A genome wide quantitative trait linkage analysis for serum lipids in type 2 diabetes in an African population

doi:10.1016/j.atherosclerosis.2004.12.049

Atherosclerosis

Volume 181, Issue 2, August 2005, Pages 389-397

https://doi.org/10.1016/j.atherosclerosis.2004.12.049 Get rights and content

Abstract

Lipid abnormalities are strongly linked with coronary heart disease and are common in type 2 diabetes. However, little is known about the genetic determinants of serum lipids in African populations. An autosomal genome scan was performed for linkage to five plasma lipid phenotypes (total cholesterol, triglycerides (TG), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C) and VLDL-cholesterol (VLDL-C)) in the Africa–America Diabetes Mellitus (AADM) study. Two hundred and ninety-five affected sibling pairs with type 2 diabetes mellitus enrolled from Ghana and Nigeria were genotyped for 390 microsatellite markers with an average inter-marker distance of 9 cM. Multipoint variance components linkage analysis showed that HDL-C had a LOD score of 4.34 near marker D7S3061 and 3.00 near marker D7S513. Some clustering of linkage evidence to several lipid phenotypes was observed on chromosomes 5 (LDL-C, total cholesterol, VLDL-C), chromosome 7 (HDL-C, TG) and chromosome 19 (total cholesterol, LDL-C, TG). Principal component analysis of the five phenotypes yielded two factors, one (TG, HDL-C and VLDL) of which was linked to QTLs on chromosomes 2, 5 and 7, while the other (total cholesterol and LDL-C) was linked to a different set of QTLs on chromosomes 2, 5 and 18. Several of these regions have been reported to be linked to lipids in other studies. Follow up investigations are warranted in view of the central role serum lipids play in the aetiopathogenesis of cardiovascular disease.

Introduction

Serum lipids play a major role in the pathogenesis of coronary heart disease. It is now well established that the risk of CHD is positively correlated with serums levels of total cholesterol, triglycerides (TG) and LDL-cholesterol (LDL-C) and is inversely correlated with HDL-cholesterol (HDL-C) levels [1], [2], [3], [4], [5], [6]. More subtle abnormalities, such as particle size, have also been shown to be risk factors for CHD. For example, LDL particle size has been shown to be associated with the risk of CHD, with small LDL particles being considered a component of an atherogenic lipoprotein phenotype [7], [8]. Due to the important role played by dyslipidaemia in CHD, the Third Adult Treatment Panel Guidelines of the US National Cholesterol Education Program (ATP III) recommended a full fasting lipoprotein profile to include total cholesterol, LDL-C, HDL-C and triglyceride levels as the initial lipid measurement in all individuals for CHD risk assessment [9]. Lipid abnormalities are known to be more common among individuals with type 2 diabetes mellitus (T2DM) and their relatives [10], [11], [12]. These lipid abnormalities, including high triglyceride and low HDL-C, predate the onset of glucose intolerance [13] and further increase the risk of CHD in this population subgroup. Therefore, detection and control of dyslipidaemia in this specific group can reduce myocardial infarction, coronary deaths and overall mortality in T2DM [14].

Several intermediate measures of lipid metabolism (including total cholesterol, TG, HDL-C and LDL-C) have been shown to have a significant genetic component with estimates of heritability ranging between 30% and 80% [15], [16], [17]. While numerous candidate genes have been tested for linkage and/or association to these traits, most of the known candidate genes explain very little of the variation in these lipid measures. Increasingly, genome scans are being used to investigate the issue further since it is likely that several (or many) genes of small effect influence serum lipid levels. Because genome scans make no a priori assumptions about the number and location of these genes, there is a greater likelihood that they will shed more light on the genomic regions influencing the variation of these lipid measures.

Various epidemiological studies conducted over the last three decades suggest that the serum lipid profiles of many populations in sub Saharan Africa differ substantially from what is known of other geographical populations. For example, studies in Nigeria, Ghana, Zimbabwe and other countries in the region show lower levels of total cholesterol, triglycerides and LDL-C with higher levels of HDL-C when compared with populations of Europe and North America [18], [19], [20], [21]. However, little is known about the genetic determinants of serum lipid levels in African populations. The few candidate gene studies that have been conducted showed that polymorphisms influencing lipid levels do exist in African populations. For example, a recent study found that several apoD polymorphisms, some unique to African populations, were associated with various lipid measures [22]. However, to our knowledge, no genome scan has been done for quantitative trait loci (QTL) linked to serum lipids in African population. In the present study, we report the findings of a genome scan for lipids conducted in the Africa–America Diabetes (AADM) Mellitus Study. We investigate linkage to five serum lipid measures: total cholesterol, triglycerides, HDC-C, LDL-C and VLDL-C. In addition, we construct composite phenotypes using principal components analysis and use these as traits in a second set of linkage analyses. We decided on this strategy because it is the strategy most likely to detect genomic regions that are linked to each phenotype, while at the same time identifying regions that are linked to two or more phenotypes (i.e. genomic regions with pleiotropic effects). Finally, we compare the areas of suggestive or significant linkage found in this study, which have been reported in other geographic populations.

