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A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci.

Abstract

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 × 10-7) 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.

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  • Authors+Show Affiliations

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    Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.

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    Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.

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    Sutter Health, Oakland, California.

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    Mayo Clinic, Jacksonville, Florida.

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    University of Utah School of Medicine, Salt Lake City, Utah.

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    Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.

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    University of California at San Francisco, San Francisco, California.

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    Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, Maryland.

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    Winship Cancer Institute, Emory University, Atlanta, Georgia.

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    Alvin J. Siteman Cancer Center, Washington University School of Medicine, Washington University, St. Louis, Missouri.

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    Mayo Clinic, Jacksonville, Florida.

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    Robert H. Lurie Cancer Center, Northwestern University, Chicago, Illinois.

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    New Jersey State Cancer Registry, New Jersey Department of Health, Trenton, New Jersey.

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    Louisiana State University School of Public Health, Louisiana State University, New Orleans, Louisiana.

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    Karmanos Cancer Institute and Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan.

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    Genomic Health, Inc., Redwood City, California.

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    Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.

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    Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.

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    Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.

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    University of Chicago, Chicago, Illinois.

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    Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.

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    University of California at San Francisco, San Francisco, California.

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    Rutgers-Robert Wood Johnson Medical School, Rutgers State University of New Jersey, New Brunswick, New Jersey.

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    Winship Cancer Institute, Emory University, Atlanta, Georgia.

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    Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.

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    Karmanos Cancer Institute and Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan.

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    Division of Cancer Epidemiology and Genetics, National Cancer Institute, U.S. NIH, Bethesda, Maryland.

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    International Epidemiology Institute, Rockville, Maryland. Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee.

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    The Translational Genomics Research Institute, Phoenix, Arizona.

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    Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.

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    Cancer Prevention Institute of California, Fremont, California. Stanford University School of Medicine and Stanford Cancer Institute, Palo Alto, California.

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    American Cancer Society, Atlanta, Georgia.

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    American Cancer Society, Atlanta, Georgia.

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    Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.

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    SWOG Statistical Center, Seattle, Washington.

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    Stony Brook University, Stony Brook, New York. Chronic Disease Research Centre and Faculty of Medical Sciences, University of the West Indies, Bridgetown, Barbados.

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    Stanford University School of Medicine and Stanford Cancer Institute, Palo Alto, California.

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    Robert H. Lurie Cancer Center, Northwestern University, Chicago, Illinois.

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    Department of Surgery, University of Arizona, Tucson, Arizona.

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    Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.

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    Glickman Urologic and Kidney Institute, Cleveland Clinic, Cleveland, Ohio.

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    Stony Brook University, Stony Brook, New York.

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    Robert H. Lurie Cancer Center, Northwestern University, Chicago, Illinois.

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    Stony Brook University, Stony Brook, New York.

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    Henry Ford Hospital, Detroit, Michigan.

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    The University of Texas MD Anderson Cancer Center, University of Texas, Houston, Texas.

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    Alvin J. Siteman Cancer Center, Washington University School of Medicine, Washington University, St. Louis, Missouri.

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    Henry Ford Hospital, Detroit, Michigan.

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    Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.

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    Harvard School of Public Health, Harvard University, Boston, Massachusetts.

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    Institute for Human Genetics, University of California, San Francisco, San Francisco, California.

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    Roswell Park Cancer Institute, Buffalo, New York.

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    Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.

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    Cancer Prevention Institute of California, Fremont, California. Stanford University School of Medicine and Stanford Cancer Institute, Palo Alto, California.

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    Division of Cancer Etiology, Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, California.

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    International Epidemiology Institute, Rockville, Maryland.

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    Gillings School of Global Public Health, and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.

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    Sylvester Comprehensive Cancer Center and Department of Epidemiology and Public Health, University of Miami Miller School of Medicine, Miami, Florida.

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    Division of Cancer Epidemiology and Genetics, National Cancer Institute, U.S. NIH, Bethesda, Maryland.

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    Gillings School of Global Public Health, and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.

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    Rutgers-Robert Wood Johnson Medical School, Rutgers State University of New Jersey, New Brunswick, New Jersey.

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    Harvard School of Public Health, Harvard University, Boston, Massachusetts.

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    Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.

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    Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.

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    University of Utah School of Medicine, Salt Lake City, Utah.

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    University of Utah School of Medicine, Salt Lake City, Utah.

