Single nucleotide polymorphisms of the HNF4α gene are associated with the conversion to type 2 diabetes mellitus: the STOP-NIDDM trial

Abstract

Hepatocyte nuclear factor 4alpha (HNF4alpha) is a transcription factor, which is necessary for normal function of human liver and pancreatic islets. We investigated whether single nucleotide polymorphisms (SNPs) of HNF4A, encoding HNF4alpha, influenced the conversion from impaired glucose tolerance (IGT) to type 2 diabetes mellitus in subjects of the STOP-NIDDM trial. This trial aimed at evaluating the effect of acarbose compared to placebo in the prevention of type 2 diabetes mellitus. Eight SNPs covering the intragenic and alternate P2 promoter regions of HNF4A were genotyped in study samples using the TaqMan Allelic Discrimination Assays. Three SNPs in the P2 promoter region (rs4810424, rs1884614, and rs2144908) were in almost complete association (D'>0.97, r (2)>0.95) and, therefore, only rs4810424 was included in further analyses. Female carriers of the less frequent C allele of rs4810424 had a 1.7-fold elevated risk [95% confidence interval (CI) 1.09-2.66; P=0.020] for the conversion to diabetes compared to women with the common genotype after the adjustment for age, treatment group (placebo or acarbose), smoking, weight at baseline, and weight change. No association was found in men. Haplotype analysis based on three SNPs (rs4810424, rs2071197, and rs3818247) representing the linkage disequilibrium blocks in our study population indicated that the conversion to type 2 diabetes mellitus was dependent on the number of risk alleles in different haplotypes in women. Our results suggest that SNPs of HNF4A and their haplotypes predispose to type 2 diabetes mellitus in female subjects of the STOP-NIDDM study population.

Single Nucleotide Polymorphisms of the Peroxisome Proliferator–Activated Receptor-α Gene (PPARA) Influence the Conversion From Impaired Glucose Tolerance to Type 2 Diabetes

“…The minor G (162V) allele of rs1800206 was associated with a 1.9-fold (P ϭ 0.035) higher risk of diabetes in the placebo group (in six of seven different populations included in the study). The same allele of rs1800206 further increased the risk of diabetes beyond that associated previously with the SNPs of PGC-1A, PPARG2 (15), and HNF4A (14). In addition, acarbose was more effective in preventing the progression from IGT to diabetes in subjects carrying either one or both risk alleles of PPARA and PGC-1A or HNF4A, indicating a genetreatment interaction.…”

“…We also tested whether rs1800206 (L162V) of PPARA had an effect on the risk of diabetes associated previously with polymorphisms of PGC-1A (Gly482Ser), PPARG2 (Pro12Ala) (15), and HNF4A (eight SNPs) (14). Genotypes of rs1800206 were therefore combined with those of other SNPs to form three new genotype combinations having no (0), one of two (1), and both (2) risk alleles of rs1800206 and SNPs of either PGC-1A, PPARG2, or HNF4A.…”

“…The Gly482Ser substitution of PGC-1A (15,23), the Pro12Ala substitution of PPARG2 (15,24), and SNPs of HNF4A (14) have been associated previously with the risk of diabetes. PGC-1␣ coactivates PPAR-␣ in the transcriptional control of fatty acid oxidation proteins (2), whereas hepatic expression of PPAR-␣ is regulated by HNF4-␣ (hepatic nuclear factor 4␣) (25).…”

“…The genotyping success rate was 100%, and rescreening of 7% of subjects gave 100% identical results. TaqMan Allelic Discrimination Assays were also used to genotype 8 SNPs of HNF4A (14), of which rs4801424 G/C (C risk allele), rs2425637 G/T (G risk allele), rs2071197 G/A (G risk allele), and rs3818247 G/T (T risk allele) have been associated with the conversion to type 2 diabetes (14). Screening methods for polymorphisms of PGC-1A (rs8192678 G/A: Gly482Ser; 482Ser risk allele) and PPARG2 (rs1801282 C/G: Pro12Ala; Pro12Pro risk genotype) have been previously described (15).…”

The Pharmacogenetics of Type 2 Diabetes: A Systematic Review

“…Two of 11 SNPs from the PPARA locus were associated with response to acarbose (20). Of six SNPs from the HNF4A locus, two were associated with response to acarbose (21). Single SNPs at the LIPC and the PPARGC1A loci were also associated with response to acarbose (22,23).…”