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

MeSH:Inflammation Weight Loss

HPO:Decreased body weight Weight loss

2 Interventions

Name: overeating fat

Name: overeating carbohydrate

Purpose: Prevention

Allocation: Randomized

Parallel Assignment

There is one SNP

SNPs

1 rs738409

A common polymorphism in PNPLA3 at rs738409 (adiponutrin) gene is associated with a markedly increase liver fat content.

HPO Nodes

HPO:

HP:0004325: Decreased body weight

Genes 1618

SMC1A WHCR SYNJ1 COL1A1 ST3GAL5 NALCN TCF4 PTS XYLT2 RRM2B OTUD6B MC2R C12ORF65 ERCC2 NOD2 EFL1 ABCC8 SETD5 BCL10 OTULIN OCRL SGO1 CHD7 FOXP3 KCNJ11 SMARCC2 SETBP1 PEX10 MALT1 ASXL1 HADHA USP9X SLC4A1 KIF7 RECQL4 MAP2K1 CDH23 ERAP1 CLTCL1 FLI1 CYB5R3 GRIN2A FOXP1 TGFB3 TSPAN7 RBBP8 NDUFS1 VPS13B ALG9 RAP1B EIF2AK3 ACTA1 PYGL GNB1 TNFSF12 FGFR1 NDUFS3 PDE11A SLC3A1 ND3 XRCC2 ELAC2 STAMBP ACTA1 COX6B1 DNM1 AGPS EBP LARP7 MLH1 TRIM37 FMR1 RYR1 NFKB1 NDUFS2 ACSF3 TRNS1 PTEN SSR4 LYRM4 DHDDS SDHC HERC1 ALB SLC9A6 PLA2G6 SSR4 GJA1 IGF1 COL6A1 TPM2 LRPPRC GCK UPF3B PAM16 PAK3 HLA-DPA1 MUSK GATA6 SDHB SNORD115-1 RPS6KA3 NNT ECHS1 STT3A ACD TOP3A BAAT ERCC3 ADAT3 NDUFB3 MVK JAK2 CDC6 SEMA3D POC1A AMACR INSR CTNS PPP1CB CYP17A1 CDK10 BRCA1 SUGCT GATA4 POR STXBP1 RFWD3 NDUFS2 ASXL1 JAK2 MPI SMPD1 HSD11B2 AGTR2 NUMA1 LIG4 TXNRD2 ND5 PEX3 COPB2 ACADVL SDHA BCL6 UBA5 ERCC2 CAV1 CSF2RA ADAT3 MAGEL2 DMD STAT5B CEP57 SUCLA2 NUS1 KMT2A COL1A2 PMM2 EXT2 MEGF10 MRPS16 ALOX12B ERCC4 DEAF1 BCOR AP1B1 MRPS7 KBTBD13 NSUN2 NSDHL LEMD3 MMUT COG4 TGFB1 BRCA2 NDUFS7 VIPAS39 KCNJ6 SLC17A5 COL12A1 GPC3 NABP1 RARB PIEZO2 CIT MBTPS1 PROK2 SPR PPP1R15B PEX1 EOGT PHGDH ALOXE3 SLC39A8 IGF1 NADK2 CDC6 HLCS ZFP57 ATM COL7A1 THPO NDUFA10 IRF6 GABRA2 KCNA1 TPM2 SCNN1A NDUFS1 USP7 ND2 SLC2A2 LETM1 LPIN2 SMC3 POLG CD3G H19 NDUFAF3 MECP2 CAMKMT RBM10 SLC46A1 CHRM3 TBX4 UBE2T GK TACO1 NDUFA9 SMAD4 SCNN1G ZSWIM6 CD79B SCN2A MAP3K20 SLC9A7 FBN2 ASCL1 FAH COX20 GATA6 FANCE ALG13 RIN2 DHCR24 RFX5 RBM10 OCLN FOXRED1 PIK3C2A DNA2 STAT6 SNCA ARCN1 SDHC NDUFV1 SEC23B NEUROG3 KIF7 