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    University of Utah School of Medicine, Salt Lake City, Utah.

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    University of Utah School of Medicine, Salt Lake City, Utah.

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    University of Iowa, Iowa City, Iowa.

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    University of California at San Francisco, San Francisco, California.

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    Mayo Clinic, Rochester, Minnesota.

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    University of California at San Francisco, San Francisco, California.

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    International Epidemiology Institute, Rockville, Maryland.

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    Division of Cancer Epidemiology and Genetics, National Cancer Institute, U.S. NIH, Bethesda, Maryland.

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    BC Cancer Agency, Vancouver, Canada.

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    Mayo Clinic, Rochester, Minnesota.

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    University of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii.

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    Division of Cancer Epidemiology and Genetics, National Cancer Institute, U.S. NIH, Bethesda, Maryland.

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    Mayo Clinic, Rochester, Minnesota.

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    Karmanos Cancer Institute and Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan.

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    Henry Ford Hospital, Detroit, Michigan.

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    Providence Hospital, Southfield, Michigan.

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    University of Alabama at Birmingham, Birmingham, Alabama.

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    School of Public Health, Drexel University, Philadelphia, Pennsylvania.

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    Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.

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    Alvin J. Siteman Cancer Center, Washington University School of Medicine, Washington University, St. Louis, Missouri.

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    Cancer Epidemiology Centre, Cancer Council of Victoria, Melbourne, Victoria, Australia. School of Population and Global Health, Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Victoria, Australia. Monash University, Melbourne, Melbourne, Victoria, Australia.

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    BC Cancer Agency, Vancouver, Canada. School of Population and Public Health, University of British Columbia, Vancouver, Canada.

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    University of Chicago, Chicago, Illinois.

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    Dana Farber Cancer Institute, Harvard School of Medicine, Harvard University, Boston, Massachusetts.

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    Dana Farber Cancer Institute, Harvard School of Medicine, Harvard University, Boston, Massachusetts.

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    Multiple Myeloma Research Foundation, Norwalk, Connecticut.

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    Karmanos Cancer Institute and Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan.

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    The University of Texas MD Anderson Cancer Center, University of Texas, Houston, Texas.

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    Winship Cancer Institute, Emory University, Atlanta, Georgia.

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    University of Utah School of Medicine, Salt Lake City, Utah.

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    Mayo Clinic, Rochester, Minnesota.

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    University of California at San Francisco, San Francisco, California.

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    Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.

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    Center for Bioinformatics and Computational Biology, Cedars Sinai Medical Center, Los Angeles, California. wcozen@usc.edu haiman@usc.edu Dennis.Hazelett@csmc.edu.

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    Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California. wcozen@usc.edu haiman@usc.edu Dennis.Hazelett@csmc.edu.

    Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California. wcozen@usc.edu haiman@usc.edu Dennis.Hazelett@csmc.edu.

    Source

    MeSH

    Adult
    African Continental Ancestry Group
    Aged
    European Continental Ancestry Group
    Female
    Genetic Loci
    Genetic Predisposition to Disease
    Genome-Wide Association Study
    Humans
    Male
    Middle Aged
    Multiple Myeloma
    Polycomb Repressive Complex 1
    Polymorphism, Single Nucleotide
    Protein-Serine-Threonine Kinases
    Repressor Proteins
    Transmembrane Activator and CAML Interactor Protein

    Pub Type(s)

    Journal Article
    Meta-Analysis
    Multicenter Study
    Research Support, U.S. Gov't, Non-P.H.S.
    Research Support, Non-U.S. Gov't
    Research Support, U.S. Gov't, P.H.S.
    Research Support, N.I.H., Extramural
    Research Support, N.I.H., Intramural

