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Title: GCKR mutations in Japanese families with clustered type 2 diabetes.
Authors: Tanaka, Daisuke  kyouindb  KAKEN_id
Nagashima, Kazuaki  kyouindb  KAKEN_id
Sasaki, Mayumi
Yamada, Chizumi
Funakoshi, Shogo
Akitomo, Kimiyo
Takenaka, Katsunobu
Harada, Kouji
Koizumi, Akio  kyouindb  KAKEN_id
Inagaki, Nobuya  kyouindb  KAKEN_id
Author's alias: 稲垣, 暢也
Keywords: Genetic susceptibility
Linkage analysis
Issue Date: Apr-2011
Publisher: Elsevier Inc.
Journal title: Molecular genetics and metabolism
Volume: 102
Issue: 4
Start page: 453
End page: 460
Abstract: [Objective]:The aim was to investigate the genetic background of familial clustering of type 2 diabetes. [Subjects and methods]:We recruited Japanese families with a 3-generation history of diabetes. Genome-wide linkage analysis was performed assuming an autosomal dominant model. Genes in the linkage region were computationally prioritized using Endeavour. We sequenced the candidate genes, and the frequencies of detected nucleotide changes were then examined in normoglycemic controls. [Results]:To exclude known genetic factors, we sequenced 6 maturity onset diabetes of the young (MODY) genes in 10 familial cases. Because we detected a MODY3 mutation HNF1A R583G in one case, we excluded this case from further investigation. Linkage analysis revealed a significant linkage region on 2p25-22 (LOD score = 3.47) for 4 families. The 23.6-Mb linkage region contained 106 genes. Those genes were scored by computational prioritization. Eleven genes, i.e., top 10% of 106 genes, were selected and considered primary candidates. Considering their functions, we eliminated 3 well characterized genes and finally sequenced 8 genes. GCKR ranked highly in the computational prioritization. Mutations (minor allele frequency less than 1%) in exons and the promoter of GCKR were found in index cases of the families (3 of 18 alleles) more frequently than in controls (0 of 36 alleles, P = 0.033). In one pedigree with 9 affected members, the mutation GCKR g.6859C>G was concordant with affection status. No mutation in other 7 genes that ranked highly in the prioritization was concordant with affection status in families. [Conclusions]:We propose that GCKR is a susceptibility gene in Japanese families with clustered diabetes. The family based approach seems to be complementary with a large population study.
Rights: © 2010 Elsevier Inc.
This is not the published version. Please cite only the published version.
DOI(Published Version): 10.1016/j.ymgme.2010.12.009
PubMed ID: 21236713
Appears in Collections:Journal Articles

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