRAS CEP290 MYORG RFXAP CYP19A1 RHBDF2 HBA1 TTC37 CD28 MCM4 CCND1 FARSB FANCG NPC2 TF RERE NRXN1 IL7R TMEM67 PTRH2 MLXIPL KCNJ11 ALDOB LETM1 ATP6 CYP27A1 PEX12 PLIN1 FANCI RPGRIP1L SLC13A5 HBG2 ABCC8 IKZF1 PEX13 APOE PIGA ZAP70 ABCC2 NRAS NKX2-5 PNPLA2 APOC2 SPTA1 TFR2 KRIT1 NSMCE2 RTEL1 EWSR1 SLCO1B3 ATP6AP1 ND1 SLC11A2 SNX10 PEX26 ABHD5 CBL RPGRIP1L ETFA TNPO3 SLC29A3 NPHP3 PKD2 PEX2 ERCC4 TRNN FBP1 NEK8 LRRC8A IER3IP1 SHPK ACAD9 ADAMTSL2 ABCC8 SLC25A13 MRPS7 TRAF3IP2 RMND1 ADA CEP290 FAN1 FAM111B SLC4A1 LBR VPS33A TANGO2 NOTCH2 DYNC2H1 MLH1 TWNK PEX3 PKHD1 BICC1 RHAG PROP1 GNE ETFB ENG GANAB PEX14 INPP5E SC5D YARS2 RBCK1 GTF2I CD247 MVK CEP83 FLI1 LIPT1 GDF2 BMPER KIF23 ANKS6 CASP10 TSHB XRCC4 MMAB KCNN3 RASA2 CA2 ATP7B DNASE1L3 DHCR7 HJV B9D2 IFNGR1 RASGRP1 PEX6 ANTXR1 CIITA COG5 NPM1 SLC37A4 SLCO1B1 LDLRAP1 SLC25A19 POLG2 ALAS2 SLCO1B1 POU2AF1 DNAJC21 COX4I2 SKIV2L SOX10 SCYL1 MUC5B VPS13A MPL COX15 SLC25A13 WT1 HNF4A TP53 TKFC HEXB LMNA TWNK KLF1 VIPAS39 CYBA ABCG5 SRP54 PAX8 PTPN3 CD79B GATA2 TERC SERPINA1 LPL LONP1 KRT17 SRSF2 PTPN11 CYP27A1 KRAS IYD NCF2 NDUFAF1 FANCC FBXL4 GFM1 DLL4 PEX13 WHCR DNAJC19 NLRP3 GUCY2D TBL2 POLD1 HMBS SLC40A1 PEX14 TREX1 PEPD HBA1 TMPRSS6 RBM8A CEP19 AP1S1 PEX3 ACADVL CDKN1B IGF2 CD70 CEL DPM2 RFX6 DGUOK TCF3 ND2 TNFRSF1A CC2D2A CYBB PIK3R1 IL1RN NOP10 DNAJC21 HADHA LIPA TNFSF12 AP1B1 CDAN1 SDHA LYST BBIP1 NHP2 TMEM231 PEX16 PEX3 IL7R HPGD EIF2AK3 BTK ENG CD55 CASP8 IDUA TKT USB1 ZMPSTE24 KRT6B PTEN CLEC7A SMAD4 BTD KPTN RFX5 BCHE AMACR PEX14 TALDO1 DKC1 ALDOA JAM2 FECH GUSB AP3B1 TET2 JAK2 FUCA1 FDX2 KRAS
HP:0001824: Weight loss
Genes 324
FANCE NALCN CBL DNAJC13 HTT TTR PDX1 COL6A2 BIRC3 ABCC8 NAB2 JAK2 SDHB CEP152 SDHAF2 GBA FANCL VHL PTEN STAT5B RFWD3 PMS2 POLG EPCAM POLG NF1 TP53 SDHB SCNN1A MEFV TP53 IL12A-AS1 SLC11A1 CTLA4 KCNJ11 ATRX MLX BRIP1 GPR35 PTEN THPO STAT3 PML TYMP IGH RRM2B HLCS HSPG2 CCR1 MALT1 SDHD GPC3 MLH3 RRM2B MSH2 CCND1 KLRC4 KCNJ18 SDHC SDHC FH JPH3 FANCF TSHR GIGYF2 POLG PALLD HLA-B TCF4 CDKN2A RUNX1 EDN3 BCOR SDHB BRCA2 ERCC3 NOD2 HLA-DRB1 KRT1 PRNP GJA1 BCL10 IRF2BP2 MRAP BCL6 SUCLA2 RHBDF2 FANCG B2M BCL2 ZBTB16 SNCA SLX4 PALB2 KIF1B HLA-DQA1 SCNN1A TGFBR2 KCNJ11 KRAS SDHD SDHA SMAD4 HLA-B INS FANCI POU6F2 UNC80 DAXX C4A IKZF1 CNTNAP1 ATM LIPA UBAC2 FANCD2 NUMA1 COL6A1 LRP12 FANCA RARA RB1 MST1 SLC39A4 EPAS1 PTPN22 SEMA4A KRT10 TRPV4 PCNT F5 SLC25A11 EWSR1 XRCC2 TRIM28 GALC NDP VPS35 MPL AK2 FIP1L1 ASXL1 CDC73 WT1 WT1 TXNRD2 SEMA3D HLA-DPB1 UBE2T TP53 HLA-DPA1 ERCC4 MPL TRIM28 TLR4 NPM1 SCNN1B ACAT1 PIK3CA GDNF SDHD FAN1 FANCB PLA2G6 FAS HLA-DQB1 CENPE RAD51 STAR ERCC5 CHEK2 SDHD IL12A IGH RET LPIN2 FANCM SLC6A8 ERCC4 SNCA SDHAF1 