Pilot Evaluation of the Effect of Riboflavin Supplementation on Blood Pressure and Possible Effect Modification by the MTHFR C677T Genotype

Hypertension, which results from a combination of multiple lifestyle and genetic factors, is a global public health problem affecting 1 billion people worldwide. The identification of cheap treatment interventions without adverse side effects would be hugely advantageous particularly in low-income settings with high prevalence of hypertension such as sub-Saharan Africa where up to 46% of adults are affected. Emerging evidence links a functional polymorphism in the MTHFR gene (rs1801133 C677T), encoding the folate-metabolising enzyme methylenetetrahydrofolate reductase to high blood pressure in adults. Variation at rs1801133 is relatively common and has 3 genotypes; homozygous "normal" CC, heterozygous CT and homozygous "variant" TT genotypes. Of these genotypes, the homozygous "variant" TT is more strongly associated with a higher BP. The precise mechanism by which MTHFR is associated with BP remains unclear. It has been recently shown in 3 separate randomized controlled trials that BP is highly responsive to riboflavin and that this response is differential by MTHFR rs1801133 genotype. In all these clinical trials, significant reduction in both systolic and diastolic blood pressure was observed in the homozygous variant TT genotype and an intermediate effect seen in those with the heterozygous CT genotype. The aim of this study is to evaluate the effect of riboflavin supplementation on blood pressure in a riboflavin-deplete population as well as comparing plasma riboflavin status before and after supplementation. This will be achieved by conducting a randomized single-blind placebo controlled trial over a period of 16 weeks. The Investigators will use the Keneba biobank to invite about 100 adults with the CT genotype and a similar number of age-, sex and village-matched CC homozygotes. Participants within each of the groups will be randomized to receive either riboflavin (5mg/d) or a matching placebo which would be supplied on a weekly basis. Blood sample, blood pressure measurement, socio-demographic data and their anthropometric measurements (height, weight, waist and hip circumference and body composition by BIA) will be taken during the initial visit. An additional blood sample will be taken at the end of the study whilst additional BP measurements will be taken respectively at 8 weeks and at the end of the intervention. The possibility that riboflavin deficiency represents a new, easily-correctible causal factor in hypertension in sub-Saharan Africa would require further large-scale interventions if this pilot study yields encouraging results.

NCT03151096 High Blood Pressure MTHFR C677T Genotype

MeSH:Hypertension

HPO:Hypertension

2 Interventions

Name: Riboflavin

Name: Placebo

Purpose: Treatment

Allocation: Randomized

Parallel Assignment

There is one SNP

SNPs

1 rs1801133

Emerging evidence links a functional polymorphism in the MTHFR gene (rs1801133 C677T), encoding the folate-metabolising enzyme methylenetetrahydrofolate reductase to high blood pressure in adults.

Variation at rs1801133 is relatively common and has 3 genotypes; homozygous "normal" CC, heterozygous CT and homozygous "variant" TT genotypes.

It has been recently shown in 3 separate randomized controlled trials that BP is highly responsive to riboflavin and that this response is differential by MTHFR rs1801133 genotype.

We would like to investigate if there is any effect modification in CC vs CT variants of rs1801133 in the MTHFR gene in response to riboflavin supplementation vs placebo.

HPO Nodes

HPO:

