Polymorphisms in the gene encoding the voltage-dependent Ca2+ channel CaV2.3 (CACNA1E) are associated with type 2 diabetes and impaired insulin secretion
Polymorphisms in the gene encoding the voltage-dependent Ca2+ channel CaV2.3 (CACNA1E) are associated with type 2 diabetes and impaired insulin secretion
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DOI：
10.1007/s00125-007-0846-2
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发表时间：
2007-12-01
期刊：
影响因子：
8.2
通讯作者：
Groop, L.
中科院分区：
文献类型：
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作者：
Holmkvist, J.;Tojjar, D.;Groop, L.
目的/假设 葡萄糖刺激的胰岛素分泌取决于 β 细胞的电活动；因此，编码β细胞离子通道的基因是2型糖尿病的潜在候选基因。编码电压依赖性 Ca2+ 通道 Ca(V)2.3 (CACNA1E) 的基因，其端粒区域与 2 型糖尿病 (1q21-q25) 存在暗示性联系，已被认为在第二阶段胰岛素分泌中发挥作用。 方法基于 52 个单倍型标记单核苷酸多态性 (SNP) 的基因分型 在 2 型糖尿病病例对照样本（n = 1,467）中，我们选择了 5 个名义上与 2 型糖尿病相关的 SNP，并将其分为以下几组：（1）来自瑞典的 6,570 名新病例对照样本； (2) Botnia 前瞻性队列中的 2,293 名个体； (3) 935 名具有 IVGTT 胰岛素分泌数据的个体。结果 rs679931 TT 基因型与 (1) Botnia 病例对照样本 [比值比 (OR) 1.4, 95% CI 1.0 - 2.0, p= 0.06] 和复制样本 (OR 1.2, 95% CI) 中 2 型糖尿病风险增加相关。 1.0-1.5， p= 0.01 单尾），合并 OR 为 1.3（95% CI 1.1-1.5，p= 0.004 双尾）； (2) OGTT 期间对照参与者的胰岛素分泌减少 [30 分钟胰岛素生成指数 p= 0.02，处置指数 (D-I) p= 0.03]； (3) IVGTT 期间 30 分钟 (p= 0.04) 和 60 分钟 (p= 0.02) 时第二相胰岛素分泌减少； (4) Botnia 前瞻性队列中 DI 随着时间的推移而减少 (p= 0.05)。 结论/解释 我们得出的结论是，CACNA1E 基因的遗传变异通过减少胰岛素分泌而导致患 2 型糖尿病的风险增加。
Aims/hypothesis Glucose-stimulated insulin secretion is dependent on the electrical activity of beta cells; hence, genes encoding beta cell ion channels are potential candidate genes for type 2 diabetes. The gene encoding the voltage-dependent Ca2+ channel Ca(V)2.3 (CACNA1E), telomeric to a region that has shown suggestive linkage to type 2 diabetes (1q21-q25), has been ascribed a role for second-phase insulin secretion.Methods Based upon the genotyping of 52 haplotype tagging single nucleotide polymorphisms (SNPs) in a type 2 diabetes case - control sample (n= 1,467), we selected five SNPs that were nominally associated with type 2 diabetes and genotyped them in the following groups (1) a new case - control sample of 6,570 individuals from Sweden; (2) 2,293 individuals from the Botnia prospective cohort; and (3) 935 individuals with insulin secretion data from an IVGTT.Results The rs679931 TT genotype was associated with (1) an increased risk of type 2 diabetes in the Botnia case - control sample [odds ratio (OR) 1.4, 95% CI 1.0 - 2.0, p= 0.06] and in the replication sample (OR 1.2, 95% CI 1.0-1.5, p= 0.01 one-tailed), with a combined OR of 1.3 (95% CI 1.1-1.5, p= 0.004 two-tailed); (2) reduced insulin secretion [insulinogenic index at 30 min p= 0.02, disposition index (D-I) p= 0.03] in control participants during an OGTT; ( 3) reduced second-phase insulin secretion at 30 min (p= 0.04) and 60 min (p= 0.02) during an IVGTT; and ( 4) reduced DI over time in the Botnia prospective cohort (p= 0.05).Conclusions/ interpretation We conclude that genetic variation in the CACNA1E gene contributes to an increased risk of the development of type 2 diabetes by reducing insulin secretion.