title: GCKR mutations in Japanese families with clustered type 2 diabetes.
abstract: OBJECTIVE
  The aim was to investigate the genetic background of familial clustering of type 2 diabetes.
  
  
  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.
authors.affiliation: Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tanaka
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Nagashima
authors.forename: Mayumi
authors.initials: M
authors.lastname: Sasaki
authors.forename: Chizumi
authors.initials: C
authors.lastname: Yamada
authors.forename: Shogo
authors.initials: S
authors.lastname: Funakoshi
authors.forename: Kimiyo
authors.initials: K
authors.lastname: Akitomo
authors.forename: Katsunobu
authors.initials: K
authors.lastname: Takenaka
authors.forename: Kouji
authors.initials: K
authors.lastname: Harada
authors.forename: Akio
authors.initials: A
authors.lastname: Koizumi
authors.forename: Nobuya
authors.initials: N
authors.lastname: Inagaki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D005091:Exons; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C485100:GCKR protein, human