SIK1 WDR60 TCF3 NRXN1 PPP1R15B HLA-B NOTCH2 UNC80 DACT1 WDR4 SCNN1B BRAF CASK TPM2 YY1AP1 IL21R TRMT10C RFXANK SLC25A24 BMPR1A GALC KDSR ST3GAL5 CENPJ TRIP13 IL23R PMS1 RFXAP KCNA2 NDUFS8 COG1 ND1 FANCA MSH6 NDUFA13 POU6F2 CDC45 NSD2 SON PIK3CA FANCM ATP6V1A VHL SDHAF1 ARHGAP31 OBSL1 EPCAM NDN UBA5 TBL1XR1 SFTPC UBR1 PEX13 RAG1 AKT1 RB1 CYP2R1 RARS2 PPP2R3C PDHA1 ND5 ATP6V1E1 NDUFB11 OTUD6B HLA-B GTF2I SMARCD2 PEX1 SON SYNGAP1 BTNL2 SLX4 KMT2D ORC4 ARPC1B TCOF1 VPS45 ALG12 SCO1 CASK SLC11A1 PNPT1 PTCHD1 USP27X WDR26 FANCI PYCR1 STT3B TP53 TRMT10A TRIO CEP152 AVP FLNA MRPS14 FIG4 WWOX CYB5A CIITA TPM3 PEX16 SNAP29 CYP7B1 PALLD DSP OSGEP ATRIP ORC1 ZNF711 PARS2 FARSB RTTN NONO PRKAR1A MED12 ARX BPTF MLH3 PEX5 SPRY4 LMNA ERCC6 IL2RG SYNE1 WT1 SRP54 DOLK GABRA3 COG8 NR0B1 IGHM TAZ FGF12 ACTB SDHD IL6 GABRD FAM111A CTBP1 DPM1 ATP8B1 LAMC2 NKX2-1 PEX12 KCNJ6 HCFC1 DAXX MST1 HADHA TNFSF12 PEX19 TCF4 SLC39A13 MCCC1 TRIM28 TERT DNAJC21 TAC3 MED17 AKT1 NAB2 EDN3 G6PC3 FAM149B1 JPH3 C12ORF65 TYMP KRAS GNAO1 PALB2 EBP MED12 RYR1 IL1RAPL1 MYH3 CACNA1A IGH RET DCLRE1C VPS33B PRNP SIL1 CTNS CYP11A1 LMNA ATP6 TRNQ NDP TP63 VPS35 TRIM8 COX8A PTF1A KCNJ18 FANCE ICOS GNB1 SDHD HLA-DRB1 TP53 GALE NDUFS2 AARS1 STT3B SMC1A HACD1 RET SUCLA2 FANCD2 KRT10 TERT ARMC5 SLC25A11 IQSEC2 BIRC3 WDR73 ABL1 ASAH1 PDE8B ND1 HSD17B4 GRIA3 NACC1 NDUFB8 ND6 GBA FLT1 COMT GBA ACTB MTFMT PROKR2 NFKB2 AK2 TRMT5 KISS1 TGFBR2 UMPS POLG THRB TRNS1 PARN DDOST COX1 LIPA EXT1 GATA2 REST CKAP2L ZBTB16 SMARCA2 MAFB FGD1 ND4 XPA CNKSR2 HMBS PTPN22 RAI1 ELN PEX19 TGFB1 CBS RAG2 RPS6KA3 USF3 COX15 XPC NAT8L ARV1 NDUFA11 CYP11B2 FANCA DYNC2LI1 RAI1 PET100 CCR1 MAD2L2 PKP1 MPDU1 GJB4 DPP6 CD3E CD19 TRNV HLA-DRB1 COX14 CRIPT AARS1 BMP4 PMPCB MCM5 GTPBP3 CD3D SLC25A13 PEX12 CLCNKB TRNN TGFB1 CYP27B1 TTN CDKN2A NDUFV1 BCS1L PTPN11 IL7R MYL2 CTLA4 RARA GPC1 IFIH1 SLC25A22 HLA-B BRCA1 ZNF335 SDHD JAK3 EPAS1 NUS1 NDP GALT KDM6A PRKCD NDUFAF4 ACTA1 NGLY1 ATXN7 TRAK1 NPM1 NDUFAF1 ARHGEF6 SLC34A3 MCCC2 PEX26 POLR1D TK2 SLC25A3 SIN3A SLC12A3 CARMIL2 PRDX1 LRRC8A COA8 