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Arg1467his of ARHGEF11 Gene Is Associated with Insulin Resistance

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Arg1467his of ARHGEF11 Gene Is Associated with Insulin Resistance Diabetes In Press, published online February 7, 2007 Variants in ARHGEF11, a Candidate Gene for the Linkage to Type 2 Diabetes Mellitus on Chromosome 1q, Are Nominally Associated With Insulin Resistance and Type 2 Diabetes Mellitus in Pima Indians Received for publication 9 May 2006 and accepted in revised form 22 January 2007. Lijun Ma1, Robert L. Hanson1, Lorem N. Que1, Anna M. G. Cali1, Mao Fu2, Janel L. Mack1, Aniello M. Infante1, Sayuko Kobes1, Clifton Bogardus1, Alan R. Shuldiner2, and Leslie J. Baier1 Running Title: ARHGEF11 Variation and Type 2 Diabetes in Pima Indians 1Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, DHHS, Phoenix, AZ 85004 2Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201 Address Correspondence to: Leslie J. Baier, PhD Diabetes Molecular Genetics Section Phoenix Epidemiology and Clinical Research Branch National Institute of Diabetes, Digestive and Kidney Diseases National Institutes of Health 445 N. Fifth Street, Suite 210 Phoenix, AZ 85004 E-mail: [email protected] Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0640. Copyright American Diabetes Association, Inc., 2007 Abstract A prior genome-wide linkage scan in Pima Indians indicated a young-onset (age<45 years) type 2 diabetes mellitus (T2DM) 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 ARHGEF11 gene, and two adjacent genes NTRK1 and INSRR, were sequenced in 24 Pima Indians who were not first-degree relatives. Sequencing of the coding regions, 5’and 3’ UTR’s 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=1228). An R1467H in ARHGEF11, and several additional non-coding variants that were in high linkage disequilibrium with this variant, were nominally associated with young-onset T2DM (P=0.01, OR=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 on-diabetic full-heritage Pima Indians who had undergone detailed metabolic testing, the risk allele H was also associated with a lower mean insulin-mediated glucose disposal rate and a lower mean non-oxidative 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 T2DM, possibly as a result of increased insulin resistance. 1 Introduction IRS-2 The Pima Indians of Arizona have (http://genecards.bcgsc.bc.ca/cgi-bin/c an extremely high prevalence of T2DM arddisp?insrr). In this study (1). Their diabetes is characterized by ARHGEF11 and the two adjacent obesity, dysfunction of insulin genes, NTRK1 and INSRR were secretion, insulin resistance (decreased analyzed as positional candidate genes insulin-mediated glucose disposal), for T2DM in the Pima Indians. and increased rates of post-absorptive endogenous glucose output (2). Studies have shown that T2DM, insulin Research Design and Method resistance, the acute insulin response and obesity are highly heritable in this Subjects and clinical characteristics population (3, 4, 5). The subjects who were sequenced A prior genome-wide linkage scan (N=24) and genotyped (N=1228) were in Pima Indians indicated a participants in our prior genome-wide susceptibility locus for young-onset linkage study for diabetes susceptibility (onset age<45 years) T2DM on loci in Pima Indians (6) and are part of chromosome 1q21-q23 at D1S1677 (6). our ongoing longitudinal study of the Linkage to T2DM on chromosome etiology of type 2 diabetes among the 1q21-23 has subsequently been Gila River Indian Community in central observed in 7 other populations who Arizona (1). All individuals in the have formed the International Type 2 longitudinal study are invited to Diabetes 1q Consortium participate in a standardized health (7,8,9,10,11,12,13,14). Within this examination biannually. To determine region of linkage, there is a cluster of diabetes status, a 75-g orally three genes (ARHGEF11, NTRK1, and administered glucose tolerance test is INSRR) located between 153 and given and the results are interpreted 154Mb, which encode proteins that according to the criteria of the World have putative roles in the insulin Health Organization (18). All studies signaling system. ARHGEF11 encodes were approved by the Tribal Council of the Rho guanine nucleotide exchange the Gila River Indian Council and the factor ARHGEF11 (PDZ-RhoGEF, Institutional Review Board of the KIAA0380). ARHGEF11 