title: A functional variant in the human betacellulin gene promoter is associated with type 2 diabetes.
abstract: Betacellulin (BTC) plays an important role in differentiation, growth, and antiapoptosis of pancreatic beta-cells. We characterized about 2.3 kb of the 5'-flanking region of human BTC gene and identified six polymorphisms (-2159A>G, -1449G>A, -1388C>T, -279C>A, -233G>C, and -226A>G). The G allele in the -226A>G polymorphism was more frequent in type 2 diabetic patients (n = 250) than in nondiabetic subjects (n = 254) (35.6% vs. 27.8%, P = 0.007), and the -2159G, -1449A, and -1388T alleles were in complete linkage disequilibrium with the -226G allele. The frequencies of the -279A and -233C alleles were low (7.0 and 2.0% in diabetic patients), and no significant differences were observed. In the diabetic group, insulin secretion ability, assessed by the serum C-peptide response to intravenous glucagon stimulation, was lower in patients with the -226G allele (G/G, 2.96 +/- 0.16 ng/ml; G/A, 3.65 +/- 0.18 ng/ml; A/A, 3.99 +/- 0.16 ng/ml at 5 min after stimulation; P = 0.008). Furthermore, in vitro functional analyses indicated that both the -226G and the -233C alleles caused an approximately 50% decrease in the promoter activity, but no effects of the -2159A>G, -1449G>A, -1388C>T, and -279C>A polymorphisms were observed. These results suggest that the -226A/G polymorphism of the BTC gene may contribute to the development of diabetes.
authors.affiliation: The First Department of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Nakano
authors.forename: Hiroto
authors.initials: H
authors.lastname: Furuta
authors.forename: Asako
authors.initials: A
authors.lastname: Doi
authors.forename: Shohei
authors.initials: S
authors.lastname: Matsuno
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shimomura
authors.forename: Setsuya
authors.initials: S
authors.lastname: Sakagashira
authors.forename: Yukio
authors.initials: Y
authors.lastname: Horikawa
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nishi
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sasaki
authors.forename: Tokio
authors.initials: T
authors.lastname: Sanke
authors.forename: Kishio
authors.initials: K
authors.lastname: Nanjo
mesh_terms: D020121:5' Untranslated Regions; D000368:Aged; D066259:Betacellulin; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000503:physiopathology; D014644:Genetic Variation; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D015810:Linkage Disequilibrium; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012016:Reference Values; D017384:Sequence Deletion
chemical_list: D020121:5' Untranslated Regions; C587851:BTC protein, human; D066259:Betacellulin; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins