ARAP1 and type 2 diabetes - a circadian connection?

A new report in the American Journal of Human Genetics shows a variant with association to type 2 diabetes and insulin levels functions within an allele-specific motif for islet cell transcription factors PAX4 and PAX6. Specifically, "measurement of allele-specific mRNA levels in human pancreatic islet samples heterozygous for rs11603334 showed that the T2D-risk and proinsulin-decreasing allele (C) is associated with increased ARAP1 expression (p < 0.02). We evaluated four candidate functional SNPs for allelic effects on transcriptional activity by performing reporter assays in rodent pancreatic beta cell lines. The C allele of rs11603334, located near one of the ARAP1 promoters, exhibited 2-fold higher transcriptional activity than did the T allele (p < 0.0001); three other candidate SNPs showed no allelic differences. Electrophoretic mobility shift assays demonstrated decreased binding of pancreatic beta cell transcriptional regulators PAX6 and PAX4 to the rs11603334 C allele."

Interestingly, Pax4 is abundantly over-represented within cis-regulatory motifs in mouse clock-controlled genes, in liver and muscle, per Table 1, and relative to peak Per2 expression in mice, the Pax4 protein recognizes a motif over-represented in the suprachiasmatic nucleus (SCN, the "master clock" in the brain) at phase 12, per Table 2. These data are from Bozek, Relogio, et al 2009 PLoS One4:e4882. That same study showed similar activity for Pax6: relative to peak Per2 expression in mice, Pax6 protein also recognizes a motif over-represented in the SCN at phase 12, per Table 2 (Bozek Relogio 2009 PLoS One 4:e4882, PMID 19287494).

This makes one wonder about the timing of the food intake that might exacerbate glucose homeostasis in carriers of the risk allele.

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.