These findings suggest that the HNF1A p.I27L (rs1169288) variant may be a significant risk factor of T2DM in normal-weight subjects and that earlier inconsistent results may have been due, in part, to subjects' weight status.
In this study, we asked whether the co-occurrence of risk alleles in or near five genes modulating insulin secretion (TCF7L2 rs7903146, IGF2BP2 rs4402960, CDKAL1 rs7754840, HHEX rs1111875, and HNF1A rs1169288) is associated with a higher risk of IGT/T2D in obese children and adolescents.
Amongst non-obese individuals, we observed significant T2D associations with HNF1A I27L [odds ratio (OR) = 1.14, P = 0.04], GCK -30G>A (OR = 1.23, P = 0.01), SLC30A8 R325W (OR = 0.87, P = 0.04), and TCF7L2 rs7903146 (OR = 1.89, P = 4.5 x 10-23), and non-significant associations with PPARG Pro12Ala (OR = 0.85, P = 0.14), ADIPOQ -11,377C>G (OR = 1.00, P = 0.97) and ENPP1 K121Q (OR = 0.99, P = 0.94).
In a new case-control (n = 1,511 and n = 2,225 respectively) data set, the I27L polymorphism was associated with increased risk of type 2 diabetes, odds ratio (OR) = 1.5 (p = 0.002; multiple logistic regression), particularly in elderly (age > 60 years) and overweight (BMI > 25 kg/m(2)) patients (OR = 2.3, p = 0.002).
Mutation p.T130I was associated with both early-onset and late-onset diabetes and caused downregulated HNF4A expression, whereas HNF1A polymorphisms p.I27L and p.S487N were associated with the age of diagnosis of diabetes.
The common variants p.I27L (rs1169288), p.A98V (rs1800574) and p.S487N (rs2464196) of the hepatocyte nuclear factor 1-α (HNF1A) gene have been inconsistently associated with impaired glucose tolerance and/or an increased risk of type 2 diabetes mellitus (T2DM).
The rs2259820_T (1.14 (1.03-1.26); P = 0.011) and rs2464196_C (1.12 (1.02-1.24); P = 0.024) were associated with type 2 diabetes mellitus (T2DM), while the rs2393791_T (1.14 (1.01-1.28); P = 0.032), rs7310409_G (1.16 (1.03-1.30); P = 0.013), and rs2464196_AG+GG (1.25 (1.05-1.49); P = 0.012) were implicated in hypertension.
We studied the effect of four common polymorphisms (rs1920792, I27L, A98V and S487N) in and upstream of the HNF-1alpha gene on transcriptional activity in vitro, and their possible association with type 2 diabetes and insulin secretion in vivo.
Direct sequencing of the ten exons and flanking introns of the gene in these subjects identified eight nucleotide substitutions including two amino acid changes, Ile-27-Leu and Ser-487-Asn, the frequencies of which were not significantly different in subjects with early-onset NIDDM and nondiabetic subjects.
The frequency of PTPN22 polymorphisms in the MODY patients was similar to those in geographically matched healthy populations, with the exception ofc.788G>A, the minor allele frequency of which was significantly elevated in the Czech hepatocyte nuclear factor 1-α (HNF1A) MODY patients [odds ratio (OR) 4.8, 95% confidence interval (CI) 2.2-10.7] and the Brazilian MODY patients (OR 8.4, 95% CI 1.8-39.1).
We confirm previous GWAS findings, namely that the minor rs1183910 A allele is associated with an increased risk of developing type 2 diabetes (p(trend) = 0.003), decreased levels of C-reactive protein (CRP; p(trend) = 6 × 10(-76)) and γ-glutamyltransferase (p(trend) = 4 × 10(-48)), and increased levels of total cholesterol (p(trend) = 3 × 10(-10)) and LDL-cholesterol (p(trend) = 3 × 10(-11)).
The rs2259820_T (1.14 (1.03-1.26); P = 0.011) and rs2464196_C (1.12 (1.02-1.24); P = 0.024) were associated with type 2 diabetes mellitus (T2DM), while the rs2393791_T (1.14 (1.01-1.28); P = 0.032), rs7310409_G (1.16 (1.03-1.30); P = 0.013), and rs2464196_AG+GG (1.25 (1.05-1.49); P = 0.012) were implicated in hypertension.
The rs2259820_T (1.14 (1.03-1.26); P = 0.011) and rs2464196_C (1.12 (1.02-1.24); P = 0.024) were associated with type 2 diabetes mellitus (T2DM), while the rs2393791_T (1.14 (1.01-1.28); P = 0.032), rs7310409_G (1.16 (1.03-1.30); P = 0.013), and rs2464196_AG+GG (1.25 (1.05-1.49); P = 0.012) were implicated in hypertension.
In multiethnic replication data sets, thep.E508K</span> </span>variant was seen only in Latino patients (n = 1443 with type 2 diabetes and 1673 without it) and was associated with type 2 diabetes (OR, 4.16; 95% CI, 1.75-9.92; P = .0013).
The rs2259820_T (1.14 (1.03-1.26); P = 0.011) and rs2464196_C (1.12 (1.02-1.24); P = 0.024) were associated with type 2 diabetes mellitus (T2DM), while the rs2393791_T (1.14 (1.01-1.28); P = 0.032), rs7310409_G (1.16 (1.03-1.30); P = 0.013), and rs2464196_AG+GG (1.25 (1.05-1.49); P = 0.012) were implicated in hypertension.