Adaptive human CDKAL1 variants underlie hormonal response variations at the enteroinsular axis.

Chia Lin Chang,Shang Yu Huang,James J Cai,Sheau Yu Teddy Hsu,Ho Yen Chueh,Po Jen Cheng,Kathrin Maedler

doi:10.1371/journal.pone.0105410

Abstract

Recent analyses have identified positively selected loci that explain differences in immune responses, body forms, and adaptations to extreme climates, but variants that describe adaptations in energy-balance regulation remain underexplored. To identify variants that confer adaptations in energy-balance regulation, we explored the evolutionary history and functional associations of candidate variants in 207 genes. We screened single nucleotide polymorphisms in genes that had been associated with energy-balance regulation for unusual genetic patterns in human populations, followed by studying associations among selected variants and serum levels of GIP, insulin, and C-peptide in pregnant women after an oral glucose tolerance test. Our analysis indicated that 5′ variants in CDKAL1, CYB5R4, GAD2, and PPARG are marked with statistically significant signals of gene–environment interactions. Importantly, studies of serum hormone levels showed that variants in CDKAL1 are associated with glucose-induced GIP and insulin responses (p<0.05). On the other hand, a GAD2 variant exhibited a significant association with glucose-induced C-peptide response. In addition, simulation analysis indicated that a type 2 diabetes risk variant in CDKAL1 (rs7754840) was selected in East Asians ∼6,900 years ago. Taken together, these data indicated that variants in CDKAL1 and GAD2 were targets of prior environmental selection. Because the selection of the CDKAL1 variant overlapped with the selection of a cluster of GIP variants in the same population ∼11,800 to 2,000 years ago, we speculate that these regulatory genes at the human enteroinsular axis could be highly responsive to environmental selection in recent human history.

Highlights

Because of the recency of our common ancestry, it is well accepted that the investigation of positively selected single nucleotide polymorphisms (SNPs) in human populations may explain arrays of phenotypic variation in humans
We identified common 59 variants in five genes—glucose-dependent insulinotropic polypeptide (GIP), Cdk5 regulatory associated protein 1-like 1 (CDKAL1), cytochrome b5 reductase 4 (CYB5R4), glutamate decarboxylase 2 (GAD2), and peroxisome proliferator-activated receptor gamma (PPARG)—as top metabolic modifier candidates
Analysis of linkage disequilibrium (LD) showed that the genomic regions surrounding CDKAL1 rs9368197, GAD2 rs2236418, and PPARG rs2920502 are characterized by long LD blocks in CEU and ASN (Fig. S2, a-c in File S1)

Summary

Introduction

Because of the recency of our common ancestry, it is well accepted that the investigation of positively selected single nucleotide polymorphisms (SNPs) in human populations may explain arrays of phenotypic variation in humans. We screened gene region SNPs for unusual patterns in derived allele frequency and linkage disequilibrium (LD) in genes that had been associated with energy-balance regulation (i.e., past clinical investigations, genome-wide association (GWA) studies, and quantitative trait loci analyses) [5,6]. In these studies, we identified common 59 variants in five genes—glucose-dependent insulinotropic polypeptide (GIP), Cdk regulatory associated protein 1-like 1 (CDKAL1), cytochrome b5 reductase 4 (CYB5R4), glutamate decarboxylase 2 (GAD2), and peroxisome proliferator-activated receptor gamma (PPARG)—as top metabolic modifier candidates. Consistent with the hypothesis, our recent studies have shown that three regulatory GIP variants were positively selected ,8,100 (11,800 to 2,000) years ago, and are associated with variations in glucose metabolism and glucoseinduced GIP response in pregnant women; a coding GIP variant (rs2291725) affects the bioactivity of GIP [5,6]

Methods

Results

Conclusion