A prior genome-wide linkage scan in Pima Indians indicated a young-onset (aged <45 years) type 2 diabetes susceptibility locus on chromosome 1q21-q23. ARHGEF11, which encodes the Rho guanine nucleotide exchange factor 11, was analyzed as a positional candidate gene for this linkage because this protein may stimulate Rho-dependent signals, such as the insulin signaling cascade. The ARH-GEF11 gene, and two adjacent genes NTRK1 and INSRR, were sequenced in 24 Pima Indians who were not firstdegree relatives. Sequencing of the coding regions, 5 and 3 untranslated regions and putative promoter regions of these genes, identified 28 variants in ARHGEF11, 11 variants in NTRK1, and 8 variants in INSSR. These 47 variants, as well as 84 additional public database variants within/ between these genes, were genotyped for association analysis in the same group of Pima Indians who had participated in the linkage study (n ‫؍‬ 1,228). An R1467H in ARHGEF11, and several additional noncoding variants that were in high linkage disequilibrium with this variant, were nominally associated with young-onset type 2 diabetes (P ‫؍‬ 0.01; odds ratio 3.39) after adjusting for sex, family membership, and Pima heritage. The risk allele H had a frequency of 0.10. In a subgroup of 262 nondiabetic, full-heritage Pima Indians who had undergone detailed metabolic testing, the risk allele H also was associated with a lower mean insulin-mediated glucose disposal rate and a lower mean nonoxidative glucose storage rate after adjusting for age, sex, nuclear family membership, and percentage of body fat (P < 0.01). These findings suggest that variation within ARHGEF11 nominally increases risk of type 2 diabetes, possibly as a result of increased insulin resistance.

OBJECTIVE-A prior genome-wide association (GWA) study in Pima Indians identified variants within PCLO that were associated with early-onset type 2 diabetes. PCLO encodes a presynaptic cytomatrix protein that functions as a Ca 2ϩ sensor that may be involved in insulin secretion and/or insulin action. Therefore, PCLO was analyzed as a candidate gene for type 2 diabetes. RESEARCH DESIGN AND METHODS-Sequencing of PCLOidentified four nonsynonymous variants and a 10 -amino acid insertion. These variants, together with 100 additional variants identified by sequencing or chosen from databases, were genotyped for association analysis in the same 895 subjects analyzed in the prior GWA study (300 case subjects with diabetes onset at aged Ͻ25 years, 334 nondiabetic control subjects aged Ͼ45 years, and 261 discordant siblings of the case or control subjects for within-family analyses), as well as 415 nondiabetic Pima Indians who had been metabolically phenotyped for predictors of diabetes. Selected variants were further genotyped in a population-based sample of 3,501 Pima Indians.RESULTS-Four variants were modestly associated with earlyonset type 2 diabetes in both general and within-family analyses (P ϭ 0.004 -0.04, recessive model), where the diabetes risk allele was also nominally associated with a lower insulin-mediated glucose disposal rate (P ϭ 0.009 -0.14, recessive model) in nondiabetic Pima Indians. However, their association with diabetes in the population-based sample was weaker (P ϭ 0.02-0.20, recessive model). T he Pima Indians of Arizona have an extremely high prevalence of type 2 diabetes (1). Their diabetes is characterized by obesity, dysfunction of insulin secretion, insulin resistance (decreased insulin-mediated glucose disposal), and increased rate of endogenous glucose output (2). Studies have shown that type 2 diabetes, insulin action, acute insulin response to glucose, and obesity are highly heritable in this population (3-5). To identify genes that underlie the development of type 2 diabetes in Pima Indians, we recently completed a genome-wide association (GWA) study using the Affymetrix 100K SNP genotyping array (6). Two single nucleotide polymorphisms (SNPs), rs10487656 and rs10487657, that ranked among the top 1% for a general association with early-onset type 2 diabetes (defined as age of onset Ͻ25 years) mapped within an intron of the PCLO gene. PCLO is located on chromosome 7q21 and encodes for a presynaptic cytomatrix protein that functions as a Ca 2ϩ sensor that could potentially have a role in insulin secretion and/or insulin action (7-10); therefore, PCLO was analyzed as a positional and physiological candidate gene for type 2 diabetes. CONCLUSIONS-Variation RESEARCH DESIGN AND METHODSAll subjects are part of our ongoing longitudinal study of the etiology of type 2 diabetes among the Gila River Indian Community in Central Arizona (1). Diabetes status is determined by a 75-g orally administered glucose tolerance test, with results interpreted according to the criteria of the World Health Orga...

Common variation in KLF11 variation does not appear to influence the population-based risk for developing T2D among full-heritage Pima Indians. Thus, KLF11 is unlikely to play a major role in the etiology of T2D among this Native American population.

A prior genome-wide linkage scan in Pima Indians indicated a young-onset (aged <45 years) type 2 diabetes susceptibility locus on chromosome 1q21-q23. ARHGEF11, which encodes the Rho guanine nucleotide exchange factor 11, was analyzed as a positional candidate gene for this linkage because this protein may stimulate Rho-dependent signals, such as the insulin signaling cascade. The ARH-GEF11 gene, and two adjacent genes NTRK1 and INSRR, were sequenced in 24 Pima Indians who were not firstdegree relatives. Sequencing of the coding regions, 5 and 3 untranslated regions and putative promoter regions of these genes, identified 28 variants in ARHGEF11, 11 variants in NTRK1, and 8 variants in INSSR. These 47 variants, as well as 84 additional public database variants within/ between these genes, were genotyped for association analysis in the same group of Pima Indians who had participated in the linkage study (n ‫؍‬ 1,228). An R1467H in ARHGEF11, and several additional noncoding variants that were in high linkage disequilibrium with this variant, were nominally associated with young-onset type 2 diabetes (P ‫؍‬ 0.01; odds ratio 3.39) after adjusting for sex, family membership, and Pima heritage. The risk allele H had a frequency of 0.10. In a subgroup of 262 nondiabetic, full-heritage Pima Indians who had undergone detailed metabolic testing, the risk allele H also was associated with a lower mean insulin-mediated glucose disposal rate and a lower mean nonoxidative glucose storage rate after adjusting for age, sex, nuclear family membership, and percentage of body fat (P < 0.01). These findings suggest that variation within ARHGEF11 nominally increases risk of type 2 diabetes, possibly as a result of increased insulin resistance.