HNF1A MODY is characterized by impaired insulin secretion but wide variability exists in the severity of hyperglycemia and in the age at which it becomes clinically manifest. Here we focus on molecular targets of the transcription factor HNF1A and variants in these genes to identify variants associated with HNF1A-MODY age of onset. GWAS on age of onset in 837 HNF1AMODY patients was done and data were used for further analysis. Imputation was done on the Michigan Imputation Server. All modeling and statistics was done in R and python. Genetic association and relatedness structure estimation was done in package 'GENESIS.' The list of HNF1A target genes was based on the TRANSFAC database. For this analysis the HNF1A causal variants were binned according to the domain: DNA-binding, trans-acting, and dimerization. For each of the target gene, variants in the intergenic regions (500kb up- and down-stream) were selected for the analysis. Several common variants: rs12510870 in AFP, rs12441817 in CYP1A2, rs10841644 in SLCO1B3, rs12647527 in MTTP, rs12094103 in CRP and rs7525711 in CSRP1 were identified to be robustly associated with age of onset of MODY3. Moreover, the effect size (beta) of these SNPs were found to be dependent on the HNF1A functional variant. rs12441817 was found to be a significant eQTL for multiple genes in the locus across various tissues, rs10841644 was found to affect SLCO1B3 in the basal ganglia, and rs7525711 was found to be associated with the non-coding RNA in the CSRP1 locus (all in the GTEx eQTL analysis).
In conclusion, common variants in HNF1A target genes are associated with age of onset of MODY3 with the strength of association being dependent on the functional variant in HNF1A.
A. Ludwig-Slomczynska: None. M. Seweryn: None. P. Kapusta: None. J. Skupien: None. B.M. Kiec-Wilk: None. J. Machlowska: None. M. Malecki: Advisory Panel; Self; Abbott Laboratories, AstraZeneca, Bioton, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi-Aventis. Speaker’s Bureau; Self; Merck & Co., Inc. P.P. Wolkow: None. T. Klupa: Advisory Panel; Self; Abbott, AstraZeneca, Bioton, Lilly Diabetes, Novo Nordisk A/S. Employee; Spouse/Partner; Ascensia Diabetes Care. Other Relationship; Self; Ascensia Diabetes Care, Boehringer Ingelheim Pharmaceuticals, Inc., Medtronic MiniMed, Inc.
European Foundation for the Study of Diabetes