Thursday, April 3, 2014

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.