SELENON LIMK1 WNT2B MRAP FIP1L1 TBL2 UBE3B BCAP31 CLDN16 NADK2 TWNK MSX1 TBL1XR1 TSHR PRNP CDC45 ATPAF2 DGAT1 ERCC1 MDH2 MMADHC STRA6 YY1 FCGR2A FBXL4 MARS1 ALG11 KIAA0586 AUH CA12 ALG3 NDUFAF2 ATP7B SLC6A8 HIRA DPM2 EXOSC9 TFAM MYH3 FGF8 KCNA4 RAD21 GDI1 HYMAI NDUFAF3 GPT2 MCM9 BUB1B ERCC3 ALDH18A1 NBN FANCF GTPBP2 AHDC1 ASNS PCCB HLA-DPB1 DLST AUTS2 POLE PTRH2 ADA EGFR SLC35A2 IGHMBP2 DUSP6 RFXANK NDUFAF5 COQ7 POLR1C MECP2 KCNJ11 ERCC2 PLK4 ERCC4 SCN3A DNMT3B NLRC4 GCDH PTDSS1 ITGA7 BTK TRNL1 KIAA0753 TIMMDC1 NSMF NDUFS4 ATRX PIK3R1 AHCY BRF1 SDHB GRIN2D SLC7A7 FGFR1 CYTB CDH23 DEGS1 PIK3R1 IQSEC2 ATP6V1A LBR CD79A ATM NEB ETHE1 PMS2 PUS3 CASR LETM1 NDUFS4 ETHE1 TRIM28 SLC34A1 RAD51C MCCC1 IL21 MYMK RRM2B CDON TCN2 FAM111A PDE6D JAG1 TMEM70 TRAC NDUFA13 ASAH1 IKZF1 NOD2 NDUFA2 MLXIPL COL12A1 EARS2 DNM1L PWAR1 GATM ALDOB ADK ARX PACS1 CAVIN1 B3GALT6 PPARG BAZ1B IL12B MAX GPR161 CHRNG NDUFV2 ABCA3 SCN8A SLC22A5 NDUFS8 CPLX1 IARS1 ACTG1 AMPD2 HIKESHI KRAS PTEN CCND1 SDHB MSH2 FBN1 NEXMIF JAK2 MMAB RET SDHA IGHM TWIST2 RAB39B FOXP1 GRIN2D SCN3A FLNA SLC25A24 TET2 WDR11 NDUFA1 SELENON MPL CDT1 GTF2IRD1 UBA1 CREBBP ATP6V1E1 KRT5 SPATA5 NDUFS7 MID2 EPG5 CSPP1 PYCR2 IL2RG TRAIP ERCC4 PYCR2 CXORF56 NR1H4 PEX1 MLX TCTN3 INSR MAP2K2 SKIV2L TTC37 DNM2 KCNB1 DOCK6 RBPJ HSD3B7 TRNL1 PNPO TGFB1 ANTXR2 NDUFV2 CR2 ABCB11 LTC4S CD3D GBA TACO1 RPS20 IL7R BMPR1A CUL4B TP53 LAT ACVR1 NDUFB11 ADA TRNK MTRR MRPL3 TBX1 PEX11B EPCAM B2M ND1 PIK3CA NFIX DCLRE1C HS6ST1 CLCNKB NFASC COX2 FASTKD2 BRCA1 CORIN CUL7 RAB33B CD81 PDX1 LRRK2 PPP3CA ACADM H19 SARS1 GLYCTK TGDS RMRP TBC1D23 TSHR COG8 GNPAT EDNRB SPINK5 HRAS NDUFB8 COX7B LAMB3 ACADS TMEM126B TBR1 IPW INS MEFV TBL1XR1 NCAPG2 HADHA ACSL4 HMGA2 CA2 ACSF3 ALAD RAG1 DDX3X DCLRE1C KANSL1 PEX7 F5 STAT3 CYP2R1 FBN1 CYB5A CHEK2 POLG2 SEC24C NUP62 B3GLCT TET2 MBL2 MSMO1 RTEL1 HCN1 CFTR FANCC SELENON AVPR2 GJA1 SDHA SDHB SDHB TACR3 WDR4 ACAT1 LMNA DIS3L2 GNPTAB COL5A2 NDUFA12 MKKS NNT NDUFV2 BCOR TIMM50 BMP1 MTRR ERCC4 B3GALT6 ZFP57 CLMP BRCA2 SZT2 MOGS SBDS VPS13A SDHD MMACHC FZD4 