PHG Foundation | Genetic link between blood fat levels and coronary heart disease

Genetic link between blood fat levels and coronary heart disease
14 May 2010 | By Dr Susmita Chowdhury | Research article

One in three people in the UK die from Cardiovascular disease which is the leading cause of death in the UK, and about half of all these deaths are due to coronary heart disease or CHD (see Heartstats website). Established risk factors for coronary heart disease (CHD) include high levels of LDL (low-density lipoproteins) or cholesterol, or low levels of HDL (high-density lipoproteins) in the blood. There has been conflicting evidence about whether increased triglyceride concentration is also a risk factor for CHD; triglycerides are the most common type of fat in the blood plasma the key component of low-density lipoprotein (VLDL). In many epidemiological studies, an apparent association between triglycerides and CHD was lost after controlling for HDL and LDL levels. Moreover, previous genetic studies have shown that a polymorphism in the promoter region of the apolipoprotein A5 gene (APOA5) is associated with elevated triglyceride levels, but were not able to assess potential disease causality.

A new paper reports the use of a novel approach called Mendelian randomisation analysis (which uses genetic information to mimic aspects of a randomised drug trial - see previous news) on a large sample of 350000 people across 101 studies, which supports a causal association between high levels of triglyceride in the blood and CHD [Sarwar N et al. (2010) Lancet 375(9726):1634-9].

The investigators first measured the effect of a single–nucleotide polymorphism (SNP) in the APOA5 gene on triglyceride concentrations and other risk factors (levels of LDL, HDL, cholesterol etc.) using data from more than 73,000 individuals in 39 studies, and found it was strongly related to increased triglyceride concentration, but either moderately or unrelated to other risk factors. They then assessed the association of the same APOA5 SNP directly with the risk of CHD by meta-analysis of around 21,000 cases and 35,000 controls, and found there was an 18% increased risk of disease for each copy of the SNP present.

Finally, they estimated the risk of CHD conferred by an increase in triglyceride concentrations similar to that observed in the first analysis in over 300,000 individuals, among whom a total of nearly 13,000 CHD events occurred. The CHD risk was found to increase in line with rising levels of circulating blood triglycerides, and the APOA5 SNP linked to biological pathways through which triglyceride could affect CHD. The authors proposed that their findings were consistent with a causal relationship between increased levels circulating triglycerides and CHD.

Comment: Mendelian randomisation assumes a simple model of causality, which may not be borne out in reality, and other complicating factors may also have influenced the results. Another limitation of this study is that the data used was from mostly European subjects, and so the results may not be generalisable to other populations. Other concerns also exist; for example, the APOA5 polymorphism might have a direct effect on CHD risk and pathogenesis (besides the effect on triglyceride levels), which could have a confounding effect on the findings. Although further investigation of the ‘triglyceride risk’ is called for, with the authors recommending large randomised trials of triglyceride-lowering medications before a final conclusion on the potentially causal effect of triglyiceride levels on CHD, their report is nevertheless one of the largest and most comprehensive studies to date showing an association between triglycerides and CHD

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PHG Foundation | Genetic link between blood fat levels and coronary heart disease