Association Analysis of Variation in/Near FTO, CDKAL1, SLC30A8, HHEX, EXT2, IGF2BP2, LOC387761, and CDKN2B With Type 2 Diabetes and Related Quantitative Traits in Pima Indians

• Published in: Diabetes (New York, N.Y.) Vol. 58; no. 2; pp. 478 - 488
• Main Authors: Rong, Rong, Hanson, Robert L., Ortiz, Daniel, Wiedrich, Christopher, Kobes, Sayuko, Knowler, William C., Bogardus, Clifton, Baier, Leslie J.
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.02.2009
• Subjects: Adolescent; Adult; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Biological and medical sciences; Body composition; Cation Transport Proteins - genetics; Cyclin-Dependent Kinase 5 - genetics; Cyclin-Dependent Kinase Inhibitor p15 - genetics; Cyclin-dependent kinases; Diabetes; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Genes; Genetic aspects; Genetic Predisposition to Disease - genetics; Genetic variation; Genetics; Genome-Wide Association Study - methods; Genomes; Genotype; Glucose; Health aspects; Health risk assessment; Homeodomain Proteins - genetics; Humans; Indians, North American - genetics; Insulin; Kinases; Longitudinal studies; Male; Medical sciences; Metabolism; Middle Aged; Multifactorial traits; N-Acetylglucosaminyltransferases - genetics; Obesity; Physiological aspects; Pimas; Plasma; Polymorphism, Single Nucleotide; Proteins - genetics; Quantitative Trait Loci - genetics; Research design; Risk factors; RNA-Binding Proteins - genetics; Transcription Factors - genetics; tRNA Methyltransferases; Type 2 diabetes; White people; Young Adult; Zinc Transporter 8; United States; Gila River; Endocrinopathy; Type 2 diabetes; Metabolic diseases; Indian; Association
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db08-0877

Association Analysis of Variation in/Near FTO , CDKAL1 , SLC30A8 , HHEX , EXT2 , IGF2BP2 , LOC387761 , and CDKN2B With Type 2 Diabetes and Related Quantitative Traits in Pima Indians Rong Rong , Robert L. Hanson , Daniel Ortiz , Christopher Wiedrich , Sayuko Kobes , William C. Knowler , Clifton Bogardus and Leslie J. Baier From the Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona Corresponding author: Leslie J. Baier, lbaier{at}phx.niddk.nih.gov Abstract OBJECTIVE— In recent genome-wide association studies, variants in CDKAL1 , SLC30A8 , HHEX , EXT2 , IGF2BP2 , CDKN2B , LOC387761 , and FTO were associated with risk for type 2 diabetes in Caucasians. We investigated the association of these single nucleotide polymorphisms (SNPs) and some additional tag SNPs with type 2 diabetes and related quantitative traits in Pima Indians. RESEARCH DESIGN AND METHODS— Forty-seven SNPs were genotyped in 3,501 Pima Indians informative for type 2 diabetes and BMI, among whom 370 had measures of quantitative traits. RESULTS— FTO provided the strongest evidence for replication, where SNPs were associated with type 2 diabetes (odds ratio = 1.20 per copy of the risk allele, P = 0.03) and BMI ( P = 0.002). None of the other previously reported SNPs were associated with type 2 diabetes; however, associations were found between CDKAL1 and HHEX variants and acute insulin response (AIR), where the Caucasian risk alleles for type 2 diabetes were associated with reduced insulin secretion in normoglycemic Pima Indians. Multiallelic analyses of carrying risk alleles for multiple genes showed correlations between number of risk alleles and type 2 diabetes and impaired insulin secretion in normoglycemic subjects ( P = 0.006 and 0.0001 for type 2 diabetes and AIR, respectively), supporting the hypothesis that many of these genes influence diabetes risk by affecting insulin secretion. CONCLUSIONS— Variation in FTO impacts BMI, but the implicated common variants in the other genes did not confer a significant risk for type 2 diabetes in Pima Indians. However, confidence intervals for their estimated effects were consistent with the small effects reported in Caucasians, and the multiallelic “genetic risk profile” identified in Caucasians is associated with diminished early insulin secretion in Pima Indians. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 13 November 2008. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted November 5, 2008. Received July 1, 2008. DIABETES