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RESEARCH PRODUCT

A genome-wide association study of monozygotic twin-pairs suggests a locus related to variability of serum high-density lipoprotein cholesterol

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Serum lipid levels have been associated with cardiovascular diseases, metabolic syndrome and type II diabetes (Kannel et al., 1961; Miller & Miller, 1975; Pilia et al., 2006). Variation in lipids levels is highly influenced by heritable factors (Friedlander et al., 1997) and 95 loci have already been associated with levels of high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides (TG) and total cholesterol (TC) in numerous study samples and replicated in various populations using genome-wide approaches (Aulchenko et al., 2008; Kathiresan et al., 2008; Kooner et al., 2008; Teslovich et al., 2010; Willer et al., 2008). However, the genetic associations affecting blood apolipoproteins have been studied mainly with the candidate gene approach. Data emerging from epidemiological studies imply that genes interact with environmental factors causing additional variability in lipid levels (Thorn et al., 1998; Visscher & Duffy, 2006). In animal and plant models G × E interactions can be studied by controlling the environmental factors. In human populations, the environment of an individual is highly variable and the individual can choose environments. This makes it difficult to find loci interacting with specified environmental factors. Recently published screen for G × E interactions identified a locus where, depending on the genotype at that locus, the connection between waist-to-hip ratio and total cholesterol differed (Surakka et al., 2011) but to detect the association, over 40,000 individuals from various population cohorts were used. The total environmental sensitivity of a locus, without specifying which environmental factors are salient, can be tested in general population samples by comparing the trait variances between different genotype classes in genome-wide association (GWA) studies. For this sensitivity association screening, monozygotic (MZ) twins offer the additional benefit of controlling for possible confounding due to possible epistatic effects. MZ twin pairs share essentially identical genomes at the sequence level and the differences within pairs; for example, lipid levels reflect environmentally influenced differences. Genetic variation may determine the extent to which environmental differences lead to phenotypic within pair variability (Magnus et al., 1981). An association with within-MZ-pair trait differences directly indicates gene–environment interaction, where one allele increases or restricts the effect of environmental factors or environmental factors affect the gene expression differently for different alleles. This is seen as elevated or diminished levels of variability in trait values. In a recent methodological article, the power to detect variability association using either difference between twins or variability in population approaches was evaluated (Visscher & Posthuma, 2010). The study showed that using MZ twins is more powerful than the approach using population variances, when the trait under examination has high within-pair correlations in MZ twin pairs. In this study we have screened for genetic ‘variability’ loci where the loci are associated with differences in lipid levels between the two members of a pair in our GWA study in monozygotic female twins. More specifically, the aim of our study was to search variability genes for HDL, LDL, TC, TG and apoliproteins A-I, A-II, B and E (APOA1, APOA2, APOB and APOE respectively). For the apolipoprotein data at hand we have additionally screened for apolipoprotein level associations.