Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion
Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion
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DOI：
10.1007/s00125-008-0926-y
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发表时间：
2008-04-01
期刊：
影响因子：
8.2
通讯作者：
Fritsche, A.
中科院分区：
文献类型：
--
作者：
Kirchhoff, K.;Machicao, F.;Fritsche, A.
目的/假设六个新的遗传基因座内的变异已被报道赋予2型糖尿病的风险，并可能与β细胞功能障碍有关。方法我们对1,065名德国参与者进行基因分型，检测TCF 7 L2中的单核苷酸多态性rs7903146，CDKAL 1中的rs7754840，HHEX中的rs7923837和rs 1111875，SLC 30 A8中的rs 13266634，CDKN 2 A/B中的rs 10811661和IGF 2 BP 2中的rs 4402960。所有参与者都接受了OGTT。在OGTT期间的0、30、60、90和120分钟测量胰岛素、胰岛素原和C肽浓度。在OGTT期间使用经验证的指数从C肽或胰岛素水平估计胰岛素分泌。结果在我们的队列中，我们证实了TCF 7 L2、CDKAL 1和HHEX变异与OGTT期间胰岛素分泌减少显著相关（p < 0.05）。SLC 30 A8、CDKN 2 A/B和IGF 2 BP 2的变异与胰岛素分泌无关。TCF 7 L2、CDKAL 1和SLC 30 A8中变异体的危险等位基因降低胰岛素原向胰岛素的转化（所有p < 0.05），而HHEX、CDKN 2 A/B和IGF 2 BP 2中的危险等位基因与降低的胰岛素原向胰岛素的转化无关（p > 0.6）。然而，β细胞功能的两个方面不一定相关，因为受损的胰岛素分泌特异性地存在于HHEX的变体中，并且受损的胰岛素原转化特异性地存在于SLC 30 A8的变体中。
Aims/hypothesis Variation within six novel genetic loci has been reported to confer risk of type 2 diabetes and may be associated with beta cell dysfunction. We investigated whether these polymorphisms are also associated with impaired proinsulin to insulin conversion.Methods We genotyped 1,065 German participants for single nucleotide polymorphisms rs7903146 in TCF7L2, rs7754840 in CDKAL1, rs7923837 and rs1111875 in HHEX, rs13266634 in SLC30A8, rs10811661 in CDKN2A/B and rs4402960 in IGF2BP2. All participants underwent an OGTT. Insulin, proinsulin and C-peptide concentrations were measured at 0, 30, 60, 90 and 120 min during the OGTT. Insulin secretion was estimated from C-peptide or insulin levels during the OGTT using validated indices. We used the ratio proinsulin/insulin during the OGTT as indicator of proinsulin conversion.Results In our cohort, we confirmed the significant association of variants in TCF7L2, CDKAL1 and HHEX with reduced insulin secretion during the OGTT (p < 0.05 for all). Variation in SLC30A8, CDKN2A/B and IGF2BP2 was not associated with insulin secretion. The risk alleles of the variants in TCF7L2, CDKAL1 and SLC30A8 reduced proinsulin to insulin conversion (p < 0.05 for all), whereas the risk alleles in HHEX, CDKN2A/B and IGF2BP2 were not associated with reduced proinsulin to insulin conversion (p > 0.6).Conclusions/Interpretation Diabetes-associated variants in TCF7L2 and CDKAL1 impair insulin secretion and conversion of proinsulin to insulin. However, both aspects of beta cell function are not necessarily linked, as impaired insulin secretion is specifically present in variants of HHEX and impaired proinsulin conversion is specifically present in a variant of SLC30A8.