Johansen A, Jensen D P, Bergholdt R, Mortensen H B, Pociot F, Nerup J, Hansen T, Pedersen O
Steno Diabetes Center and Hagedorn Research Institute, Gentofte, Copenhagen, Denmark.
Diabetes Obes Metab. 2006 Jan;8(1):75-82. doi: 10.1111/j.1463-1326.2005.00471.x.
Type 1 diabetes mellitus (T1DM) is a chronic disorder primarily triggered by environmental and immunological factors in genetically susceptible individuals. Despite the fact that there are indications of common aetiological features of T1DM and type 2 diabetes (T2DM), variation in genes involved in insulin secretion and insulin signalling has to a large extent been ignored as potential modifiers in the pathogenesis of T1DM. Recent studies suggest, however, that proven T2DM susceptibility gene variants may be involved in the pathogenesis of T1DM. The objective of this study was to estimate the impact of four selected amino acid polymorphisms -IRS-1 Gly972Arg, Kir6.2 Glu23Lys, HNF-1alpha Ala98Val and PPARgamma2 Pro12Ala in a Danish population of T1DM families.
All variants were genotyped in 490 simplex- and multiplex-T1DM families applying polymerase chain reaction-restriction fragment length polymorphism, and results were evaluated by means of a transmission disequilibrium test (TDT) analysis.
TDT analysis revealed that the Arg972 IRS-1, the Lys23 Kir6.2 and the Val98 HNF-1alpha variants were transmitted from heterozygous parents to affected probands at frequencies of 49.1%, 47.0% and 54.1%, respectively (p > 0.05 for all). This was similar to the rate of transmission to unaffected siblings. The transmission rate of the Ala12 PPARgamma2 variant to affected probands was 46.5% (p > 0.05) which differed significantly from the transmission to unaffected offspring (p = 0.024). A combined analysis of the present and published pertinent data of 1691 transmissions showed a significantly decreased transmission of the PPARgamma2 Ala12 allele to affected probands (p = 0.0045).
The Pro12Ala variant of PPARgamma2 is associated with T1DM, the minor Ala allele conferring a reduced risk. This same finding has been reported in patients with T2DM.
1型糖尿病（T1DM）是一种主要由环境和免疫因素在遗传易感个体中引发的慢性疾病。尽管有迹象表明T1DM和2型糖尿病（T2DM）存在共同的病因特征，但胰岛素分泌和胰岛素信号传导相关基因的变异在很大程度上被忽视，未被视为T1DM发病机制中的潜在调节因素。然而，最近的研究表明，已证实的T2DM易感基因变异可能参与T1DM的发病机制。本研究的目的是评估丹麦T1DM家系群体中四个选定的氨基酸多态性——胰岛素受体底物-1（IRS-1）基因Gly972Arg、内向整流钾离子通道蛋白6.2（Kir6.2）基因Glu23Lys、肝细胞核因子-1α（HNF-1α）基因Ala98Val和过氧化物酶体增殖物激活受体γ2（PPARγ2）基因Pro12Ala的影响。
采用聚合酶链反应-限制性片段长度多态性方法对490个单亲和多重T1DM家系中的所有变异进行基因分型，并通过传递不平衡检验（TDT）分析评估结果。
TDT分析显示，IRS-1基因的Arg972、Kir6.2基因的Lys23和HNF-1α基因的Val98变异分别以49.1%、47.0%和54.1%的频率从杂合子父母传递给患病先证者（所有p>0.05）。这与传递给未患病同胞的频率相似。PPARγ2基因Ala12变异传递给患病先证者的频率为46.5%（p>0.05），这与传递给未患病后代的频率有显著差异（p=0.024）。对本研究和已发表的1691次传递的相关数据进行综合分析显示PPARγ2基因Ala12等位基因传递给患病先证者的频率显著降低（p=0.0045）。
PPARγ2基因的Pro12Ala变异与TIDM相关，次要的Ala等位基因降低患病风险。在T2DM患者中也报道了同样的发现。