Section snippets

Subjects and methods

The participants in this study were all enrolled from the Africa–America Diabetes Study, which has been described more fully elsewhere [23]. The protocol was approved by the institutional review board (IRB) of each participating institution and written informed consent was obtained from each participant.

Results

Two hundred and ninety-five siblings pairs were studied. Characteristics of this study sample are shown in Table 1. The mean age was about 53 years and did not differ between men and women. Women had greater adiposity than men did, as evidenced by a greater mean BMI, FM and PBF. One-quarter of the women had a BMI ≥ 30 kg² in contrast to only 11% of the men. More than one-half of the participants had hypertension (Table 1).

The descriptive statistics, covariates and sib–sib correlations of the five

Discussion

Serum lipid abnormalities have major public health significance, being some of the most potent risk factors for CHD and occurring in association with T2DM and the metabolic syndrome. For these reasons, delineating their environmental and genetic determinants has been a major focus of several teams of investigators over several decades. The geographic population studied is of particular interest because serum lipid profiles of many populations in sub Saharan Africa differ substantially from what

Acknowledgements

Support for the AADM study is provided by NIH Grant No. 3T37TW00041-03S2 from the Office of Research on Minority Health. This project is also supported in part by the National Center for Research Resources (NCRR), National Human Genome Research Institute (NHGRI) and by the NIDDK grant DK-54001. Genotyping was done by the Center for Inherited Disease Research (CIDR) and detailed information on laboratory methods and markers can be found at http://www.cidr.jhmi.edu. The marker map used was from

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Although linkage for lipid traits has been observed on almost every chromosome, 19p13.3-q13.32 is the most frequently and consistently reported region of linkage for TC and/or LDL-C in the literature. Linkage to this region has been implicated for lipid traits in at least fifteen independent studies [14–25], and in a meta-analysis of published genome scans for quantitative lipid traits conducted in families ascertained for T2DM, we [26] observed strong and consistent support for linkage of TC on 19p13.3-p12 (6.57–38.05 cM; P = 0.00026), 19p12-q13.13 (38.05–69.53 cM; P = 0.00001), and 19q13.13-q13.43 (69.53–101.1 cM; P = 0.00033), and of LDL-C on 19p13.3-p12 (P = 0.00041). Results from multiple genome-wide association studies (GWAS) have also identified loci underlying lipid traits on chromosome 19 [27–32].
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We used a positional and biological candidate gene approach to prioritize genes. A positional candidate gene approach identified genes that lie under linkage peaks for lipid traits based on four studies that performed genome wide scans to identify loci that may affect lipoprotein metabolism in African ancestry populations: Hypertension Genetic Epidemiology Network (22), HERITAGE Family Study (23, 24), African-American Diabetes Mellitus Study (25), and Genetics of NIDDM Study (26). The strongest linkage signals reported were: 5q33 for LDL-C (25), 19p13 and 19q13 for TRIG (24, 26), 1q25 and 7p21 for HDL-C (25), and 21q22 for LDL-C, HDL-C, and TRIG (22).
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A genome wide quantitative trait linkage analysis for serum lipids in type 2 diabetes in an African population

Abstract

Introduction

Section snippets

Subjects and methods

Results

Discussion

Acknowledgements

Am Heart J

Am J Cardiol

Atherosclerosis

Lancet

Am J Hum Genet

Atherosclerosis

Ann Epidemiol

Am J Hum Genet

Am J Hum Genet

Serum cholesterol, lipoproteins, and the risk of coronary heart disease. The Framingham study

Ann Intern Med

HDL cholesterol and other lipids in coronary heart disease. The cooperative lipoprotein phenotyping study

Circulation

Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk

Circulation

Genetic epidemiology of low-density lipoprotein subclass phenotypes

Ann Med

Lipoprotein distribution in the metabolic syndrome, type 2 diabetes mellitus, and familial combined hyperlipidemia

Am J Cardiol

Insulin resistance and hypertriglyceridemia in nondiabetic relatives of patients with noninsulin-dependent diabetes mellitus

J Clin Endocrinol Metab

Dyslipidemias among normoglycemic members of familial NIDDM pedigrees

Diab Care

Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset of clinical diabetes?

JAMA

Cardiovascular disease, hypertension, and lipids

BMJ

Familial aggregation of lipids and lipoproteins in families ascertained through random and nonrandom probands in the Stanford Lipid Research Clinics Family Study

Am J Med Genet

Factors of insulin resistance syndrome-related phenotypes are linked to genetic locations on chromosomes 6 and 7 in nondiabetic Mexican–Americans

Diabetes