PEX5 MAP2K1 SLC25A13 FIG4 WDR11 GLI1 PSMB4 ELN LRP5 YWHAG PTEN AVPR2 NDUFAF6 PIGP PSMD12 PEX10 RIPK1 HADHB FGF17 MMUT PEX26 NONO CASK RREB1 SLC19A3 PSAT1 MPL IKBKB FANCC GCK PEX13 PGM3 CARS2 GYS2 KLLN PEX2 TRPV4 STXBP1 RAI1 HLA-DRB1 SERAC1 EPHX1 WRN AQP2 SARS2 SOX9 SBDS GP1BB EFL1 COX4I2 STING1 CYFIP2 NDUFAF1 NRTN DKC1 FRMPD4 POLA1 AUTS2 AHDC1 CACNA1S SP110 UBR1 PUS1 PRTN3 RECQL4 IL2RB GNRHR HESX1 GNRH1 CCND1 ZNF81 TRNF MKRN3-AS1 CD247 ACTL6B NDUFA6 TRAK1 PTEN CHD7 CLTC PRDM16 CYP17A1 STAT3 NFE2L2 ATP6V0A2 ITCH PEX6 ZAP70 CNTNAP2 SKI CYP19A1 GPT2 PRKAR1A CTCF CD96 KDM6A KCNJ10 SCO2 PEX2 USP8 ND4 KIF1B ZMPSTE24 MTR UFC1 PML PPM1B VHL AQP2 POMC DYRK1A SRP54 SLC12A1 SLC3A1 EPRS1 AKR1D1 SLC39A4 PEX16 RERE NDUFS4 SUCLG1 IGF2 TAF13 EIF2S3 INTU FANCL PDX1 SDHA PEX14 FUCA1 DDOST ELMO2 ESR2 BCL2 NSD2 HPD NDUFS6 GABRB2 CASP8 RAP1A RNF13 CLIP2 PEX5 HSD11B2 CAVIN1 PSMB9 RFXAP TRMT1 IGH ATP5F1A FANCI LMBRD1 GRIA3 POLG2 CCDC8 TIMMDC1 TMEM127 STAR TUBB4A TRIT1 TNFRSF13C MAP3K7 UBAC2 POLG GTF2E2 RFT1 PNP NFIX NOTCH2 ST3GAL5 NAGS KISS1R UBE3B ADA HSD3B7 RAG2 RMRP PCSK1 NGLY1 DNAJC13 AGTPBP1 KRT1 FLNA HTT IL2RG SLC6A8 LMBRD1 HPD RET CPLANE1 PNPO LMNA KCNJ18 DPYD KRAS ANOS1 SDHAF2 LRP12 ITGB4 GNAS ATP6V0A4 ANOS1 IGH NACC1 NALCN PREPL FANCD2 CYP24A1 PPP3CA TCIRG1 SMAD4 NHLRC2 CPLANE1 BRCA2 KCNJ1 DLL4 MYPN NUP214 PCNT SDHC SLC39A4 TRNW RNU4ATAC DNA2 BCS1L FTO ARFGEF2 KMT2A SAMD9 TRNH ATP6V1A KRT14 B4GALT7 NFU1 CLCNKA RPS19 GPR35 TBX1 ATP6 AP3B2 HCCS NEB NSMCE3 NUBPL TCTN3 SNRPN CENPE SEMA3C MCCC2 CCDC47 RAG2 HIBCH NPAP1 FAN1 CDC73 FAS POLA1 CYP7B1 HADH VPS13B RBBP8 COL6A2 COL1A1 ATP6V0A2 RNF168 LIPT1 NTRK2 VAC14 IFNGR1 CFTR PEX16 MPV17 GALT ADAR RPS6KA3 IGLL1 SURF1 CYP11A1 TALDO1 AGXT NECAP1 ARID1B PEX5 PEX13 POLR3A TRAIP JAK3 CYP27B1 PEX6 ACOX1 YARS2 DCLRE1C JPH3 KRT14 PREPL EVC2 BSCL2 AHCY SKI IL12A WT1 ERCC6 PWRN1 KCNJ11 STOX1 IGF1R PLAA SDHD CNTNAP1 ORC1 COG7 MYH7 PSMB8 KCNA2 GPIHBP1 CPS1 IL12A-AS1 NELFA SURF1 MYH3 EXOSC8 AMER1 COX10 HDAC8 PEX2 LYRM7 ATP6V0A2 HBA1 LCK NEB SETBP1 KMT2A NEUROD2 ORC6 ACO2 KRAS ERCC5 RFT1 