The incidence of type 2 diabetes (T2DM) continues to rise and increasingly affects individuals of all ages across all ethnic groups;however, individuals from certain ethnic groups including Mexican Americans have an increased propensity towards developing T2DM. The increased risk of T2DM in Mexican Americans may indicate an increased genetic susceptibility. Hence, we performed a genome-wide linkage scan to localize those genes in the San Antonio Family Diabetes/Gallbladder Study (SAFDGS), an extended pedigree study comprised of 39 Mexican Americans families with 906 individuals. Using follow-up data which used each subject's most recent diabetic status, we observed significant evidence for linkage of the traits diabetes and diabetes age-of-onset to a genetic region on chromosome 3p (empirical multipoint LOD score of 3.76, p=0.000016). This region has previously been implicated by numerous independent studies to be linked to diabetes and related traits. In addition, we have recently observed the expression profiles of known and novel transcripts from this region to be highly correlated with diabetes risk in an independent, large study of Mexican Americans. Therefore, there is growing evidence that this region may harbor a gene influencing susceptibility to T2DM and deserves exploration. The 1.5-LOD support interval around our peak spans an approximately 15 Mb region and harbors approximately 59 identified genes and ESTs. A number of these genes appear to have biologic relevance to the pathophysiology of diabetes, whereas the function of many is still unknown. This proposal aims to identify the gene(s) in this region that influences diabetes susceptibility and/or diabetes age-of-onset by identifying DNA sequence variants that are associated with diabetes and account for the observed linkage signal. In order to efficiently and thoroughly investigate this locus, we will conduct association tests for variants at intervals of approximately 1 per 1.6 kilobases (Specific Aim 1). We will also conduct comprehensive analyses of candidate genes in the region (Specific Aim 2). In addition, the utilization of a novel statistical functional genomic analysis (BQTN) in the 3rd specific aim of this proposal should enhance the final stage of identifying the specific variants involved.
