A gene is considered a candidate gene for type 2 diabetes in Pima Indians if 1) it has a known physiological function in a pathway relevant to type 2 diabetes/obesity or 2) it is associated with diabetes/obesity in another human population or in an animal model. In the past year we have directly sequenced and genotyped all detected variants in more than 60 physiologic candidate genes for associations with BMI or diabetes. Genotyping was performed in two large population based samples of individuals collected from the Gila River Indian Community. We reported that Sim1 is the first major susceptibility gene for obesity in the Pima Indians, where variation in this gene accounts for approximately 16 lbs. We also reported on the FTO gene, which has been reproducibly associated with BMI in multiple populations. This gene shows a similar association with BMI in Pima Indians. In contrast, we have studied 6 additional genes that are reproducibly associated with BMI in Caucasian populations, but only variation in TMEM18 appears to affect body weight in Pima Indians. We also reported that genes which have been well-replicated for their association with type 2 diabetes in other ethnic groups (TCF7L2, CDKAL1, SLC30A8, HHEX, EXT2, IGF2BP2 and CDKN2B) do not have a have an impact on type 2 diabetes in the Pima Indians, although variation in some of these genes appear to influence insulin secretion among Pima Indians with normal glucose tolerance. In contrast, a type 2 diabetes gene (KCNQ1) identified in a Chinese population appears to have a significant role in determining type 2 diabetes, obesity, and early insulin secretion response in Pima Indians. A novel gene for type 2 diabetes (UBE2E2) has recently been reported in a Japanese genome-wide association study. In Pima Indians, this gene has very significant associations with BMI, but not type 2 diabetes. In collaboration with a group from Mexico, we have also found that a variant in the ABCA1 gene is associated with low HDL-C levels and shows evidence of positive selection in Native Americans.
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