CERS3 SEMA4A UFD1 SCNN1A LRBA FGFRL1 TGM1 TMEM216 DNAJC21 CSNK2A1 DHCR24 FOS COL6A2 CREB3L1 TPM3 BRCA2 RBCK1 NFKB2 NDUFB11 JMJD1C PALB2 RAG2 DGUOK ND3 SNORD116-1 GABRA5 STAG2 POMP FUT8 NDUFS2 RTTN NDUFAF5 RAD51 EWSR1 GIGYF2 MMAA INSR ATR PEX19 PIGQ ZIC3 HYMAI BCAP31 SMOC1 EVC SLC25A4 TIMM50 RPL5 OCRL SLC52A2 HBA2 LAMA3 KRT5 ERCC4 PUS7 IRF2BP2 TCF4 SLC25A13 GDNF STAT4 HCFC1 COG1 NDUFAF4 GMNN AUH SYP ND2 PRPS1 HADHB STRADA LAMA2 DLD PDX1 ANKLE2 MED12 HMGCL ZNF41 UNC80 KIF15 PCCA SNCA BRAF OTC TUBB4A CYP11B2 ABCC8 TINF2 CSF2RB MRPS2 PEX14 RAG1 ASL ALPL ERCC5 UBTF BMPR1A COX10 DNAJC21 ABCC8 COL6A3 PDHA1 NDUFS1 NDUFAF2 HLA-DRB1 KAT6B NDUFB9 MYH7 ORAI1 FOXRED1 NECTIN1 EIF4G1 TAPT1 GHSR TMEM216 RFC2 COL6A1 STRADA SHROOM4 ND6 PET100 EP300 PEX3 COX15 MC2R GNPTAB VDR TRNW SCNN1B MBTPS2 PHOX2B MICOS13 PRF1 SC5D PMM2 PIK3R1 LIPA POLR1A HAVCR2 KLRC4 TMPRSS15 KIF1B PNPLA1 PLAGL1 KCNAB2 BRAF AGPAT2 POLG ABCA12 RIT1 FH INS LAMB3 RELB SLC1A2 AARS2 PROKR2 MTO1 SPRTN GJB3 DNAJC3 OFD1 IL7R NDUFS3 ACAD9 HERC2 SCNN1G RHBDF2 MPL ACTB MMACHC SFTPB HNRNPH2 JAK2 WT1 TP53 RAI1 SURF1 SELENON BANF1 STAG1 FGFR1 CYP11B2 CD79A GRIA4 BRIP1 DCTN1 SLC5A1 CACNA1S NIPBL BLNK ALG8 SLC26A3 PCGF2 TMEM126B DHCR7 RET CNKSR2 NSDHL ACTA1 ASXL3 SLC10A2 ERCC2 NOTCH1 HSPG2 MDH2 EHMT1 TTC37 TMEM165 C4A TNFRSF13B CALR PTPN22 TTR CIITA VPS37A CLCN4 LARS1 MAGEL2 ALG13 IGF2 ORC6 EEF1A2 FLII SLC25A15 MKRN3 MGAT2 SKIV2L PRNP SAR1B SLC12A3 POLG SLC46A1 CACNA1B DLG3 LHX4 RAB3GAP1 TPM3 GBE1 SCN1B DDB2 TJP2 TLR4 PLP1 PIK3CA NDUFB10 NDUFAF5 COG4 SMAD4 STT3A CNTN1 MCTP2 IL10 SAR1B PEX11B RAG1 COA8 EMG1 GMNN TFRC BSND NIPAL4 MCEE ROBO1 ORC4 NPHS1 PLEC ARVCF FTSJ1 GBA ATP6V0A2 COX3 ZAP70 POLR3A PLAA CDKL5 PCLO NUP62 CCNQ SIX2 TYMP COL5A1 PTF1A NDUFA4 FH COG6 SLC7A7 LAMC2 NLRP1 RFX5 MS4A1 JAGN1 PUF60 DHDDS CENPJ TRNS2 HRAS FANCG KLHL7 LIG4 PNPLA6 TSHR PRKACA FLCN SNX10 SLC9A6 RRM2B MIPEP GABRG2 AIMP1 SLC25A15 NR3C2 FANCB MAP2K1 SLC13A5 KLHL41 HLA-DQB1 SLC52A3 NAGS ECE1 MECP2 COL6A3 ERMARD PARN PANK2 PNKP NDUFB3 LAMA3 SALL1 PTPRC HUWE1 MECP2 ASS1 CD96 PEX12 DCTN1 CDT1

Protein Mutations 0

SNP 0

HP:0001824: Weight loss

Genes 325

TRNF SCNN1B WT1 EPAS1 SCNN1A GABRA3 TRAIP COL1A1 PTEN MLX LIPA TCF4 STAT3 INSR LPIN2 HAVCR2 KLRC4 MC2R NPM1 JPH3 KIF1B H19 NOD2 PLAGL1 IL6 MECP2 IL12A WT1 TRNL1 POLG PRKAR1A BCL10 MRAP FOXP3 FIP1L1 KCNJ11 SDHD UBE2T INS CNTNAP1 KIF1B DAXX MST1 PML MALT1 VHL TBL1XR1 IL12A-AS1 TSHR PRNP CDH23 ERAP1 RPS20 MDH2 FLI1 BMPR1A CUL4B TP53 GJB3 FOXP1 TRIM28 B2M ND1 FANCL PDX1 SDHA ATP7B SCNN1G RHBDF2 RBBP8 MPL AKT1 NAB2 JAK2 ERCC5 WT1 COX2 EDN3 TP53 BCL2 JPH3 STAT6 TYMP EIF2AK3 KRAS PALB2 SNCA SEMA4A SDHC LRRK2 BRIP1 DCTN1 ACADM CACNA1S NBN FANCF IGH RET XRCC2 COL6A2 PRNP TSHR BRCA2 IGH HLA-B TRNQ NDP EDNRB UNC80 HLA-DPB1 DLST VPS35 PALB2 HSPG2 MLH1 TRIM37 TMEM127 STAR MEFV KCNJ18 FANCE C4A BMPR1A UBAC2 SDHD CALR PTPN22 KDSR POLG HLA-DRB1 KCNJ11 TRNS1 ERCC2 PTEN TRIP13 PLK4 TP53 RAD51 TTR EWSR1 IL23R PMS1 GIGYF2 F5 STAT3 ATR CHEK2 DNAJC13 BTK HYMAI FANCA MSH6 KRT1 POU6F2 HTT SLC9A6 PLA2G6 SUCLA2 FANCD2 TET2 SLC6A8 GJA1 ATRX PIK3CA PRNP KRT10 FANCM RET VHL CFTR SLC52A2 SDHAF1 SDHB SLC25A11 TLR4 BIRC3 ERCC4 SDHB GCK EPCAM IRF2BP2 LMNA KCNJ18 PIK3R1 HLA-DPA1 KRAS GDNF ACAT1 STAT4 SDHAF2 LRP12 SDHB DIS3L2 IL10 ATM COL5A2 IGH RB1 NNT NALCN PMS2 CYP24A1 BCOR SMAD4 ERCC3 BRCA2 ERCC4 TRIM28 PCNT SDHC BRCA2 RAD51C HLA-B JAK2 VPS13A SLC39A4 SDHD GBA SEMA3D AK2 TRNW COX3 RRM2B TGFBR2 HMGCL POLG UNC80 BRCA1 TYMP GATA4 COL5A1 RFWD3 SNCA BTNL2 SLX4 TRNH COX1 FH IKZF1 NOD2 GATA2 JAK2 REST ZBTB16 ABCC8 NUMA1 GPR35 TXNRD2 ND5 MAFB ND4 SLC11A1 BCL6 CENPJ TRNS2 COL12A1 HMBS PTPN22 FANCG STAT5B FANCI TP53 TGFB1 CENPE SEMA3C CEP152 AVP ABCC8 MPL RRM2B FAN1 FANCC CDC73 IL12B MAX ERCC4 FAS HLA-DRB1 CCR1 MAD2L2 FANCB TRPV4 GJB4 PALLD HLA-DRB1 HLA-DQB1 SLC52A3 EIF4G1 ATRIP PTEN CCND1 HLA-DRB1 RNF168 GPC3 NABP1 SDHB MSH2 ECE1 COL6A1 IFNGR1 JAK2 COL6A3 RET SDHA NRTN PANK2 CDKN2A GALT CACNA1S MLH3 ND6 CTLA4 PRTN3 RARA HLCS CCND1 TET2 ZFP57 HLA-B BRCA1 MPL THPO GNPTAB DCTN1 SDHD

Protein Mutations 2

I148M P12A

SNP 3

rs1885988 rs738409 rs9939609