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 30 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. One of the investigated genes was KCNQ1. This gene was initially identified as a type 2 diabetes gene in a Chinese population, but it also appears to have a significant role in determining type 2 diabetes, obesity, and early insulin secretion response in Pima Indians. Variants in this gene exhibit parent of origin effects, such that the variants have different effects on disease risk if they were inherited maternally or paternally. Another gene that was invesigated was LEPR. The leptin signaling system has been well studied and LEPR knockout mice are obese. In a very few cases, mutations in LEPR have been found in morbidly obese children. The LEPR and leptin overlapping transcript (LEPROT) genes were selected for sequencing and genotyping in our population-based samples for association analyses with obesity-related phenotypes. Selected variants (n=80) spanning these genes were genotyped in a sample of full-heritage Pima Indians (n=2842) and several common variants including rs2025804 were nominally associated with BMI (P=0.05-0.003 adjusted for age, sex, birth year, and family membership). Four common tag variants associated with BMI in the full-heritage Pima Indian sample were genotyped in a second sample of mixed-heritage Native Americans (n=2969) and 3 of the variants showed nominal replication (P=0.03-0.006 adjusted as above and additionally for Indian heritage). Combining both samples provided the strongest evidence for association (adjusted P=0.0003-0.0001). A subset of these individuals (n=403) had been metabolically characterized for predictors of obesity and the BMI risk alleles for the variants tagged by rs2025804 were also associated with lower 24 hour energy expenditure as assessed in a human respiratory chamber (P=0.0007 adjusted for age, sex, fat mass, fat free mass, activity, and family membership). We conclude that common non-coding variation in the LEPR gene is associated with higher BMI and lower energy expenditure in Native Americans.

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