Coincident Linkage of Type 2 Diabetes, Metabolic Syndrome, and Measures of Cardiovascular Disease in a Genome Scan of the Diabetes Heart Study

• Published in: Diabetes (New York, N.Y.) Vol. 55; no. 7; pp. 1985 - 1994
• Main Authors: Bowden, Donald W., Rudock, Megan, Ziegler, Julie, Lehtinen, Allison B., Xu, Jianzhao, Wagenknecht, Lynne E., Herrington, David, Rich, Stephen S., Freedman, Barry I., Carr, J. Jeffrey, Langefeld, Carl D.
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.07.2006
• Subjects: Aged; Calcinosis - genetics; Cardiovascular diseases; Cardiovascular Diseases - epidemiology; Cardiovascular Diseases - genetics; Carotid Artery Diseases - genetics; Diabetes Mellitus, Type 2 - genetics; Diabetic Angiopathies - genetics; Diabetics; Genetic aspects; Genetic Linkage; Genetic research; Genome, Human; Health aspects; Humans; Male; Metabolic Syndrome - genetics; Metabolic syndrome X; Middle Aged; Phenotype; Prevalence; Reference Values; Regression Analysis; Risk factors
• DOI: 10.2337/db06-0003
• ISSN: 0012-1797

Coincident Linkage of Type 2 Diabetes, Metabolic Syndrome, and Measures of Cardiovascular Disease in a Genome Scan of the Diabetes Heart Study Donald W. Bowden 1 2 , Megan Rudock 2 , Julie Ziegler 3 , Allison B. Lehtinen 1 2 , Jianzhao Xu 3 , Lynne E. Wagenknecht 3 , David Herrington 4 , Stephen S. Rich 3 , Barry I. Freedman 4 , J. Jeffrey Carr 5 and Carl D. Langefeld 3 1 Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 2 Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina 3 Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina 4 Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 5 Department of Radiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina Address correspondence and reprint requests to Donald W. Bowden, Center for Human Genomics, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. E-mail: dbowden{at}wfubmc.edu Abstract Cardiovascular disease (CVD) is a major contributor to morbidity and mortality in type 2 diabetes, but the relationship between CVD and type 2 diabetes is not well understood. The Diabetes Heart Study is a study of type 2 diabetes–enriched families extensively phenotyped for measures of CVD, type 2 diabetes, and metabolic syndrome. A total of 977 Caucasian subjects from 358 pedigrees (575 type 2 diabetic relative pairs) with at least two individuals with type 2 diabetes and, where possible, unaffected siblings were included in a genome scan. Qualitative traits evaluated in this analysis are with or without the presence of coronary calcified plaque (CCP) and with or without carotid calcified plaque (CarCP) measured by electrocardiogram–gated helical computed tomography. In addition, prevalent CVD was measured using two definitions: CVD1, based on self-reported history of clinical CVD (393 subjects), and CVD2, defined as CVD1 and/or CCP >400 (606 subjects). These discrete traits (type 2 diabetes, metabolic syndrome, CVD1, CVD2, CCP, and CarCP) frequently coincide in the same individuals with concordance ranging from 42.9 to 99%. Multipoint nonparametric linkage analysis revealed evidence for coincident mapping of each trait (type 2 diabetes, metabolic syndrome, CVD1, CVD2, CCP, and CarCP) to three different genomic regions: a broad region on chromosome 3 (70–160 cM; logarithm of odds [LOD] scores ranging between 1.15 and 2.71), chromosome 4q31 (peak LOD 146 cM; LOD scores ranging between 0.90 and 2.41), and on chromosome 14p (peak LOD 23 cM; LOD scores ranging between 1.43 and 2.31). Ordered subset analysis (OSA) suggests that the linked chromosome 3 region consists of at least two separate loci on 3p and 3q. In addition, OSA based on lipid measures and other traits identify family subsets with significantly stronger evidence of linkage (e.g., CVD2 on chromosome 3 at 87 cM subsetting on low HDL with an initial LOD of 2.19 is maximized to an LOD of 7.04 in a subset of 25% of the families and CVD2 on chromosome 14 at 22 cM subsetting on high triglycerides with an initial LOD of 1.99 maximized to an LOD of 4.90 in 44% of the families). When subjects are defined as affected by the presence of each trait (type 2 diabetes, metabolic syndrome, CVD1, and CCP), significant evidence for linkage to the 3p locus is observed with a peak LOD of 4.13 at 87 cM. While the correlated nature of the traits makes it unclear whether these loci represent distinct type 2 diabetes, metabolic syndrome, or CVD loci or single loci with pleiotropic effects, the coincident linkage suggests that identification of the underlying genes may help clarify the relationship of diabetes, metabolic syndrome, and CVD. CarCP, carotid calcified plaque CCP, coronary calcified plaque CT, computed tomography CVD, cardiovascular disease ECG, electrocardiogram LOD, logarithm of odds MI, myocardial infarction NPL, nonparametric linkage OSA, ordered subset analysis Footnotes 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 April 10, 2006. Received January 3, 2006. DIABETES