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

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Coincident Linkage of Type 2 Diabetes, Metabolic Syndrome, and Measures of Cardiovascular Disease in a Genome Scan of the Diabetes Heart Study
Medscape Today
Posted 07/19/2006

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. Langefeld3
1Department 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;
3Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina;
4Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina;
5Department of Radiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Abstract and Introduction

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.

Introduction
Diabetes has been widely recognized as an independent risk factor for the development of clinical atherosclerotic cardiovascular disease (CVD).[1-5] For example, the relative risk of cardiovascular death was 2.1 for men and 4.9 for women, comparing diabetes-affected with nondiabetic subjects in the Framingham Study.[1] Diabetes substantially contributes to the development of premature mortality and morbidity from CVD and atherosclerotic heart disease, and patients with diabetes are at increased risk of mortality from coronary heart disease.[6] In individuals with diabetes, genetic susceptibility as well as other factors (hypertension, microalbuminuria, blood glucose control, etc.) ultimately culminates in a diffuse disease process: diabetic macrovascular disease. These complications are common, afflicting the majority of diabetes-affected individuals. CVD accounts for 65% of deaths in diabetes-affected individuals, and in the state of North Carolina alone diabetes accounts for a quarter of all CVD hospitalizations, costing $629 million in hospital charges in 2000[7] and representing a 50% increase from 1997. For a problem of such magnitude, little is known about the underlying biological basis for the association of diabetes and CVD. The identification of genetic components and their correlation with environmental risk may help focus on both treatment and intervention strategies.

While the relationship between CVD risk and type 2 diabetes risk has been extensively documented, the relationship of incidence and progression of diabetes and macrovascular disease has not been adequately addressed. Risks for CVD and type 2 diabetes are widely accepted as being due to genetic and environmental risk factors; indeed, many of the risk factors for CVD and type 2 diabetes are thought to be determined (at least in part) by underlying genetic factors (e.g., insulin resistance and obesity).

Several hypotheses have been put forth to explain the relationship between CVD and diabetes. Some reports indicate that the primary biochemical abnormality of diabetes, i.e., chronic hyperglycemia, directly (and independently of other CVD risk factors) leads to an increased risk of CVD.[8] In an opposing hypothesis, the atherogenic risk factor profile in diabetes, and not glucose per se, is implicated. Diabetes is known to worsen CVD risk factors such as insulin resistance, obesity, HDL cholesterol, and blood pressure. All of these factors are known to contribute to an increased risk of CVD. Others[9,10] have challenged these hypotheses with a theory that CVD is not a consequence of diabetes but that these two conditions share common antecedents. The insulin resistance or metabolic syndrome has been hypothesized as one such common antecedent.[9] Another theorized common antecedent is genetic susceptibility.[9,10] That is, a single gene or several genes are responsible for both chronic diseases.

The Diabetes Heart Study[11,12] is a study of genetic and environmental factors of CVD in families highly enriched for type 2 diabetes. It represents one of the few, if not the only, study in which diabetes and multiple measures of CVD, including vascular calcification, can be simultaneously evaluated to assess the relationship between genetic and environmental contributions. In this report, we describe linkage analysis of discrete traits: type 2 diabetes, metabolic syndrome, and multiple CVD measures.

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