title: Adaptive human CDKAL1 variants underlie hormonal response variations at the enteroinsular axis.
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.
authors.affiliation: Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Kweishan, Taoyuan, Taiwan.
authors.forename: Chia Lin
authors.initials: CL
authors.lastname: Chang
authors.affiliation: Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, United States of America.
authors.forename: James J
authors.initials: JJ
authors.lastname: Cai
authors.affiliation: Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Kweishan, Taoyuan, Taiwan.
authors.forename: Shang Yu
authors.initials: SY
authors.lastname: Huang
authors.affiliation: Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Kweishan, Taoyuan, Taiwan.
authors.forename: Po Jen
authors.initials: PJ
authors.lastname: Cheng
authors.affiliation: Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Kweishan, Taoyuan, Taiwan.
authors.forename: Ho Yen
authors.initials: HY
authors.lastname: Chueh
authors.affiliation: Reproductive Biology and Stem Cell Research Program, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Sheau Yu Teddy
authors.initials: SY
authors.lastname: Hsu
mesh_terms: D044466:Asian People / Q000235:genetics; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics*; D019143:Evolution, Molecular; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000235:genetics; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin; D015810:Linkage Disequilibrium; D047495:PPAR gamma / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D012641:Selection, Genetic; D012359:tRNA Methyltransferases
chemical_list: D007328:Insulin; D047495:PPAR gamma; D005749:Gastric Inhibitory Polypeptide; D012359:tRNA Methyltransferases; D051360:Cyclin-Dependent Kinase 5; C525110:CDKAL1 protein, human