HP:0000822: Hypertension

Genes 418

PDE11A WT1 BBS10 TGFB2 COL1A1 KCTD1 MLX ND5 SCNN1A GPR101 TRNS2 B2M CFI NOTCH3 ALX4 TNFRSF11A GATA5 EXT2 LYZ MUC1 ERCC6 TRNL1 STOX1 COX3 PRKACA MTTP BSCL2 TRNS1 PKD2 KRT8 TRNL1 SLC2A10 CDH23 LEMD3 WT1 TBX1 TRIM28 KCTD1 ND1 CYTB WNK1 ELP1 WDR19 AIP COX2 LOX TGFBR2 GCH1 KRT18 SCNN1B CORIN UFD1 CFH SCNN1G HGD PDE11A COL4A4 BRCA2 NR3C1 CACNA1D LMNA FBN1 ND1 TRNQ VHL JMJD1C CBS RPGRIP1L TGFBR3 POR SDHD TRNS1 ALMS1 CACNA1H TSC1 LRP6 CD2AP FBN1 COX2 DYRK1B SEC24C ADA2 HPSE2 NF1 LDLRAP1 HLA-DRB1 WNK4 ACVRL1 CCND1 FBN1 VHL GLA PDE3A ABCG8 SH2B3 MMP2 SLC52A2 ARMC5 SLC25A11 ERCC4 BBIP1 PAM16 HLA-DPA1 PDE8B ACAT1 LMNA GLA GUCY1A1 MAFB DIS3L2 COL5A2 NKX2-5 CYP11B1 TRNL1 BBS1 FGFR2 LEMD3 MYH7 PPARG FLT1 FN1 COMT MYMK MTRR FOXF1 FN1 CFB MKKS SDHD CYP11B1 MGP SDCCAG8 GJA1 SH2B3 CYP17A1 SUGCT TGFB3 COX1 ANGPTL6 ELN ACTN4 REST HMBS HSD11B2 ND5 SDHD SMAD4 ND4 KCNJ5 LRIG2 NPHP1 TRNQ FMO3 HMBS PTPN22 FGFR2 GBA ELN KIF1B SDHB SLC2A10 COX1 ENG RREB1 CCR6 CYP11B1 PLIN1 CCN2 LMX1B ACTA2 CD46 VHL CACNA1D G6PC PPARG MMP14 NPHP1 WRN APOA1 GP1BB KCNJ5 GPC3 ARHGAP31 RFC2 SMAD3 ND6 MAX SCNN1B ND6 CTLA4 PRTN3 SCNN1G RET PLIN1 USP8 C3 XYLT1 HLA-B XYLT2 FGA TRNC TRNF EPAS1 APOB BBS7 BBS2 BNC2 FOXE3 SDHC IQCB1 NOS3 BBS9 ABCC6 KIF1B COL4A5 H19 EDA2R CYP17A1 ELN PKHD1 HBB ENPP1 LIMK1 TBL2 LZTFL1 CPOX CEP164 USP8 CALR KIF1B SLC37A4 ZMPSTE24 TRNF SERPINA6 TMEM67 VHL JAK2 MDH2 ARMC5 SMARCAL1 FUZ ABCC6 TRNW POU3F4 SDHB NSMCE2 OFD1 MEF2A WT1 KLHL3 XPNPEP3 HIRA GNAS TP53 PDE3A CEP19 BANF1 SPRY2 INVS ADA2 BBS1 FBN1 NOD2 SDHC CLIP2 ERCC8 HSD11B2 NPHP3 TMEM127 HLA-DPB1 TNFRSF11B SDCCAG8 DLST MC4R CEP290 EGFR STAT1 TMEM127 COL3A1 YY1AP1 CAV1 COQ7 INVS ADA2 NOTCH1 TRNK BBS12 NFIX TRIP13 TRPC6 IDUA OFD1 LMX1B WDR35 ENPP1 BMPR2 CEP290 MFAP5 LMNA TRNK MKS1 POU6F2 PKD1 CC2D2A MAT2A MYH11 LDLR RET COL3A1 VHL CCDC28B SCN2B SDHB NOTCH2 ECE1 CDH23 IFT27 TRNV SMAD4 TRIM32 SDHAF2 GNAS MYLK ALMS1 ARL6 TSC2 AIP PRKAR1A WT1 ITGA8 TRIM28 ARVCF GTF2I LARS2 TRNW THPO COX3 CYP11B2 TMEM237 SLC37A4 CYP11B1 IFT172 COL5A1 SMAD6 TRAF3IP1 TMEM70 TRNH FH DNAJB11 NFU1 CFHR1 TBX1 BBS4 KCNJ5 COL4A3 AIP TRNS2 NR3C1 MLXIPL NPHP1 LMNA GUCY1A1 EDA SLC25A11 ACTA2 SCNN1A CFHR3 FMR1 LMNA TTC8 PRKG1 PRKACA TGFBR1 FIG4 ELP1 BAZ1B IL12B MAX IRF5 NPHP4 PHF21A ABCC6 RET WDPCP YY1AP1 CUL3 COL4A3 ADAMTSL4 BBS5 SLC52A3 OSGEP GANAB GNAS CYP21A2 TRNE SDHB ABCB6 VAC14 JAK2 RET SDHA PRKAR1A SDHD PCSK9 GDNF WT1 TET2 NR3C2 SMAD4 CLCN2 ABCG5 MPL C8ORF37 GTF2IRD1 VANGL1 TRNK THBD PRKAR1A

Protein Mutations 18

A1166C A118G C282Y C344T C677T D565H E298D G1051A G1691A G20210A G308A G3514C G389R H295R M235T S49G T393C V617F

SNP 9

rs1017783 rs10177833 rs13333226 rs1801133 rs2398162 rs2540923 rs254093 rs5068 rs7571842