Mendelian randomization study of B-type natriuretic peptide and type 2 diabetes: evidence of causal association from population studies.
Mendelian randomization study of B-type natriuretic peptide and type 2 diabetes: evidence of causal association from population studies.
复制标题
Mendelian随机研究B型纳地钠肽和2型糖尿病：人群研究的因果关系证据。
DOI：
10.1371/journal.pmed.1001112
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发表时间：
2011-10
期刊：
影响因子：
15.8
通讯作者：
Wareham NJ
中科院分区：
文献类型：
--
作者：
Pfister R;Sharp S;Luben R;Welsh P;Barroso I;Salomaa V;Meirhaeghe A;Khaw KT;Sattar N;Langenberg C;Wareham NJ
通过孟德尔随机化，Roman Pfister和他的同事们证明了低水平的b型利钠肽（一种由受损心脏释放的激素）和2型糖尿病之间存在潜在的因果关系。遗传和流行病学证据表明，血液中b型利钠肽（BNP）水平与2型糖尿病（T2D）的风险呈负相关，但BNP与T2D的前瞻性关联尚不确定，也不清楚这种关联是否存在混淆。在一项前瞻性病例队列研究中，我们分析了血液中亲BNP n端片段（NT-pro-BNP）水平与T2D发生风险之间的关系，并在三项T2D病例对照研究中对BNP位点内的变异rs198389进行了基因分型。我们将我们的结果与11项病例对照研究的荟萃分析中的现有数据相结合。采用孟德尔随机化方法，我们比较了rs198389与T2D之间观察到的关联、NT-pro-BNP水平与T2D之间的关联以及rs198389每个C等位基因的NT-pro-BNP差异。在我们的病例队列研究中，基线时无T2D和心血管疾病的参与者中，我们观察到每一个标准差（SD）的log-transformed nt -前bnp水平升高21% (95% CI 3%-36%)，在分析中调整了年龄、性别、体重指数、收缩压、吸烟、T2D家族史、高血压史、甘油三酯、高密度脂蛋白胆固醇和低密度脂蛋白胆固醇的水平。病例对照研究中观察到的rs198389与T2D之间的相关性（比值比= 0.94 / C等位基因，95% CI 0.91-0.97）与基于本研究和已发表数据的荟萃分析得出的log-NT-pro-BNP水平与T2D相关性的汇总估计（风险比= 0.82 / SD, 0.74-0.90）和rs198389每个C等位基因NT-pro-BNP水平差异（0.22 SD, 0.15-0.29）的预期（0.96,0.93-0.98）相似。rs198389基因型与潜在混杂因素无显著相关性。我们的结果为BNP系统在T2D病因学中的潜在因果作用提供了证据。需要进一步的研究来调查这种关联的机制和预防性干预的可能性。全球有近2.5亿人患有糖尿病，而且这个数字还在迅速增加。糖尿病的特点是血液中的糖（葡萄糖）含量达到危险水平。血糖水平通常由胰岛素控制，胰岛素是胰腺在饭后释放的一种激素（食物的消化会产生葡萄糖）。在2型糖尿病（最常见的糖尿病）患者中，血糖控制失败是因为脂肪和肌肉细胞通常通过从血液中去除糖来对胰岛素做出反应，从而产生胰岛素抵抗。2型糖尿病可以通过饮食和锻炼来控制，并使用帮助胰腺产生更多胰岛素或使细胞对胰岛素更敏感的药物。糖尿病的长期并发症包括肾衰竭和心血管疾病（如心脏病和中风）的风险增加，与没有糖尿病的人相比，糖尿病患者的预期寿命减少了大约10年。由于对2型糖尿病的病因了解甚少，因此很难设计出预防这种疾病的方法。最近，在横断面研究中，b型利钠肽（BNP，一种由受损心脏释放的激素）与2型糖尿病的发展有关（在人群中收集单个时间点的数据以寻找疾病与潜在危险因素之间的关联的调查）。尽管这些研究表明高水平的BNP可以预防2型糖尿病，但它们不能证明BNP水平与糖尿病之间的因果关系，因为低BNP水平的研究参与者可能有另一个未知因素（一个混杂因素），这是糖尿病和BNP水平改变的真正原因。在这里，研究人员使用一种称为“孟德尔随机化”的方法来检查BNP水平降低是否会导致2型糖尿病。众所周知，基因组区域中编码BNP的常见遗传变异（rs198389）与2型糖尿病风险降低有关。因为基因变异是随机遗传的，所以不会产生混淆。因此，通过研究改变NT-pro-BNP （BNP产生时产生的一种分子）水平的BNP基因变异与2型糖尿病发展之间的关系，研究人员可以发现BNP是否与这种慢性疾病有因果关系。研究人员分析了440名EPIC-Norfolk研究（一项基于前瞻性人群的生活方式因素和慢性疾病风险研究）参与者和740名未患糖尿病的参与者在基线时血液中NT-pro-BNP水平之间的关系。在这项前瞻性病例队列研究中，发生2型糖尿病的风险与较低的NT-pro-BNP水平相关。他们还对3个2型糖尿病病例对照研究参与者的rs198389基因进行了分型（测序）（这些研究在2型糖尿病患者和生活在英格兰东部的匹配对照人群中检查了2型糖尿病的潜在危险因素），并将这些结果与8个类似的已发表的病例对照研究相结合。最后，研究人员表明，病例对照研究中测量的rs198389与2型糖尿病之间的关联与前瞻性病例队列研究中NT-pro-BNP水平与2型糖尿病之间的关联以及EPIC-Norfolk研究和其他已发表研究中rs198389与BNP水平之间的关联计算的预期关联相似。这项孟德尔随机化研究的结果为BNP激素系统在2型糖尿病发展中的因果保护作用提供了证据。也就是说，这些发现表明低水平的BNP是2型糖尿病发展的部分原因。由于本分析中所有个体研究的参与者都是欧洲血统，因此这些发现可能无法推广到其他种族。此外，他们没有解释BNP激素系统的改变如何影响2型糖尿病的发展。然而，BNP激素系统与2型糖尿病之间的因果关系表明，BNP可能是预防2型糖尿病干预措施的潜在目标，特别是在心血管疾病患者中已经证实用药物改变BNP水平的可行性。请通过本摘要的在线版本（http://dx.doi.org/10.1371/journal.pmed.1001112）访问这些网站。国际糖尿病联合会提供有关糖尿病各方面的信息，美国国家糖尿病信息交换所为患者、卫生保健专业人员、英国国家健康服务选择网站也为患者和护理人员提供关于2型糖尿病的信息，包括人们关于糖尿病的故事。MedlinePlus提供关于糖尿病的更多资源和建议的链接（英语和西班牙语）。维基百科有关于BNP和孟德尔随机化的页面(注：维基百科是一个免费的在线百科全书，任何人都可以编辑；慈善机构Healthtalkonline对人们进行了采访，了解他们的糖尿病经历；英国糖尿病慈善机构还有更多糖尿病患者的故事
Using mendelian randomization, Roman Pfister and colleagues demonstrate a potentially causal link between low levels of B-type natriuretic peptide (BNP), a hormone released by damaged hearts, and the development of type 2 diabetes. Genetic and epidemiological evidence suggests an inverse association between B-type natriuretic peptide (BNP) levels in blood and risk of type 2 diabetes (T2D), but the prospective association of BNP with T2D is uncertain, and it is unclear whether the association is confounded. We analysed the association between levels of the N-terminal fragment of pro-BNP (NT-pro-BNP) in blood and risk of incident T2D in a prospective case-cohort study and genotyped the variant rs198389 within the BNP locus in three T2D case-control