前蛋白转化酶枯草溶菌素1（PCSK1）常见非同义变异对体重指数变化及肥胖风险的贡献：一项基于多达331175例个体证据的系统评价和荟萃分析

Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331 175 individuals.

作者信息

Nead Kevin T, Li Aihua, Wehner Mackenzie R, Neupane Binod, Gustafsson Stefan, Butterworth Adam, Engert James C, Davis A Darlene, Hegele Robert A, Miller Ruby, den Hoed Marcel, Khaw Kay-Tee, Kilpeläinen Tuomas O, Wareham Nick, Edwards Todd L, Hallmans Göran, Varga Tibor V, Kardia Sharon L R, Smith Jennifer A, Zhao Wei, Faul Jessica D, Weir David, Mi Jie, Xi Bo, Quinteros Samuel Canizales, Cooper Cyrus, Sayer Avan Aihie, Jameson Karen, Grøntved Anders, Fornage Myriam, Sidney Stephen, Hanis Craig L, Highland Heather M, Häring Hans-Ulrich, Heni Martin, Lasky-Su Jessica, Weiss Scott T, Gerhard Glenn S, Still Christopher, Melka Melkaey M, Pausova Zdenka, Paus Tomáš, Grant Struan F A, Hakonarson Hakon, Price R Arlen, Wang Kai, Scherag Andre, Hebebrand Johannes, Hinney Anke, Franks Paul W, Frayling Timothy M, McCarthy Mark I, Hirschhorn Joel N, Loos Ruth J, Ingelsson Erik, Gerstein Hertzel C, Yusuf Salim, Beyene Joseph, Anand Sonia S, Meyre David

机构信息

Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.

Department of Clinical Epidemiology and Biostatistics.

出版信息

Hum Mol Genet. 2015 Jun 15;24(12):3582-94. doi: 10.1093/hmg/ddv097. Epub 2015 Mar 17.

DOI:10.1093/hmg/ddv097

PMID:25784503

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4498155/

Abstract

Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) ≥ 40 kg/m(2)], but their contribution to common obesity (BMI ≥ 30 kg/m(2)) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CIs) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR = 1.15, 95% CI 1.06-1.24, P = 6.08 × 10(-6)) and rs6234/rs6235 (OR = 1.07, 95% CI 1.04-1.10, P = 3.00 × 10(-7)). Similarly, significant associations were found with continuous BMI for rs6232 (β = 0.03, 95% CI 0.00-0.07; P = 0.047) and rs6234/rs6235 (β = 0.02, 95% CI 0.00-0.03; P = 5.57 × 10(-4)). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology.

摘要

前蛋白转化酶枯草溶菌素1（PCSK1）基因中的rs6232和rs6234/rs6235多态性与极端肥胖[如体重指数（BMI）≥40kg/m²]相关，但其在多民族背景下对常见肥胖（BMI≥30kg/m²）及BMI变异的影响尚不清楚。为填补这一空白，我们收集了多达331175名不同种族个体的表型和基因数据。这一过程包括对PubMed、科学网、Embase和美国国立卫生研究院全基因组关联研究（GWAS）目录中的文献进行系统综述，并从联合体和单项研究中已有的GWAS或定制阵列中提取数据作为补充。我们采用最近开发的全球荟萃分析随机效应方法，分别计算肥胖状态和BMI分析的汇总比值比（OR）及95%置信区间（CI），或β估计值和标准误（SE）。发现rs6232（OR = 1.15，95%CI 1.06 - 1.24，P = 6.08×10⁻⁶）和rs6234/rs6235（OR = 1.07，95%CI 1.04 - 1.10，P = 3.00×10⁻⁷）与二元肥胖状态存在显著关联。同样，发现rs6232（β = 0.03，95%CI 0.00 - 0.07；P = 0.047）和rs6234/rs6235（β = 0.02，95%CI 0.00 - 0.03；P = 5.57×10⁻⁴）与连续性BMI存在显著关联。种族、年龄和研究确定方法显著调节了PCSK1多态性与肥胖的关联。总之，在遗传流行病学领域迄今为止发表的最大规模已知荟萃分析中，我们证明了PCSK1常见基因变异对BMI变异及常见肥胖易感性有影响的证据。