Yoneyama Sachiko, Guo Yiran, Lanktree Matthew B, Barnes Michael R, Elbers Clara C, Karczewski Konrad J, Padmanabhan Sandosh, Bauer Florianne, Baumert Jens, Beitelshees Amber, Berenson Gerald S, Boer Jolanda M A, Burke Gregory, Cade Brian, Chen Wei, Cooper-Dehoff Rhonda M, Gaunt Tom R, Gieger Christian, Gong Yan, Gorski Mathias, Heard-Costa Nancy, Johnson Toby, Lamonte Michael J, McDonough Caitrin, Monda Keri L, Onland-Moret N Charlotte, Nelson Christopher P, O'Connell Jeffrey R, Ordovas Jose, Peter Inga, Peters Annette, Shaffer Jonathan, Shen Haiqinq, Smith Erin, Speilotes Liz, Thomas Fridtjof, Thorand Barbara, Monique Verschuren W M, Anand Sonia S, Dominiczak Anna, Davidson Karina W, Hegele Robert A, Heid Iris, Hofker Marten H, Huggins Gordon S, Illig Thomas, Johnson Julie A, Kirkland Susan, König Wolfgang, Langaee Taimour Y, McCaffery Jeanne, Melander Olle, Mitchell Braxton D, Munroe Patricia, Murray Sarah S, Papanicolaou George, Redline Susan, Reilly Muredach, Samani Nilesh J, Schork Nicholas J, Van Der Schouw Yvonne T, Shimbo Daichi, Shuldiner Alan R, Tobin Martin D, Wijmenga Cisca, Yusuf Salim, Hakonarson Hakon, Lange Leslie A, Demerath Ellen W, Fox Caroline S, North Kari E, Reiner Alex P, Keating Brendan, Taylor Kira C
Gillings School of Global Public Health.
Hum Mol Genet. 2014 May 1;23(9):2498-510. doi: 10.1093/hmg/ddt626. Epub 2013 Dec 17.
Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (β ± SE, 0.048 ± 0.008, P = 7.7 × 10(-9)) as was rs7302703-G in HOXC10 (β = 0.044 ± 0.008, P = 2.9 × 10(-7)) and rs936108-C in PEMT (β = 0.035 ± 0.007, P = 1.9 × 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (β = 0.10 ± 0.02, P = 1.9 × 10(-6)) and rs1037575-A in ATBDB4 (β = 0.046 ± 0.01, P = 2.2 × 10(-6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.
腰围（WC）和腰臀比（WHR）是中心性肥胖的替代指标，与不良心血管事件、2型糖尿病和癌症相关，且独立于体重指数（BMI）。WC和WHR具有高度遗传性，迄今已确定多个易感基因座。我们在与美国国立心肺血液研究所候选基因关联资源（CARe）项目合作的22个队列中，对多达57412名欧洲血统个体进行了单核苷酸多态性（SNP）与BMI校正后的WC和WHR以及未校正的WC之间的关联评估。研究人群包括年龄在20至80岁之间的男性和女性。研究参与者使用ITMAT/布罗德/CARE芯片进行基因分型，该芯片包含约2100个心血管相关基因中的约50000个全球标签SNP。每个性状被建模为年龄、研究地点和主成分的函数，以控制人群分层，我们进行了固定效应荟萃分析。未观察到WC的新基因座。对于WHR分析，三个新基因座显著相关（P < 2.4 × 10⁻⁶）。此前未报告的TMCC1附近的rs2811337 - G与WHR增加相关（β ± SE，0.048 ± 0.008，P = 7.7 × 10⁻⁹），HOXC10中的rs7302703 - G（β = 0.044 ± 0.008，P = 2.9 × 10⁻⁷）和PEMT中的rs936108 - C（β = 0.035 ± 0.007，P = 1.9 × 10⁻⁶）也与之相关。按性别分层分析仅在女性中发现另外两个新信号，SHC1中的rs12076073 - A（β = 0.10 ± 0.02，P = 1.9 × 10⁻⁶）和ATBDB4中的rs1037575 - A（β = 0.046 ± 0.01，P = 2.2 × 10⁻⁶），支持了中心性肥胖相关基因变异已确立的性别二态性。使用ENCODE和表达定量性状基因座（eQTL）数据库进行的功能分析表明，这些基因座中的几个位于脂肪组织的调控区域或具有差异表达的区域。
