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There is wide variation in the age at diagnosis of diabetes in individuals with maturity-onset diabetes of the young (MODY) due to a mutation in the HNF1A gene. We hypothesized that common variants at the HNF1A locus (rs1169288 [I27L], rs1800574 [A98V]), which are associated with type 2 diabetes susceptibility, may modify age at diabetes diagnosis in individuals with HNF1A-MODY. Meta-analysis of two independent cohorts, comprising 781 individuals with HNF1A-MODY, found no significant associations between genotype and age at diagnosis. However after stratifying according to type of mutation (protein-truncating variant [PTV] or missense), we found each 27L allele to be associated with a 1.6-year decrease (95% CI -2.6, -0.7) in age at diagnosis, specifically in the subset (n = 444) of individuals with a PTV. The effect size was similar and significant across the two independent cohorts of individuals with HNF1A-MODY. We report a robust genetic modifier of HNF1A-MODY age at diagnosis that further illustrates the strong effect of genetic variation within HNF1A upon diabetes phenotype. [ABSTRACT FROM AUTHOR]

The BAIR consortium has been formed to provide insight into the biological processes underlying insulin resistance through multidisciplinary research combining various genomic/proteomic/metabolomic approaches in animal models, followed by haman genetic analysis. Based on previously described associations, function and on BAIR biological data, we selected 11 candidate genes (ARNT; RBP4; HIF1a; EIF2S1; AKT1; ONECUT1; RPS6KB1; TRB3; FOXA2; PCK1; FOXO3A) for investigation. Pairwise tags (r²>0.8) spanning these genes were selected based on HapMap phase II CEU data to exhaustively capture common variation (MAF>0.05). 103 SNPs were genotyped in 5,602 samples (935 UKT2D, 1927 UK-controls, 926 French T2D, 934 French obese and 880 French controls) by iPLEX & SNPlex methods. Single-point analyses on 92 SNPs were carried out after stringent quality control. Coverage of common variation remained high (74%-100% per gene). There was no significant association with T2D or obesity (at the p=0.01 level) in 9 of the strong candidate genes examined. In the UK population, rs11908628 of PCK1 (encoding phosphoenolpyruvate carboxykinase 1, the main control point for the regulation of gluconeogenesis) was found to be protective against diabetes (MAFs 2.7% v 4.3%, OR(95%CIs): 0.62 (0.44-0.86); p=0.003 additive). Mantel-Haenszel meta-analysis of rs11908628 across the UK and French T2D samples provided additional support for this finding (p=0.002), although further investigation, given low MAFs, is warranted. When comparing genotypes between T2D cases and controls in the French population, 2 independent associations were seen in RPS6KB1: rs180535 (MAFs 18% v 15%; OR 1.29 (1.07 -1.55); p=0.006) and rs180531 (24% v 28%; OR 0.81 (0.69-0.95) p=0.008) (r²=0.06 in controls). RPS6KB1 codes for ribosomal protein S6 kinase 70KD 1, which negatively regulates insulin signalling. Interestingly, rs180531 (23% v 28%; OR 0.80 (0.69-0.94) p=0.005) was also associated with protection against obesity in the French. In conclusion, our genetic data suggest modest effects of the BAIR insulin resistance candidates PEPCK and S6K1 gene variation in UK (T2D) and French (T2D and obese) samples, results that require replication in additional populations. [ABSTRACT FROM AUTHOR]

Permanent neonatal diabetes (PND), requiring insulin within the first months of life, is unexplained at the molecular level in most cases. It has very recently been shown that heterozygous activating mutations in the KCNJ11 gene, encoding the Kir6.2 subunit of the pancreatic ATP-sensitive K(+) channel involved in the regulation of insulin secretion, cause PND. In the present study, we screened the KCNJ11 gene for mutations in French patients with PND. Patients were recruited through the French network for the study of neonatal diabetes. Seventeen at-term babies with a median age at diagnosis of diabetes of 64 days (range 1-260) were included. We identified in nine patients seven heterozygous nonsynonymous mutations: three of them (V59M, R201C, and R201H) were already described, and the four novel mutations resulted in an amino acid change of Kir6.2 at positions F35L, G53N, E322K, and Y330C. More patients with a Kir6.2 mutation (six of nine) were reported to have a smaller birth weight than those without mutation (two of eight). Although Kir6.2 mutation carriers do not represent a phenotypically specific form of PND, an impaired function of Kir6.2 is associated with in utero insulin secretory insufficiency and growth retardation. In conclusion, we confirmed that Kir6.2 mutations are a common cause (53%) of PND in Caucasians.