Positive selection and risk of heart disease

We have just submitted a review article discussing the role of genetic variants under positive selection that have roles in dyslipidemia, obesity or heart disease. Many of the identified SNPs show interactions with environmental or dietary factors, which means that one allele of the SNP, typically the risk allele, shows an effect on the phenotype only when the environment or diet passes a certain threshold. Specifically, SNP 3111 T>C (rs1801260) of the CLOCK gene shows significantly increased waist circumference for the C allele only when the saturated fat constituent of the diet is above 11.8% of total energy. Our results from variants in the CLOCK gene are published at Am J Clin Nutr 2009;90:1466–75 (www.ncbi.nlm.nih.gov/pubmed/19846548). This SNP is also under positive selection or can be called an adaptive variant. Think of natural selection.

The implication that genetic variants under positive selection have a role in human disease is profound. These polymorphisms sense the local environment - diet, sunlight, sleep, exercise, alochol and tobacco use, exposure to pathogen, etc. - and participate in an allele-specific response of the cell, tissue, organism to that stimulus if you will. Thus, modification of one's lifestyle choices based on genotypes may be a viable choice to maintain a heathly condition. Before that, though, it will be necessary to define the effects of many, many more genetic polymorphisms, both SNPs and copy number variants (CNVs). To date we've compiled over 650 such examples where the SNP-phenotype association is modified by environment/diet. These pertain mostly to blood lipids such as LDL-cholesterol, HDL-cholesterol, triglycerides and total cholesterol. CNVs are generally under-studied in such work.

A summary of the review article is here:
Purpose of review: Obesity, cardiovascular disease and unhealthy levels of blood lipids known as dyslipidemia are complex and arise from both genetic and environmental factors as well as their interrelationships. Both large-scale genetic experiments and approaches focused on a single gene have resulted in identification of many genetic variants that are related to lipid and obesity measures. However, these variants still account for only a small fraction of the observed differences in these measures.

Recent findings: That many such genetic associations to obesity and lipid measures involve genetic variants under natural selection and that those variants are sensitive to environmental cues together suggest prominent roles for both natural selection and the interaction with the environment. Genetic variants under natural selection which interact with the environment modulate susceptibility to disease but the level to which those variants contribute to dyslipidemia and obesity and how environmental factors, especially diet, alter the genetic relationship is not yet completely described.

Summary: It is evident that genetic variants under natural selection make important contributions to obesity and heart disease risk. Advances in resequencing the entire human genome will enable accurate identification of genetic variants under positive selection. This will add power to large-scale genetic studies and allow for characterization of the relationship between natural selection and the obese and dyslipidemic conditions.