title: Positive natural selection of TRIB2, a novel gene that influences visceral fat accumulation, in East Asia.
abstract: Accumulation of visceral fat increases cardiovascular mortality in industrialized societies. However, during the evolution of the modern human, visceral fat may have acted as energy storage facility to survive in times of famine. Therefore, past natural selection might contribute to shaping the variation of visceral fat accumulation in present populations. Here, we report that the gene encoding tribbles homolog 2 (TRIB2) influenced visceral fat accumulation and was operated by recent positive natural selection in East Asians. Our candidate gene association analysis on 11 metabolic traits of 5,810 East Asians revealed that rs1057001, a T/A transversion polymorphism in 3'untranslated region (UTR) of TRIB2, was strongly associated with visceral fat area (VFA) and waist circumference adjusted for body mass index (P = 2.7 × 10(-6) and P = 9.0 × 10(-6), respectively). rs1057001 was in absolute linkage disequilibrium with a conserved insertion-deletion polymorphism in the 3'UTR and was associated with allelic imbalance of TRIB2 transcript levels in adipose tissues. rs1057001 showed high degree of interpopulation variation of the allele frequency; the low-VFA-associated A allele was found with high frequencies in East Asians. Haplotypes containing the rs1057001 A allele exhibited a signature of a selective sweep, which may have occurred 16,546-27,827 years ago in East Asians. Given the predominance of the thrifty gene hypothesis, it is surprising that the apparently non-thrifty allele was selectively favored in the evolution of modern humans. Environmental/physiological factors other than famine would be needed to explain the non-neutral evolution of TRIB2 in East Asians.
authors.affiliation: Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, Yakushiji, Shimotsuke, Tochigi, Japan. nakayama@jichi.ac.jp
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakayama
authors.forename: Ayumi
authors.initials: A
authors.lastname: Ogawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyashita
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Tabara
authors.forename: Michiya
authors.initials: M
authors.lastname: Igase
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Kohara
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Miki
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Kagawa
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Yanagisawa
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Katashima
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Onda
authors.forename: Koichi
authors.initials: K
authors.lastname: Okada
authors.forename: Shogo
authors.initials: S
authors.lastname: Fukushima
authors.forename: Sadahiko
authors.initials: S
authors.lastname: Iwamoto
mesh_terms: D000483:Alleles; D022981:Allelic Imbalance; D044466:Asian People / Q000235:genetics*; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019143:Evolution, Molecular; D005202:Asia, Eastern; D005786:Gene Expression Regulation; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D006801:Humans; D050152:Intra-Abdominal Fat / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D056128:Obesity, Abdominal / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012641:Selection, Genetic
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C489044:TRIB2 protein, human