In the UK, cardiovascular disease is the leading cause of death, accounting for around 1 in 3 deaths (see British Heart Foundation statistics). Of the heritable risk factors involved in cardiovascular disease, blood lipid concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) are amongst the most studied for their key roles as targets for therapeutic intervention (see previous news). To date, over 30 genetic loci have been identified, using genome-wide association studies (GWAS), that contribute to blood lipid variation, although these studies have largely been limited to the European population.
A new study published in the journal Nature has focused on trying to answer questions about whether loci identified in European populations are also relevant in non-European populations and also how clinically and biologically relevant these identified loci are [Teslovich et al. Nature (2010) doi:10.1038/nature09270]. The study, undertaken through a large-scale collaboration by researchers based in the USA, Europe, and Asia, identified 95 loci associated with at least one of the four traits tested (TC, LDL-C, HDL-C, TG) in around 100,000 individuals of European ancestry using a meta-analytic approach. These included the 36 previously reported and 59 novel loci. Of these 59, 39 were associated with TC, 31 with HDL-C, 22 with LDL-C, and 16 with TG. Interestingly, 21 of the 36 known loci showed association with another lipid phenotype in addition to that previously reported.
Additional analyses were undertaken in populations with East Asian, South Asian, and African American ancestry using a different cohort of Europeans as a control group. The SNPs found in this control European cohort were largely replicated in the non-European populations, albeit to a lesser extent in the African American population.
In order to assess the clinical relevance of these loci, associations with coronary artery disease were assessed in 25,000 cases and 66,000 controls of European descent. Thirteen loci showed association, with most of them also being associated with LDL-C, showing consistency with LDL-C as a causal risk factor. A second clinical phenotype, hyperlipidaemia, was also assessed in a smaller study, where individuals with greater numbers of risk loci showed higher lipid levels.
Comment: An accompanying editorial commented that “Despite the outstanding power of this study to detect common variants of very small effect, the 95 loci identified explain only about 10-12% of the total variance in blood-lipid levels, which corresponds to about 25-30% of the genetic variance.” Despite the large size of this study, which allowed multiple loci with very small effect sizes to be identified due to the increased power, a large proportion of genetic variance is still unaccounted for, as is common in studies of this type (see comment in previous news).
However, this study did identify a large number of loci associated with blood lipids in both European and non-European populations, as well as providing clinical and biological evidence that increases the strength of these associations. As the editorial quite rightly points out, many clinically relevant questions must now be answered following on from this work, with translation the often ignored little brother.