The paired-box (PAX) gene family encodes a group of transcription factors that have emerged as important regulators of organogenesis in all species [27] and PAX2 has been shown to be expressed in endocrine pancreas where one of its functions may be the regulation of pancreatic hormone genes [28]. This could be of relevance in the pathogenesis of diabetes and other endocrine disorders; however, whether rs6725556 is indeed a functional polymorphism affecting IRS1 expression needs to be proven in future functional studies. Moreover, we acknowledge that these results are preliminary and that replication C59 wnt order of our findings in independent cohorts is essential. We also acknowledge that a limitation of our study

is that it is underpowered to detect an association in the Indian Asian cohort. We only have 24% power to detect the association

found by Rung and colleagues [13] (OR = 0.84) for rs2943641. However, for the Whites we have 99% power to detect a OR of 0.84. If we take account of multiple comparisons for the 6 traits ( Supplementary Table 4) we would still have 94% power. In summary, this report confirms the association of the major C-allele of rs2943641 near IRS1 with increased risk of T2D, fasting- and glucose-stimulated hyperinsulinemia and impaired insulin sensitivity. Our data also suggest that rs2943641 and an IRS1 putative promoter variant (rs6725556) may independently influence T2D risk, although further studies with larger cohorts are needed to confirm the etiological SNPs and to analyze their interactions in different populations. We thank our clinical colleagues Dr Steve Hurel and Dr Hugh Mathur for supporting see more the recruitment of the UDACS and EDS patients, respectively. The contribution of other members of the PREDICT Study group [29] is gratefully acknowledged

including A. Dunlop Epothilone B (EPO906, Patupilone) and A. Widdowson. Financial support: This work on WHII was supported by the British Heart Foundation (BHF) PG/07/133/24260, RG/08/008, SP/07/007/23671 and a Senior Fellowship to Professor ADH (FS/2005/125). Dr MK’s time on this manuscript was partially supported by the National Heart Lung and Blood Institute (NHLBI: HL36310). The WHII study has been supported by grants from the Medical Research Council; British Heart Foundation; Health and Safety Executive; Department of Health; National Heart, Lung, and Blood Institute (HL036310) and National Institute on Aging (AG13196), US, NIH; Agency for Health Care Policy Research (HS06516); and the John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health. NPHSII was supported by the UK Medical Research Council, the US National Institutes of Health (grant NHLBI 33014) and Du Pont Pharma, Wilmington, USA. EARSII was supported by the European Community (EU-Biomed 2 BMG4-98-3324) and the full list of participants is presented in the Supplementary information. EDS recruitment was supported by the Coronary Thrombosis Trust.