CRLF1 DLST REST PANK2 SLC9A6 SDHA PRKAR1A LRRK2 EDNRB BMPR1A FLI1 CACNA1S TET2 TET2 ABCC8 PTEN MC2R ATP7B ERCC4 UNC80 GNPTAB NABP1 ATRIP IL10 IFNGR1 IL12B GCK SCNN1G HLA-DRB1 STAT4 RNF168 ZFP57 COL6A3 IL23R BMPR1A COL12A1 DIS3L2 ERAP1 FOXP1 CACNA1S STAT3 STAT6 CALR VPS13A MPL MAFB CENPJ TSHR WT1 BRCA1 TRIP13 NNT TP53 RAD51C BRCA2 AKT1 COL5A1 BTNL2 TBL1XR1 GJB4 CCND1 PTPN22 MSH6 PMS1 ERCC2 PRNP GJB3 TYMP NOS1 JPH3 TMEM127 ACADM GATA2 SDHB BRCA1 CYP24A1 LMNA PRTN3 MLH1 MDH2 SRSF2 DNMT3A HLA-B IGH KRAS DCTN1 BRCA2 JAK2 HMGCL MAD2L2 RET FANCC COL1A1 PLK4 PRNP GATA4 ECE1 AVP FOXP3 TRIM37 PLAGL1 HMBS RBBP8 NOD2 DCTN1 KDSR SEMA3C PIK3R1 MAX SCNN1G KIF1B RPS20 JAK2 GALT COL5A2 RET NRTN H19 CFTR ATR TRAIP KCNJ18 HLA-DQB1 HLA-DRB1 PSAP CDH23 EIF2AK3 MECP2 BTK HLA-DRB1 HYMAI IL6 EIF4G1 CUL4B NBN TGFB1 PALB2 VHL SCNN1B HAVCR2 TET2 JAK2 GABRA3
Protein Mutations 2
I148M P12A
HP:0003119: Abnormal circulating lipid concentration
Genes 290
PLIN1 DHCR7 LIMK1 KCNJ1 PIGH PHKA2 PEX19 SLC25A13 ADCY3 SLC22A5 NGLY1 LTC4S TRNE ALB PPARG ELN LCAT ALMS1 NADK2 PCSK9 LMNA TDP1 APOE LIPE ABCA1 RAI1 APOC3 SYNE2 SLC29A3 PHYH CAV1 CAV3 LMNA PANK2 TBCK HADH PEX26 GLA PNLIP APOB NSDHL BSCL2 AEBP1 LMNA PHKG2 CETP PLA2G4A TRNE UBE3B CFH LMNA PIK3R5 LRP6 PEX7 LIPE SMPD1 TRNK ABCD1 PEX3 ALB ABCG8 AGL RAI1 SYNE1 SLC37A4 CYP19A1 XRCC4 BSCL2 NPC2 HSD3B7 LMNB2 LMAN1 CIDEC AGL GYS2 LMNA CYP11A1 FBN1 HMGCL ABCA1 KCNJ11 ACADVL GPD1 HAVCR2 CYP27A1 PEX12 NUP107 PLIN1 SMPD1 STX11 CYP7A1 ABCG8 ACADL LMNA NADK2 TRMU ABCC8 RSPO1 PEX1 PEX13 DGAT1 FLCN APOA5 SLC25A20 PSMB8 LDLR PNPLA2 CYP11A1 APOC2 APTX NPHS2 MC4R PPP1R17 IQSEC2 BAZ1B PCSK9 UBR1 LDLRAP1 FOS ABHD5 GK APOB RAI1 TNPO3 MYO5A APOA5 MTTP GHR DCAF17 OCRL PPARG EBP UNC13D PEX2 DCAF17 AGPAT2 EBP SLC52A1 SLC25A13 PEX1 ABCA1 PMM2 GTF2IRD1 PEX16 PPARG CAVIN1 PEX11B PYGL NPC1 GPIHBP1 LBR TANGO2 PEX5 JAG1 CAV1 SPIB PRF1 RFC2 BSCL2 LDLR PSMB9 TMEM199 LPL CPT1A PEX12 SC5D SGPL1 HNF1A SAR1B GTF2I EMD PEX2 OCRL ZMPSTE24 PIGT XRCC4 TMEM43 LMNA XIAP DEAF1 DHCR7 PEX5 LMNA MEF2A CLIP2 MSMO1 NPHS1 PEX6 SLC37A4 LDLRAP1 G6PC STXBP2 POU2AF1 RAB27A AKT2 APOC3 PEX5 GHR DMPK TTPA UCP2 SLC25A13 LEP HNF4A PEX19 SLC25A13 LMNA CFHR1 ABCG5 LMNA ACADM LIPC LMNA IL12A LCAT CCDC115 FLII LPL CYP27A1 LEPR ALMS1 CIDEC TRNL1 PLVAP ABCA2 PHKG2 ANGPTL3 ACOX2 NUP107 LCAT IL12RB1 PEX10 TBL2 POLD1 FHL1 HMBS PEX14 TANGO2 ACAD8 DHCR24 DLD ABCA1 CEP19 CAV1 ACADVL POLR3A CPT2 CCT5 SLC12A1 PEX7 CPT1A MMEL1 AGPAT2 PSMB4 PLA2G7 AR APOA2 COG4 LIPA PHKA2 PYGL IRF5 ACAD9 APOA1 SLC7A7 CAVIN1 BSCL2 TFG CTNS ZMPSTE24 CETP SAR1B ZMPSTE24 ACAD8 TDP1 APOB PEX10 TNFSF15 ACTN4 PNPLA2 DYRK1B NSMCE2 POLR3A MCFD2 FECH ACADM CFHR3 LIPA SETX EPHX2