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Additional information on genetic susceptibility effects relevant to type 2 diabetes pathogenesis can be extracted from existing genome scans by extending examination to related phenotypes such as age at disease onset. In this study, we report the reanalysis of data from 573 U.K. sibships ascertained for multiplex type 2 diabetes, using age at onset (assessed by the proxy measure of age at diagnosis) as the phenotype of interest. Genome-wide evidence for linkage to age at diagnosis was evaluated using both variance components and Haseman-Elston (HECOM) regression approaches, with extensive simulations to derive empirical significance values. There was broad agreement across analyses with six regions of interest (logarithm of odds [LOD] >/==" BORDER="0">1.18) identified on chromosomes 1qter, 4p15-4q12, 5p15, 12p13-12q13, 12q24, and 14q12-14q21. The strongest empirically "suggestive" evidence for linkage comes from regions on chromosome 12. The first region (12p13-12q13), peaking at D12S310 (variance components LOD [LOD(VC)] = 2.08, empirical pointwise P = 0.0007; HECOM LOD [LOD(HECOM)] = 2.58, P = 0.0010) seems to be novel. The second (12q24) peaking between D12S324 and D12S1659 (LOD(VC) = 1.87, P = 0.0016; LOD(HECOM) = 1.93, P = 0.0027) overlaps a region showing substantial prior evidence for diabetes linkage. These data provide additional evidence that genes mapping to these chromosomal regions are involved in the susceptibility to, and/or development of, type 2 diabetes. [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]