studies. We combined our results with existing data in a meta-analysis of 11 case-control studies. Using a Mendelian randomization approach, we compared the observed association between rs198389 and T2D to that expected from the NT-pro-BNP level to T2D association and the NT-pro-BNP difference per C allele of rs198389. In participants of our case-cohort study who were free of T2D and cardiovascular disease at baseline, we observed a 21% (95% CI 3%–36%) decreased risk of incident T2D per one standard deviation (SD) higher log-transformed NT-pro-BNP levels in analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking, family history of T2D, history of hypertension, and levels of triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. The association between rs198389 and T2D observed in case-control studies (odds ratio = 0.94 per C allele, 95% CI 0.91–0.97) was similar to that expected (0.96, 0.93–0.98) based on the pooled estimate for the log-NT-pro-BNP level to T2D association derived from a meta-analysis of our study and published data (hazard ratio = 0.82 per SD, 0.74–0.90) and the difference in NT-pro-BNP levels (0.22 SD, 0.15–0.29) per C allele of rs198389. No significant associations were observed between the rs198389 genotype and potential confounders. Our results provide evidence for a potential causal role of the BNP system in the aetiology of T2D. Further studies are needed to investigate the mechanisms underlying this association and possibilities for preventive interventions. Please see later in the article for the Editors' Summary Worldwide, nearly 250 million people have diabetes, and this number is increasing rapidly. Diabetes is characterized by dangerous amounts of sugar (glucose) in the blood. Blood sugar levels are normally controlled by insulin, a hormone that the pancreas releases after meals (digestion of food produces glucose). In people with type 2 diabetes (the most common form of diabetes), blood sugar control fails because the fat and muscle cells that usually respond to insulin by removing sugar from the blood become insulin resistant. Type 2 diabetes can be controlled with diet and exercise, and with drugs that help the pancreas make more insulin or that make cells more sensitive to insulin. The long-term complications of diabetes, which include kidney failure and an increased risk of cardiovascular problems such as heart disease and stroke, reduce the life expectancy of people with diabetes by about 10 years compared to people without diabetes. Because the causes of type 2 diabetes are poorly understood, it is hard to devise ways to prevent the condition. Recently, B-type natriuretic peptide (BNP, a hormone released by damaged hearts) has been implicated in type 2 diabetes development in cross-sectional studies (investigations in which data are collected at a single time point from a population to look for associations between an illness and potential risk factors). Although these studies suggest that high levels of BNP may protect against type 2 diabetes, they cannot prove a causal link between BNP levels and diabetes because the study participants with low BNP levels may share some another unknown factor (a confounding factor) that is the real cause of both diabetes and altered BNP levels. Here, the researchers use an approach called “Mendelian randomization” to examine whether reduced BNP levels contribute to causing type 2 diabetes. It is known that a common genetic variant (rs198389) within the genome region that encodes BNP is associated with a reduced risk of type 2 diabetes. Because gene variants are inherited randomly, they are not subject to confounding. So, by investigating the association between BNP gene variants that alter NT-pro-BNP (a molecule created when