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The KCNJ9gene encodes a G-protein-coupled inwardly rectifying potassium channel and is located within a region on human chromosome 1 that has been linked with type 2 diabetes mellitus in Pima Indians and Caucasians. To assess the potential contribution of genetic alterations within KCNJ9to diabetes susceptibility in the Pimas, we have genotyped 11 single nucleotide polymorphisms (SNPs) in 50 Pimas with diabetes and 50 Pimas over the age of 45 without diabetes and in 51 sib pairs, discordant for the disease, who were characterized by decreased allele sharing at the chromosomal location of the maximum LOD score. We detected three SNP clusters exhibiting distinct linkage disequilibria. Polymorphisms in intron 2, exon 3, and the 3′-UTR were in statistically significant linkage disequilibrium with diabetes in the case-control group (P= 0.006), but not the sibling pairs (P= 0.097). A weak association with diabetes was also found in the original linkage set comprising 1150 Pimas (odds ratio = 0.64/P= 0.079 for a dominant model and OR = 0.67/P= 0.005 for a recessive model). However, no effect on linkage was detected following adjustment for one of the most strongly associated SNPs in the entire original linkage set. Our results indicate that variants in KCNJ9are associated with diabetes in Pimas but do not account for the linkage of 1q with diabetes in this population.

Large subcutaneous abdominal adipocyte size (s.c. abd. AS) is associated with insulin resistance and predicts type 2 diabetes in Pima Indians. Because type 2 diabetes is familial, we aimed to determine whether mean s.c. abd. AS is also familial and if so, to identify chromosomal regions linked to this measure. Body composition (hydrodensitometry) and mean s.c. abd. AS (fat biopsy) were measured in 295 Pima Indians (179 with normal, 80 with impaired, and 36 with diabetic glucose tolerance) representing 164 nuclear families. Mean s.c. abd. AS, adjusted for age, sex, and percentage body fat was a familial trait (heritability h2= 0.48, P< 0.0001). A genome-wide autosomal scan revealed suggestive evidence for linkage (LOD 1.73) of adjusted mean s.c. abd. AS to chromosome 1q21–q23, a region containing LMNA,the gene encoding for the nuclear envelope proteins lamin A/C. Rare mutations in LMNAwere recently shown to underlie familial partial lipodystrophy (FPLD), a syndrome characterized by regional loss of adipose tissue, insulin resistance, and glucose intolerance. A common (allelic frequency 0.43) single nucleotide polymorphism (silent 1908C → T substitution) in exon 10 of LMNA(GenBank X03444) was associated with reduced age-, sex- and percentage body fat-adjusted mean s.c. abd. AS [0.80 ± 0.17 (CC), 0.76 ± 0.15 (CT), 0.73 ± 0.16 (TT) μg lipid/cell, P< 0.05 for CC vs TT]. These findings indicate that approximately half of the variance in mean s.c. abd. AS can be attributed to familial factors and that genetic variation in LMNAmight not only underlie rare cases of FPLD, but may also contribute to variation in adipocyte size in the general population.