The insulin gene variable number tandem repeat (INS-VNTR) is proposed to exert pleiotropic genetic effects on birth weight and diabetes susceptibility. In our study, we examined the influence of a polymorphism in tight linkage disequilibrium with INS-VNTR (؊23Hph1) on birth weight and type 2 diabetes in the Pima population. A parent-offspring "trio" design was used to assess parent-of-origin effects and population stratification. The presence of the -23Hph1 T-allele was associated with lower birth weight (n ‫؍‬ 192; ؊140 g per copy of the T-allele; P ‫؍‬ 0.04), even after adjustment for effects of population stratification (P ‫؍‬ 0.03). The effects of paternally transmitted T-alleles were greater than those of maternally transmitted alleles (paternally transmitted: -250 g, P ‫؍‬ 0.05; maternally transmitted: -111 g, P ‫؍‬ 0.43), but this difference was not statistically significant (P ‫؍‬ 0.50). The ؊23Hph1 T-allele was associated with an increased prevalence of type 2 diabetes (P ‫؍‬ 0.009), which family-based association analysis suggested was attributable to population structure (P ‫؍‬ 0.04) without significant evidence of linkage disequilibrium between diabetes prevalence and genotype (P ‫؍‬ 0.86). Thus allelic variation of the INS gene is associated with lower birth weight and increased prevalence of type 2 diabetes. Significant linkage disequilibrium was found between -23Hph1 and birth weight but not type 2 diabetes, an observation that supports a potential functional role of INS polymorphisms in the regulation of birth weight. Diabetes 52: [187][188][189][190][191][192][193] 2003

OBJECTIVES: To investigate whether (a) variants within the dopamine D2 receptor gene (DRD2) are associated with obesity and type 2 diabetes in Pima Indians, and (b) whether variation in this gene could be responsible for previously observed linkage to these phenotypes, at chromosome location 11q23 ± 24, in this population. DESIGN: Two single nucleotide polymorphisms (SNPs), Ser311Cys and TaqIA, within the DRD2 gene were genotyped by allelic discrimination PCR in subjects who had provided evidence of linkage to diabetes and obesity in an autosome-wide scan. SUBJECTS: A total of 1187 subjects were genotyped, including 947 full heritage Pima Indians (80%). Descriptive statistics for all subjects analyzed, for whom clinical data were available, were (mean AE s.d.): age at time of last exam 41 AE 15 y; birth year 1950 AE 14; age-sex-adjusted body mass index (BMI; adjusted to a mean age of 35 y) 36 AE 8 kgam 2 ; male 44%; diabetic 57%. For full heritage Pimas only: age 43 AE 15 y; birth year 1948 AE 14; sex ± age-adjusted BMI 36 AE 8 kgam 2 ; male 43%; diabetic 59%. RESULTS: Neither polymorphism was signi®cantly associated with diabetes in full heritage Pimas. Individuals with à CG' genotype at the Ser311Cys SNP had a higher BMI than those with a`CC' genotype (36.7 vs 35.5 kgam 2 , P 0.04). Linkage analysis of BMI, adjusted for either polymorphism, resulted in LOD scores that were similar to those obtained without adjustment. CONCLUSION: Heterozygotes at the Ser311Cys DRD2 polymorphism had a slightly higher BMI than homozygotes, however neither the Ser311Cys nor the TaqIA polymorphism accounted for the linkage with BMI on chromosome 11 in Pima Indians.

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