Combining information from common type 2 diabetes risk polymorphisms improves disease prediction.
Combining information from common type 2 diabetes risk polymorphisms improves disease prediction.
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DOI：
10.1371/journal.pmed.0030374
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发表时间：
2006-10
期刊：
影响因子：
15.8
通讯作者：
Frayling TM
中科院分区：
文献类型：
--
作者：
Weedon MN;McCarthy MI;Hitman G;Walker M;Groves CJ;Zeggini E;Rayner NW;Shields B;Owen KR;Hattersley AT;Frayling TM
有限数量的研究在结合几种易感多态性的信息时评估了常见疾病的风险。在大多数情况下，个体多态性只会适度增加风险（约20%），并且它们被认为对临床评估个体风险没有帮助。同时分析多个等位基因的价值还没有得到很好的研究。这通常是因为，对于任何给定的疾病，很少有常见的危险等位基因得到确认。在许多大型研究中，三种常见变异（KCNJ11的Lys23， PPARG的Pro12和TCF7L2的rs7903146的T等位基因）已被证明易患2型糖尿病。在对照组中，风险等位基因频率从0.30到0.88不等。为了评估多个易感等位基因的综合影响，我们在一项大型病例对照研究中对这些变异进行了基因分型（3668例对照，2409例对照）。个体等位基因优势比（or）范围为1.14(95%可信区间[CI]， 1.05 ~ 1.23) ~ 1.48 （95% CI, 1.36 ~ 1.60）。我们没有发现基因-基因相互作用的证据，多个等位基因的风险与乘法模型一致。每增加一个风险等位基因，患2型糖尿病的几率增加1.28倍（95% CI, 1.21 - 1.35）。与没有风险等位基因的参与者相比，具有所有六个风险等位基因的参与者的OR为5.71 （95% CI， 1.15至28.3）。8.1%的TCF7L2和Pro12Ala风险等位基因双纯合的参与者的OR为3.16 (95% CI， 2.22至4.50)，而4.3%的参与者没有TCF7L2风险等位基因，没有或只有一个Glu23Lys或Pro12Ala风险等位基因。结合几个已知的常见风险多态性的信息，可以识别出与使用单一多态性获得的人群相比，患2型糖尿病风险显著不同的人群亚群。这种方法可能在未来常见的多基因疾病的预防措施中发挥作用。结合几个已知的常见风险多态性的信息，可以识别出患2型糖尿病风险显著不同的人群亚群。糖尿病是一个重要且日益普遍的全球健康问题；世界卫生组织估计，目前全球约有1.7亿人患有糖尿病。一种特殊的形式是2型糖尿病，当体内的细胞无法对一种叫做胰岛素的激素做出反应时，就会出现这种情况。胰岛素通常由胰腺释放，控制身体细胞吸收葡萄糖（糖）的能力。因此，当细胞对胰岛素变得不敏感时，就像2型糖尿病患者一样，体内的葡萄糖水平没有得到很好的控制，可能会在血液中变得危险的高。这些高水平会对身体的各个器官产生长期的破坏性影响，尤其是眼睛、神经、心脏和肾脏。有许多不同的因素会影响一个人是否可能患上2型糖尿病。这些因素大致可分为两类：环境因素和遗传因素。环境因素，如肥胖、高糖饮食和久坐不动的生活方式都是晚年患2型糖尿病的危险因素。从遗传学上讲，许多不同基因中的许多变异可能会影响患这种疾病的风险。一般来说，这些基因变异在人群中很常见，但每种基因变异只会轻微增加拥有它的人患2型糖尿病的风险。进行这项研究的研究人员想要了解不同的基因变异是如何结合起来影响个体患2型糖尿病的风险的。也就是说，如果一个人携带许多不同的变异基因，他们的总体风险是增加很多还是只增加一点点？首先，研究人员调查了已发表的报告，以确定那些有强有力证据表明与2型糖尿病相关的基因变异。他们发现了三个基因的突变，这些基因在不同的研究中被证明与2型糖尿病有关：PPARG（其产物参与脂肪组织的调节），KCNJ11（其产物参与胰岛素的产生）和TCF7L2（其产物被认为参与控制糖水平）。然后，他们比较了两组英国白人：2409名2型糖尿病患者（“病例”）和3668名普通人群（“对照组”）。研究人员对两组进行了比较，看看哪些个体拥有哪些基因变异，并进行了统计测试，以确定基因变异的特定组合在多大程度上影响了个体成为“病例”与“对照组”的机会。他们的研究结果表明，在所研究的人群中，基因变异数量不断增加会增加患糖尿病的风险。没有任何基因变异的人患2型糖尿病的风险约为2%，而所有基因变异的人患2型糖尿病的风险约为10%。这些结果表明，如果一个人拥有本研究中检测的所有基因变异，那么患2型糖尿病的风险就会更大。分析还表明，在预测未来风险时，使用所有三种变体的信息，而不是只使用一种变体的信息，可能更准确。如何将这些遗传信息与其他众所周知的预防措施（如改变生活方式）一起使用，还需要进一步研究。请通过本摘要的在线版本http://dx.doi.org/10.1371/journal.pmed.0030374访问这些网站。国民保健服务直接患者糖尿病信息国家糖尿病信息交流中心2型糖尿病信息世界卫生组织糖尿病计划疾病控制中心糖尿病公共卫生资源
A limited number of studies have assessed the risk of common diseases when combining information from several predisposing polymorphisms. In most cases, individual polymorphisms only moderately increase risk (~20%), and they are thought to be unhelpful in assessing individuals' risk clinically. The value of analyzing multiple alleles simultaneously is not well studied. This is often because, for any given disease, very few common risk alleles have been confirmed. Three common variants (Lys23 of KCNJ11, Pro12 of PPARG, and the T allele at rs7903146 of TCF7L2) have been shown to predispose to type 2 diabetes mellitus across many large studies. Risk allele frequencies ranged from 0.30 to 0.88 in controls. To assess the combined effect of multiple susceptibility alleles, we genotyped these variants in a large case-control study (3,668 controls versus 2,409 cases). Individual allele odds ratios (ORs) ranged from 1.14 (95% confidence interval [CI], 1.05 to 1.23) to 1.48 (95% CI, 1.36 to 1.60). We found no evidence of gene-gene interaction, and the risks of multiple alleles were consistent with a multiplicative model. Each additional risk allele increased the odds of type 2 diabetes by 1.28 (95% CI, 1.21 to 1.35) times. Participants with all six risk alleles had an OR of 5.71 (95% CI, 1.15 to 28.3) compared to those with no risk alleles. The 8.1% of participants that were double-homozygous for the risk alleles at TCF7L2 and Pro12Ala had an OR of 3.16 (95% CI, 2.22 to 4.50), compared to 4.3% with no TCF7L2 risk alleles and either no or one Glu23Lys or Pro12Ala risk alleles. Combining information from several known common risk polymorphisms allows the identification