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

• Published in: PloS one Vol. 9; no. 9; p. e105410
• Main Authors: Chang, Chia Lin, Cai, James J, Huang, Shang Yu, Cheng, Po Jen, Chueh, Ho Yen, Hsu, Sheau Yu Teddy
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15.09.2014; Public Library of Science (PLoS)
• Subjects: Adaptation; Adaptations; Asian Continental Ancestry Group - genetics; Biological evolution; Biology and Life Sciences; Body mass index; Climate; Climatic extremes; Cyclin-Dependent Kinase 5 - genetics; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - genetics; Energy balance; Energy Metabolism - genetics; Evolution, Molecular; Female; Gastric Inhibitory Polypeptide - genetics; Gene expression; Gene Frequency; Genes; Genetic Association Studies; Genetic Predisposition to Disease; Genomes; Genotype; Glucose; Glucose tolerance; Glucose Tolerance Test; Gynecology; Haplotypes; Health risks; Hospitals; Human populations; Humans; Immune response; Immunological tolerance; Insulin; Linkage Disequilibrium; Medicine and Health Sciences; Metabolism; Obesity; Obstetrics; Peroxisome proliferator-activated receptors; Physiology; Polymorphism, Single Nucleotide; Polypeptides; Population genetics; PPAR gamma - genetics; Pregnancy; Regulation; Selection, Genetic; Serum levels; Simulation analysis; Single-nucleotide polymorphism; Statistical analysis; Studies; tRNA Methyltransferases
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0105410

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.