GCKR mutations in Japanese families with clustered type 2 diabetes
GCKR mutations in Japanese families with clustered type 2 diabetes
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DOI：
10.1016/j.ymgme.2010.12.009
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发表时间：
2011-04-01
影响因子：
3.8
通讯作者：
Inagaki, Nobuya
中科院分区：
文献类型：
--
作者：
Tanaka, Daisuke;Nagashima, Kazuaki;Inagaki, Nobuya
目的：探讨2型糖尿病家族聚类的遗传背景。研究对象和方法：我们招募有3代糖尿病病史的日本家庭。全基因组连锁分析假设常染色体显性模型。在连锁区域的基因被计算优先使用奋进。我们对候选基因进行了测序，然后在正常血糖控制中检测到核苷酸变化的频率。结果：为了排除已知的遗传因素，我们对10例家族病例中的6个成熟型糖尿病（MODY）基因进行了测序。由于我们在一个病例中检测到MODY3突变HNF1A R583G，我们将该病例排除在进一步的研究之外。连锁分析显示，4个家族在2p25-22位点上存在显著连锁区（LOD评分= 3.47）。23.6 mb连锁区包含106个基因。这些基因通过计算优先级进行评分。从106个基因中选出前10%的11个基因作为主要候选基因。考虑到它们的功能，我们剔除了3个特征较好的基因，最终对8个基因进行了测序。GCKR在计算优先级上排名很高。GCKR外显子和启动子突变（次要等位基因频率小于1%）在家族指数病例（18个等位基因中的3个）中出现频率高于对照组（36个等位基因中的0个，P = 0.033）。在一个有9个患病成员的家系中，突变GCKR G . 6859c >G与情感状态一致。其他7个优先级高的基因没有突变与家庭情感状况一致。结论：GCKR基因是日本聚集性糖尿病家族的易感基因。以家庭为基础的方法似乎与大规模人口研究相辅相成。(C) 2010爱思唯尔公司版权所有。
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. (C) 2010 Elsevier Inc. All rights reserved.