of population subgroups with markedly differing risks of developing type 2 diabetes compared to those obtained using single polymorphisms. This approach may have a role in future preventative measures for common, polygenic diseases. Combining information from several known common risk polymorphisms allows the identification of subgroups of the population with markedly differing risks of developing type 2 diabetes. Diabetes is an important and increasingly common global health problem; the World Health Organization has estimated that about 170 million people currently have diabetes worldwide. One particular form, type 2 diabetes, develops when cells in the body become unable to respond to a hormone called insulin. Insulin is normally released by the pancreas and controls the ability of body cells to take in glucose (sugar). Therefore, when cells become insensitive to insulin as in people with type 2 diabetes, glucose levels in the body are not well controlled and may become dangerously high in the blood. These high levels can have long-term damaging effects on various organs in the body, particularly the eyes, nerves, heart, and kidneys. There are many different factors that affect whether someone is likely to develop type 2 diabetes. These factors can be broadly grouped into two categories: environmental and genetic. Environmental factors such as obesity, a diet high in sugar, and a sedentary lifestyle are all risk factors for developing type 2 diabetes in later life. Genetically, a number of variants in many different genes may affect the risk of developing the disease. Generally, these gene variants are common in human populations but each gene variant only mildly increases the risk that a person possessing it will get type 2 diabetes. The investigators performing this study wanted to understand how different gene variants combine to affect an individual's risk of getting type 2 diabetes. That is, if a person carries many different variants, does their overall risk increase a lot or only a little? First, the researchers surveyed the published reports to identify those gene variants for which there was strong evidence of an association with type 2 diabetes. They found mutations in three genes that had been shown reproducibly to be associated with type 2 diabetes in different studies: PPARG (whose product is involved in regulation of fat tissue), KCNJ11 (whose product is involved in insulin production), and TCF7L2 (whose product is thought to be involved in controlling sugar levels). Then, they compared two groups of white people in the UK: 2,409 people with type 2 diabetes (“cases”), and 3,668 people from the general population (“controls”). The researchers compared the two groups to see which individuals possessed which gene variants, and did statistical testing to work out to what extent having particular combinations of the gene variants affected an individual's chance of being a “case” versus a “control.” Their results showed that in the groups studied, having an ever-increasing number of gene variants increased the risk of developing diabetes. The risk that someone with none of the gene variants would develop type 2 diabetes was about 2%, while the chance for someone with all gene variants was about10%. These results show that the risk of developing type 2 diabetes is greater if an individual possesses all of the gene variants that were examined in this study. The analysis also suggests that using information on all three variants, rather than just one, is likely to be more accurate in predicting future risk. How this genetic information should be used alongside other well-known preventative measures such as altered lifestyle requires further study. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030374. NHS Direct patient information on diabetes National Diabetes Information Clearinghouse information on type 2 diabetes World Health Organization Diabetes Programme Centers for Disease ControlDiabetes Public Health Resource
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