A genome wide quantitative trait linkage analysis for serum lipids in type 2 diabetes in an African population
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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2016, Molecular Genetics and MetabolismCitation Excerpt :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].
Genetic epidemiology of type 2 diabetes and cardiovascular diseases in Africa
2013, Progress in Cardiovascular DiseasesCitation Excerpt :Mutations in the hepatocyte nuclear factor-1alpha (HNF1A) gene have been implicated in maturity onset diabetes of the young type 3 (MODY3), a form of diabetes mellitus found in 2–5% of patients with T2D.14 The AADM study also investigated linkage evidence for several T2D-related quantitative traits including intraocular pressure – a risk factor for retinopathy (5q22 and 14q22),15 renal function – a major consequence of diabetes,16 obesity (e.g. percent body fat on 2p13, fat mass on 2p13 and 5q14),17 serum lipids such as high density lipoprotein cholesterol (HDL-C, 7q31),18 and C-peptide plasma levels (10q23, 4p15).19 The loci found to influence C-peptide plasma levels harbor multiple T2D candidate genes (phosphatase and tensin homolog – PTEN, protein phosphatase 1, regulatory subunit 3C – PPP1R3C, insulin degrading enzyme – IDE, and peroxisome proliferator activated receptor gamma, coactivator 1 alpha – PPARGC1).19
Genetic loci for blood lipid levels identified by linkage and association analyses in Caribbean Hispanics
2011, Journal of Lipid ResearchCitation Excerpt :In our polygenic analysis adjusted for covariates, the heritability estimates ranged from 41-57% for the five quantitative lipid traits in Caribbean families. These estimates are very comparable to those obtained in most reported family studies from different populations (5, 13–17) and, therefore, provide further evidence that blood lipids are largely under genetic control. In this report, the largest linkage peak was mapped to chromosome 7p for LDL-C/HDL-C.
Association analysis of 33 lipoprotein candidate genes in multi-generational families of African ancestry
2010, Journal of Lipid ResearchCitation Excerpt :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).