Genetic Epidemiology and Lipids - A Pattern So Grand and Complex

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Topics

• Clinical/medical genetics > Disease related (typology of disorder)
• Molecular genetics > Studies of DNA > Studies of DNA (as a sequence) > Disease-associated alterations (mutation/deletion/duplication/insertion)
• Clinical/medical genetics > Patient related
• Molecular genetics > Techniques > Molecular techniques
• Statistical genetics > Genetic epidemiology
• Molecular genetics > Studies of RNA > Studies of coding RNA > Studies of protein

Abstract

Thesis in English with a summary in English and Dutch Cardiovascular disease, despite decades of research, remains the leading cause of mortality in much of the world. Circulating (serum and plasma) lipid levels are important determinants of cardiovascular disease risk. Total cholesterol, low-density lipoprotein cholesterol (LDL), and triglyceride levels lead to increased incidence of disease, while high-density lipoprotein cholesterol (HDL) leads to decreased incidence. The levels of these lipid particles are determined in large measure by genetic factors. Despite years of searching for these genes, and the vast strides made thus far, there are still many unknown genetic factors affecting lipid levels. In this thesis, a large number of genetic epidemiology tools are applied to the task of identifying and characterizing genes involved in lipid transport, metabolism, and homeostasis. Two types of approaches are implemented: candidate-gene analysis and genome-wide analysis. These broad classes of analyses were utilized in both population-based and family-based studies, in both general and selected populations (including a Dutch genetic isolate), and yielded a number of important insights. The first chapter begins with a general overview of both lipids and genetic epidemiological methods. It continues, in chapter 1.2, with a study designed to estimate the proportion of lipid parameter variation attributable to genetic factors. This study also examined the effects of inbreeding on lipid levels and the influence of the well-characterized Apolipoprotein E ε 2/3/4 isoforms. These analyses determined that between a quarter (triglycerides) and a half (HDL) of the variance in these measurements are due to genetic causes. Inbreeding contributes to this variation, particularly for total cholesterol and LDL. Apolipoprotein E isoforms, while important, do not explain a large portion of lipid variance. The influence of a promoter polymorphism in the hepatic lipase gene promoter was studied in chapter 1.3. Using meta-analysis to synthesize the data from 25 publications, the –514C>T single nucleotide polymorphism (SNP) was determined to significantly decrease hepatic lipase activity and, subsequently, increase HDL levels. In chapter 2, candidate gene approaches were implemented to study a variety of genes, or regions, known, or suspected, of influencing lipid levels. In chapter 2.1, the effects of an amino acid shift polymorphism in the cholesteryl ester transfer protein gene was explored. The mutation caused an increase in serum HDL levels, which, in turn, led to a decreased risk of myocardial infarction in men. The joint effect of this polymorphism and the hepatic lipase promoter polymorphism were tested in chapter 2.2. The hepatic lipase variant was associated with higher HDL levels overall, and an increased risk of heart attack in males; together, the two polymorphisms exerted a strong effect on HDL. In chapters 2.3 and 2.4, polymorphisms in two candidate genes, upstream stimulatory factor one (USF1) and Apolipoprotein A-V (ApoA-V), were evaluated in a set of families ascertained for familial combined hyperlipidemia (FCH). USF1, previously reported to be a major player in FCH, did not play a role in the disease in these Dutch families, although the SNPs, both individually and in haplotypic analysis, influenced total cholesterol levels. ApoA-V, by contrast, affected FCH risk, as well as numerous lipid phenotypes, including total cholesterol; triglycerides; apolipoprotein B; HDL; small, dense LDL; and remnant-like particle cholesterol. The effects of the tested genetic variants extended to the normo-lipidemic relatives and spouses of the FCH probands, suggesting that ApoA-V is an important determinant of lipid levels in a general population. An interesting set of genes located on chromosome 22, the apolipoprotein L (ApoL) cluster, was studied in chapter 2.5. A large number of SNPs (n = 66) were analyzed in a sample of Dutch individuals, and followed-up in a sample of Finns. Three SNPs, located in the ApoL-V gene, affected triglyerides, HDL, and their ratio. Haplotype analysis revealed a shared haplotype in both populations that led to these associations. As these phenotypes form an important component of atherogenic dyslipidemia, this finding is of particular interest. Chapter 3.1 presents results from a genome-wide association study of lipid levels, utilizing a recently published piece of software developed in-house (GenABEL). This study reported two novel loci that reached genome-wide significance. The first, located on chromosome 1, suggests that the estrogen receptor-related protein 3 gene (ERR3) influences total cholesterol and LDL. Other nuclear orphan receptors, similar to ERR3, were previously implicated in lipid metabolism. The second region, located on chromosome 6, affected triglycerides and triglyceride/ HDL ratio. Although the region is not well characterized, the polymorphisms are located in a putative transcript site, which may harbor an as yet unknown gene. In chapter 4, the results from these studies are discussed in a more general manner, and findings are placed in a broader context. In total, they suggest that genetics play an important role in determining lipid levels, and that these genetic variants are also involved in subsequent disease. Although the numbers of genes involved, and their complex interactions with each other and with environmental factors, make the goal of fully elucidating these systems a distant dream, substantial progress has been, and will continue to be, made.

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A. Isaacs. Genetic Epidemiology and Lipids - A Pattern So Grand and Complex. EUROGENE portal. October 2010. online: http://eurogene.open.ac.uk/content/genetic-epidemiology-and-lipids-pattern-so-grand-and-complex

Keywords

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