    Language

    eng

    PubMed ID

    27587788

    Citation

    Rand, Kristin A., et al. "A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci." Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored By the American Society of Preventive Oncology, vol. 25, no. 12, 2016, pp. 1609-1618.
    Rand KA, Song C, Dean E, et al. A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci. Cancer Epidemiol Biomarkers Prev. 2016;25(12):1609-1618.
    Rand, K. A., Song, C., Dean, E., Serie, D. J., Curtin, K., Sheng, X., ... Cozen, W. (2016). A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci. Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored By the American Society of Preventive Oncology, 25(12), pp. 1609-1618.
    Rand KA, et al. A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci. Cancer Epidemiol Biomarkers Prev. 2016;25(12):1609-1618. PubMed PMID: 27587788.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci. AU - Rand,Kristin A, AU - Song,Chi, AU - Dean,Eric, AU - Serie,Daniel J, AU - Curtin,Karen, AU - Sheng,Xin, AU - Hu,Donglei, AU - Huff,Carol Ann, AU - Bernal-Mizrachi,Leon, AU - Tomasson,Michael H, AU - Ailawadhi,Sikander, AU - Singhal,Seema, AU - Pawlish,Karen, AU - Peters,Edward S, AU - Bock,Cathryn H, AU - Stram,Alex, AU - Van Den Berg,David J, AU - Edlund,Christopher K, AU - Conti,David V, AU - Zimmerman,Todd, AU - Hwang,Amie E, AU - Huntsman,Scott, AU - Graff,John, AU - Nooka,Ajay, AU - Kong,Yinfei, AU - Pregja,Silvana L, AU - Berndt,Sonja I, AU - Blot,William J, AU - Carpten,John, AU - Casey,Graham, AU - Chu,Lisa, AU - Diver,W Ryan, AU - Stevens,Victoria L, AU - Lieber,Michael R, AU - Goodman,Phyllis J, AU - Hennis,Anselm J M, AU - Hsing,Ann W, AU - Mehta,Jayesh, AU - Kittles,Rick A, AU - Kolb,Suzanne, AU - Klein,Eric A, AU - Leske,Cristina, AU - Murphy,Adam B, AU - Nemesure,Barbara, AU - Neslund-Dudas,Christine, AU - Strom,Sara S, AU - Vij,Ravi, AU - Rybicki,Benjamin A, AU - Stanford,Janet L, AU - Signorello,Lisa B, AU - Witte,John S, AU - Ambrosone,Christine B, AU - Bhatti,Parveen, AU - John,Esther M, AU - Bernstein,Leslie, AU - Zheng,Wei, AU - Olshan,Andrew F, AU - Hu,Jennifer J, AU - Ziegler,Regina G, AU - Nyante,Sarah J, AU - Bandera,Elisa V, AU - Birmann,Brenda M, AU - Ingles,Sue A, AU - Press,Michael F, AU - Atanackovic,Djordje, AU - Glenn,Martha J, AU - Cannon-Albright,Lisa A, AU - Jones,Brandt, AU - Tricot,Guido, AU - Martin,Thomas G, AU - Kumar,Shaji K, AU - Wolf,Jeffrey L, AU - Deming Halverson,Sandra L, AU - Rothman,Nathaniel, AU - Brooks-Wilson,Angela R, AU - Rajkumar,S Vincent, AU - Kolonel,Laurence N, AU - Chanock,Stephen J, AU - Slager,Susan L, AU - Severson,Richard K, AU - Janakiraman,Nalini, AU - Terebelo,Howard R, AU - Brown,Elizabeth E, AU - De Roos,Anneclaire J, AU - Mohrbacher,Ann F, AU - Colditz,Graham A, AU - Giles,Graham G, AU - Spinelli,John J, AU - Chiu,Brian C, AU - Munshi,Nikhil C, AU - Anderson,Kenneth C, AU - Levy,Joan, AU - Zonder,Jeffrey A, AU - Orlowski,Robert Z, AU - Lonial,Sagar, AU - Camp,Nicola J, AU - Vachon,Celine M, AU - Ziv,Elad, AU - Stram,Daniel O, AU - Hazelett,Dennis J, AU - Haiman,Christopher A, AU - Cozen,Wendy, Y1 - 2016/09/01/ PY - 2015/11/21/received PY - 2016/06/20/revised PY - 2016/07/05/accepted PY - 2016/9/3/pubmed PY - 2018/2/27/medline PY - 2016/9/3/entrez SP - 1609 EP - 1618 JF - Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology JO - Cancer Epidemiol. Biomarkers Prev. VL - 25 IS - 12 N2 - 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 × 10-7) 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. SN - 1538-7755 UR - https://www.unboundmedicine.com/medline/citation/27587788/A_Meta_analysis_of_Multiple_Myeloma_Risk_Regions_in_African_and_European_Ancestry_Populations_Identifies_Putatively_Functional_Loci_ L2 - http://cebp.aacrjournals.org/cgi/pmidlookup?view=long&amp;pmid=27587788 DB - PRIME DP - Unbound Medicine ER -