非洲和欧洲裔人群多发性骨髓瘤风险区域的荟萃分析确定了可能具有功能的基因座。
A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci.
作者信息
Rand Kristin A, Song Chi, Dean Eric, Serie Daniel J, Curtin Karen, Sheng Xin, Hu Donglei, Huff Carol Ann, Bernal-Mizrachi Leon, Tomasson Michael H, Ailawadhi Sikander, Singhal Seema, Pawlish Karen, Peters Edward S, Bock Cathryn H, Stram Alex, Van Den Berg David J, Edlund Christopher K, Conti David V, Zimmerman Todd, Hwang Amie E, Huntsman Scott, Graff John, Nooka Ajay, Kong Yinfei, Pregja Silvana L, Berndt Sonja I, Blot William J, Carpten John, Casey Graham, Chu Lisa, Diver W Ryan, Stevens Victoria L, Lieber Michael R, Goodman Phyllis J, Hennis Anselm J M, Hsing Ann W, Mehta Jayesh, Kittles Rick A, Kolb Suzanne, Klein Eric A, Leske Cristina, Murphy Adam B, Nemesure Barbara, Neslund-Dudas Christine, Strom Sara S, Vij Ravi, Rybicki Benjamin A, Stanford Janet L, Signorello Lisa B, Witte John S, Ambrosone Christine B, Bhatti Parveen, John Esther M, Bernstein Leslie, Zheng Wei, Olshan Andrew F, Hu Jennifer J, Ziegler Regina G, Nyante Sarah J, Bandera Elisa V, Birmann Brenda M, Ingles Sue A, Press Michael F, Atanackovic Djordje, Glenn Martha J, Cannon-Albright Lisa A, Jones Brandt, Tricot Guido, Martin Thomas G, Kumar Shaji K, Wolf Jeffrey L, Deming Halverson Sandra L, Rothman Nathaniel, Brooks-Wilson Angela R, Rajkumar S Vincent, Kolonel Laurence N, Chanock Stephen J, Slager Susan L, Severson Richard K, Janakiraman Nalini, Terebelo Howard R, Brown Elizabeth E, De Roos Anneclaire J, Mohrbacher Ann F, Colditz Graham A, Giles Graham G, Spinelli John J, Chiu Brian C, Munshi Nikhil C, Anderson Kenneth C, Levy Joan, Zonder Jeffrey A, Orlowski Robert Z, Lonial Sagar, Camp Nicola J, Vachon Celine M, Ziv Elad, Stram Daniel O, Hazelett Dennis J, Haiman Christopher A, Cozen Wendy
机构信息
Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
Sutter Health, Oakland, California.
出版信息
Cancer Epidemiol Biomarkers Prev. 2016 Dec;25(12):1609-1618. doi: 10.1158/1055-9965.EPI-15-1193. Epub 2016 Sep 1.
BACKGROUND
Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma.
METHODS
We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality.
RESULTS
We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry-European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4 Correlated variants in 7p15.3 clustered around an enhancer at the 3' end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-κB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7 CONCLUSIONS: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles.
IMPACT
A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional. Cancer Epidemiol Biomarkers Prev; 25(12); 1609-18. ©2016 AACR.
背景
欧洲人群的全基因组关联研究（GWAS）已鉴定出与多发性骨髓瘤相关的遗传风险变异。
方法
我们对1318例欧洲血统的多发性骨髓瘤患者和1480例对照，以及1305例非洲血统的多发性骨髓瘤患者和7078例对照的8个区域的常见变异进行了关联测试，并进行了荟萃分析以定位信号，使用表观遗传注释来预测功能。
结果
我们发现，7p15.3、17p11.2、22q13.1中的变异在非洲血统和欧洲血统的人群中与多发性骨髓瘤风险存在统计学显著关联（P<0.05），而3p22.1中的变异仅在欧洲血统人群中有关联。在非洲血统-欧洲血统的联合荟萃分析中，五个区域（2p23.3、3p22.1、7p15.3、17p11.2、22q13.1）的变异与多发性骨髓瘤风险存在统计学显著关联。在3p22.1中，相关变异聚集在ULK4基因体内。7p15.3中的相关变异聚集在CDCA7L转录终止位点3'端的一个增强子周围。17p11.2处的一个错义变异（rs34562254，Pro251Leu，OR，1.32；P = 2.93×10）在TNFRSF13B中编码一种TNF受体家族中的淋巴细胞特异性蛋白，该蛋白与NF-κB途径相互作用。与22q13.1中的索引信号相关的单核苷酸多态性聚集在CBX7的启动子和增强子区域周围。结论：我们发现，报告的多发性骨髓瘤易感区域包含在不同人群中都很重要的风险变异，支持使用具有不同潜在遗传结构的多个种族/族裔群体来加强对假定功能性等位基因的定位和识别。
影响
报告的多发性骨髓瘤风险位点的一个子集在不同人群中具有一致的效应，并且可能具有功能性。癌症流行病学、生物标志物与预防；25(12)；1609 - 18。©2016美国癌症研究协会。
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