interacts National Institutes of Diabetes and with small GTPases (G-protein, Digestive and Kidney Diseases. guanine nucleotide binding proteins) such as Rho, that function as molecular Among the 1228 subjects that were switches in signaling pathways that genotyped, 262 of the non-diabetic include the insulin signaling cascade subjects had additionally been studied (15, 16). NTRK1 encodes the for measures of pre-diabetic neurotrophic tyrosine kinase receptor phenotypes in our Clinical Research type 1 which recruits IRS-1 and IRS-2 Center. Only individuals, age 18-45 (17) and INSRR encodes the insulin years, who are confirmed to be healthy receptor related receptor which by medical history, physical potentially phosphorylates IRS-1 and examination, and routine laboratory tests, and are not taking medications, are studied. Oral glucose tolerance is Glucose and lipid oxidation rates were measured after 2–3 days on a normalized to estimated metabolic weight-maintaining diet of mixed body size (fat-free mass + 17.7) as composition. Blood for plasma glucose described (19, 20). Body composition and insulin measurements is drawn was estimated by underwater weighing before ingesting 75 g of glucose, at 30, until January of 1996 and is currently 60, 120, and 180 min thereafter. measured by dual energy X-ray Subjects also receive a 25-g intravenous absorptiometry (DPX-1; Lunar injection of glucose over 3 min to Radiation, Madison, WI). A conversion measure the acute insulin response. equation derived from comparative Blood samples were collected before analyses is used to make estimates of infusion, and at 3, 4, 5, 6, 8, and 10 min body composition comparable between after infusion for determination of methods (21). plasma glucose and insulin concentrations. The acute insulin Single nucleotide polymorphism response was calculated as the mean identification and genotyping increment in plasma insulin To identify sequence variants, all concentrations from 3 to 5 min. (19). exons, exon-intron boundaries, 5’ and The hyperinsulinemic-euglycemic 3’ untranslated regions, and 2 kb of the clamp technique was used to determine putative promoter regions of basal glucose appearance and ARHGEF11, NTRK1, and INSRR were insulin-stimulated glucose PCR amplified and sequenced in DNA disappearance (uptake) rates (19). samples from 24 non-first-degree Briefly, insulin was infused to achieve related Pima Indians. Among these 24 physiologic plasma insulin subjects, 12 developed diabetes before concentrations (137 ± 3 µU/ml) for 100 the age of 25 years, and 12 were min. Plasma glucose concentrations non-diabetic and were at least 45years were held constant at 100 mg/dl by a of age. Sequencing was performed variable 20% glucose infusion. using the Big Dye Terminator (Applied Tritiated glucose was infused for 2 h Biosystems) on an automated DNA before the insulin infusion to calculate capillary sequencer (model 3730xl; glucose disappearance rates during the Applied Biosystems). Single nucleotide insulin infusion. During the last 40 min polymorphisms (SNPs) identified by of the insulin infusion, the rate of sequencing were genotyped in DNA insulin-stimulated glucose disposal was from 1228 subjects using the TaqMan calculated, adjusted for steady-state Allelic Discrimination (AD) Assay plasma glucose and insulin (Applied Biosystems), direct concentration, and normalized to sequencing (as described above; estimated metabolic body size (EMBS Applied Biosystems) or SNPplex = fat-free mass + 17.7 kg) as described following the manufactures protocol (19,20). Ventilated-hood indirect (Applied Biosystems). Sequence calorimetry was used to estimate rates information for all oligonucleotide of glucose and lipid oxidation before primers and probes is available upon and during the insulin infusions (20). request. 1 Statistical Analysis family members, it does not provide a For the association analysis with specific within-family test of young onset T2DM, only siblings who association and, thus, is still potentially were confirmed to have developed confounded by population stratification. T2DM before the age of 45 years (N= Therefore, data were also analyzed 525) or confirmed to be non-diabetic using a modification of the method of and at least 45 years of age (N=88) Abecasis et al (22) to test for were analyzed. Statistical analyses within-family association. In
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