Identification of genetic variation that determines human trehalase activity and its association with type 2 diabetes.
Identification of genetic variation that determines human trehalase activity and its association with type 2 diabetes.
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DOI：
10.1007/s00439-013-1278-3
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发表时间：
2013-06
期刊：
影响因子：
5.3
通讯作者：
Baier, Leslie J.
中科院分区：
文献类型：
--
作者：
Muller, Yunhua L.;Hanson, Robert L.;Knowler, William C.;Fleming, Jamie;Goswami, Jayita;Huang, Ke;Traurig, Michael;Sutherland, Jeff;Wiedrich, Chris;Wiedrich, Kim;Mahkee, Darin;Ossowski, Vicky;Kobes, Sayuko;Bogardus, Clifton;Baier, Leslie J.
先前在皮马印第安人中进行的连锁扫描确定了染色体11 q23 -25上2型糖尿病（T2 D）和体重指数（BMI）的假定位点。跨该地区的关联映射确定了与T2 D相关的海藻糖酶基因（TREH）中的单核苷酸多态性（SNP）。为了评估海藻糖酶活性和T2 D之间的假定联系，我们对570名Pima印第安人的海藻糖酶活性进行了连锁研究。在TREH基因座中观察到血浆海藻糖酶活性（LOD = 7.0）连锁的强有力证据。在这些受试者中对TREH中的四个标签SNP进行了基因分型，血浆海藻糖酶活性与三个SNP高度相关：rs 2276064，rs 117619140和rs 558907（p = 2.2 × 10−11-1.4 × 10−23），第四个SNP rs 10790256与这三个SNP有条件相关（p = 2.9 × 10−7）。总之，四个标签SNP解释了血浆海藻糖酶活性的51%的方差和归因于连锁基因座的79%的方差。这四个标签SNP在828名受试者中进一步进行基因分型，用于T2 D的关联映射，rs 558907与T2 D相关（比值比（OR）1.94，p = 0.002）。为了评估T2 D相关性的复制，在两个非重叠的美洲原住民样本中对所有四个标签SNP进行额外的基因分型。在2，942名完全遗传的皮马印第安人（OR 1.27 p = 0.03）和3，897名“混合”遗传的美洲原住民（OR 1.21，p = 0.03）中，Rs 558907与T2 D可重复相关，最强有力的相关证据来自合并所有样本（OR 1.27 p = 1.6 × 10−4，n = 7，667）。然而，在320名纵向研究的受试者中，非糖尿病检查的海藻糖酶活性测量结果并不能预测最终患糖尿病的受试者与保持非糖尿病的受试者（海藻糖酶活性的风险比为0.94/SD，p = 0.29）。我们得出结论，TRH的变体控制海藻糖酶活性，尽管这些变体之一也可重复地与T2 D相关，但SNP对T2 D风险的影响可能是通过不同于影响海藻糖酶活性的机制发生的。或者，TREH变体可以标记附近的T2 D基因座。本文的在线版本（doi：10.1007/s 00439 -013-1278-3）包含补充材料，可供授权用户使用。
A prior linkage scan in Pima Indians identified a putative locus for type two diabetes (T2D) and body mass index (BMI) on chromosome 11q23-25. Association mapping across this region identified single nucleotide polymorphisms (SNPs) in the trehalase gene (TREH) that were associated with T2D. To assess the putative connection between trehalase activity and T2D, we performed a linkage study for trehalase activity in 570 Pima Indians who had measures of trehalase activity. Strong evidence of linkage of plasma trehalase activity (LOD = 7.0) was observed in the TREH locus. Four tag SNPs in TREH were genotyped in these subjects and plasma trehalase activity was highly associated with three SNPs: rs2276064, rs117619140 and rs558907 (p = 2.2 × 10−11–1.4 × 10−23), and the fourth SNP, rs10790256, was associated conditionally on these three (p = 2.9 × 10−7). Together, the four tag SNPs explained 51 % of the variance in plasma trehalase activity and 79 % of the variance attributed to the linked locus. These four tag SNPs were further genotyped in 828 subjects used for association mapping of T2D, and rs558907 was associated with T2D (odds ratio (OR) 1.94, p = 0.002). To assess replication of the T2D association, all four tag SNPs were additionally genotyped in two non-overlapping samples of Native Americans. Rs558907 was reproducibly associated with T2D in 2,942 full-heritage Pima Indians (OR 1.27 p = 0.03) and 3,897 “mixed” heritage Native Americans (OR 1.21, p = 0.03), and the strongest evidence for association came from combining all samples (OR 1.27 p = 1.6 × 10−4, n = 7,667). However, among 320 longitudinally studied subjects, measures of trehalase activity from a non-diabetic exam did not predict those who would eventually develop diabetes versus those who would remain non-diabetic (hazard ratio 0.94 per SD of trehalase activity, p = 0.29). We conclude that variants in TREH control trehalase activity, and although one of these variants is also reproducibly associated with T2D, it is likely that the effect of the SNP on risk of T2D occurs by a mechanism different than affecting trehalase activity. Alternatively, TREH variants may be tagging a nearby T2D locus. The online version of this article (doi:10.1007/s00439-013-1278-3) contains supplementary material, which is available to authorized users.
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