BNP is being produced) levels and the development of type 2 diabetes, the researchers can discover whether BNP is causally involved in this chronic condition. The researchers analyzed the association between blood levels of NT-pro-BNP at baseline in 440 participants of the EPIC-Norfolk study (a prospective population-based study of lifestyle factors and the risk of chronic diseases) who subsequently developed diabetes and in 740 participants who did not develop diabetes. In this prospective case-cohort study, the risk of developing type 2 diabetes was associated with lower NT-pro-BNP levels. They also genotyped (sequenced) rs198389 in the participants of three case-control studies of type 2 diabetes (studies in which potential risk factors for type 2 diabetes were examined in people with type 2 diabetes and matched controls living in the East of England), and combined these results with those of eight similar published case-control studies. Finally, the researchers showed that the association between rs198389 and type 2 diabetes measured in the case-control studies was similar to the expected association calculated from the association between NT-pro-BNP level and type 2 diabetes obtained from the prospective case-cohort study and the association between rs198389 and BNP levels obtained from the EPIC-Norfolk study and other published studies. The results of this Mendelian randomization study provide evidence for a causal, protective role of the BNP hormone system in the development of type 2 diabetes. That is, these findings suggest that low levels of BNP are partly responsible for the development of type 2 diabetes. Because the participants in all the individual studies included in this analysis were of European descent, these findings may not be generalizable to other ethnicities. Moreover, they provide no explanation of how alterations in the BNP hormone system might affect the development of type 2 diabetes. Nevertheless, the demonstration of a causal link between the BNP hormone system and type 2 diabetes suggests that BNP may be a potential target for interventions designed to prevent type 2 diabetes, particularly since the feasibility of altering BNP levels with drugs has already been proven in patients with cardiovascular disease. Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001112. The International Diabetes Federation provides information about all aspects of diabetes The US National Diabetes Information Clearinghouse provides detailed information about diabetes for patients, health-care professionals, and the general public (in English and Spanish) The UK National Health Service Choices website also provides information for patients and carers about type 2 diabetes and includes people's stories about diabetes MedlinePlus provides links to further resources and advice about diabetes (in English and Spanish) Wikipedia has pages on BNP and on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages) The charity Healthtalkonline has interviews with people about their experiences of diabetes; the charity Diabetes UK has a further selection of stories from people with diabetes
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影响因子：
168.9
作者：
Tabak, Adam G.;Jokela, Markus;Akbaraly, Tasnime N.;Brunner, Eric J.;Kivimaki, Mika;Witte, Daniel R.
通讯作者：
Witte, Daniel R.
影响因子：
7.7
作者：
Miyashita K;Itoh H;Tsujimoto H;Tamura N;Fukunaga Y;Sone M;Yamahara K;Taura D;Inuzuka M;Sonoyama T;Nakao K
通讯作者：
Nakao K
影响因子：
--
作者：
Soriano, Sergi;Ropero, Ana B.;Nadal, Angel
通讯作者：
Nadal, Angel
影响因子：
2.8
作者：
Chainani-Wu, Nita;Weidner, Gerdi;Ornish, Dean
通讯作者：
Ornish, Dean
影响因子：
3.7
作者：
Salomaa V;Havulinna A;Saarela O;Zeller T;Jousilahti P;Jula A;Muenzel T;Aromaa A;Evans A;Kuulasmaa K;Blankenberg S
通讯作者：
Blankenberg S