Genetics of coronary heart disease

Note: This is a guest-post, authored by geneticist and molecular biologist Dr. Chao-Qiang Lai; with edits added by LP.

Last week, Nature Genetics published three letters reporting results from genome-wide association studies (GWAS) for coronary heart disease (CAD). The studies reported a number of markers that reached the threshold of statistical significance for association to CAD with concomitant association to traditional biomarkers of disease risk, such as elevated LDL-cholesterol (LDL-C), elevated total cholesterol, decreased HDL-cholesterol (HDL-C), hypertension, obesity (as measured by elevated body mass index), or type 2 diabetes. However, the two larger and more highly powered GWAS (C4D Genetics Consortium, Schunkert, et al.) also identified CAD-associated variants that are not associated with traditional biomarkers. The third study is of interest because it examines CAD in Chinese populations, but beginning with a discovery set of 130 cases and 130 controls leaves it a bit under-powered. They report a unique association between a SNP in C6orf105 and CAD, which is not found in European or south Asian populations. Curiously, this gene has also been implicated in non-syndromic oral cleft.

There are many sources of CAD. Blood lipids are most commonly thought of as the prime source, but blood pressure in the form of hypertension is also a source. Traditional biomarkers such as LDL-C, HDL-C, triglycerides, and hypertension have been used almost as the sole surrogates for measuring the devolvement and progression of CAD over the course of some 50 years. Meta-analyses of GWAS based on over 100,000 subjects (22,233 cases and 64,762 controls from 14 GWAS) thus far have identified 23 genetic variants associating with CAD. The eye-opening aspect to this is these variants account for about 10% of CAD cases with the shocking observation that 17 of 23 confirmed loci appear to have no association with traditional markers. This observation then suggests two possible explanations.

One possibility is when we assume that the remainder of the CAD cases (90%) contribute to risk associated with traditional markers, such genetic factors cannot be detected based on current GWAS methodology. This is likely to be true because of to the effect sizes of these variants are too small, or their effects are camouflaged by gene-gene (GxG) and gene-environment (GxE) interactions or by epigenetic mechanisms.

This second possibility rests on the fundamental premise that all markers associating with CAD have more or less equal chance to be detected. It then follows that a majority of genetic factors that contribute to CAD has nothing to do with traditional markers. If this is indeed the case, it opens a new avenue to identify the new mechanism(s) and new biomarkers that lead to CAD. In fact, this possibility is supported by many observations. For example, 50% of those individuals who have CAD have low LDL-C (Braunwald & Shattuck; Ridker).

These genes – for example, ADAMTS7, PDGFD, ABO and PPAP2B – point to new mechanisms. While GxG, GxE and epigenetic interactions remain as viable contributors to CAD risk, the path to better understanding of the other component(s) to CAD risk will likely transit through metabolic profiling to identify the compounds that distinguish elevated from nominal risk. Furthermore, research will need to be conducted in model organisms based on these newly discovered genes, perhaps in pig as this is a good model for heart function and disease in human.

The Complexity of a Complex Disorder

A group of researchers led by Timothy Aitman of the MRC Clinical Sciences Centre and Imperial College London used the SHR (spontaneously hypertensive rat) to identify the few genes they thought predisposed this strain to hypertension (several genes had already been identified but the group knew or felt a few others remained to be discovered). Sequencing this SHR rat with the NextGen approach and comparing those data to the rat reference genome, led to quite a surprise. 788 genes are mutated in SHR compared to the reference genome, including 60 that are deleted altogether.

My take on this is many genes are likely involved in a complex disorder and many genes - with specific variants - may work in concert to produce the disease phenotype – either via gene-gene interactions or affecting interconnecting pathways.

This type of result is very likely to be repeated with other metabolically sensitive disorders and afflictions such as dyslipidemia, obesity and type 2 diabetes. A series of variations in genes combined with deviations from a standard environment - both in terms of diet and microbiome - are likely to combine to tip the balance and enhance onset and/or progression of said affliction.

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Reference

EurekAlert: Hypertensive rat genome sequence expected to uncover genetic basis of human hypertension

Atanur SS, Birol I, Guryev V, Hirst M, Hummel O, Morrissey C, Behmoaras J, Fernandez-Suarez XM, Johnson MD, McLaren WM, Patone G, Petretto E, Plessy C, Rockland KS, Rockland C, Saar K, Zhao Y, Carninci P, Flicek P, Kurtz T, Cuppen E, Pravenec M, Hubner N, Jones SJM, Birney E, Timothy J. Aitman TJ. (2010) The genome sequence of the spontaneously hypertensive rat: Analysis and functional significance. Genome Res. (in press).