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

Kristin A Rand; Eric A Klein; Elisa V Bandera; Chi Song; Eric Dean; Daniel J Serie; Karen Curtin; Xin Sheng; Donglei Hu; Carol Ann Huff; Leon Bernal-Mizrachi; Michael H Tomasson; Sikander Ailawadhi; Seema Singhal; Karen Pawlish; Edward S Peters; Cathryn H Bock; Alex Stram; David J Van Den Berg; Christopher K Edlund; David V Conti; Todd Zimmerman; Amie E Hwang; Scott Huntsman; John Graff; Ajay Nooka; Yinfei Kong; Silvana L Pregja; Sonja I Berndt; William J Blot; John Carpten; Graham Casey; Lisa Chu; W Ryan Diver; Victoria L Stevens; Michael R Lieber; Phyllis J Goodman; Anselm J M Hennis; Ann W Hsing; Jayesh Mehta; Rick A Kittles; Suzanne Kolb; Cristina Leske; Adam B Murphy; Barbara Nemesure; Christine Neslund-Dudas; Sara S Strom; Ravi Vij; Benjamin A Rybicki; Janet L Stanford; Lisa B Signorello; John S Witte; Christine B Ambrosone; Parveen Bhatti; Esther M John; Leslie Bernstein; Wei Zheng; Andrew F Olshan; Jennifer J Hu; Regina G Ziegler; Sarah J Nyante; Brenda M Birmann; Sue A Ingles; Michael F Press; Djordje Atanackovic; Martha J Glenn; Lisa A Cannon-Albright; Brandt Jones; Guido Tricot; Thomas G Martin; Shaji K Kumar; Jeffrey L Wolf; Sandra L Deming Halverson; Nathaniel Rothman; Angela R Brooks-Wilson; S Vincent Rajkumar; Laurence N Kolonel; Stephen J Chanock; Susan L Slager; Richard K Severson; Nalini Janakiraman; Howard R Terebelo; Elizabeth E Brown; Anneclaire J De Roos; Ann F Mohrbacher; Graham A Colditz; Graham G Giles; John J Spinelli; Brian C Chiu; Nikhil C Munshi; Kenneth C Anderson; Joan Levy; Jeffrey A Zonder; Robert Z Orlowski; Sagar Lonial; Nicola J Camp; Celine M Vachon; Elad Ziv; Daniel O Stram; Dennis J Hazelett; Christopher A Haiman; Wendy Cozen

doi:10.1158/1055-9965.EPI-15-1193

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

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

Kristin A Rand, Eric A Klein, Elisa V Bandera, Chi Song, Eric Dean, Daniel J Serie, Karen Curtin, Xin Sheng, Donglei Hu, Carol Ann Huff, …

Cancer epidemiology, biomarkers & prevention, Vol.25(12), pp.1609-1618

12/2016

DOI: https://doi.org/10.1158/1055-9965.EPI-15-1193

PMCID: PMC5524541

PMID: 27587788

Abstract

Adult

African Continental Ancestry Group - genetics

Aged

European Continental Ancestry Group - genetics

Female

Genetic Loci

Genetic Predisposition to Disease

Genome-Wide Association Study

Humans

Male

Middle Aged

Multiple Myeloma - genetics

Multiple Myeloma - metabolism

Polycomb Repressive Complex 1 - genetics

Polymorphism, Single Nucleotide

Protein-Serine-Threonine Kinases - genetics

Repressor Proteins - genetics

Transmembrane Activator and CAML Interactor Protein - genetics

Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma. 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. 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. 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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Title: A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci
Creators: Kristin A Rand - Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
Eric A Klein - Glickman Urologic and Kidney Institute, Cleveland Clinic, Cleveland, Ohio
Elisa V Bandera - Rutgers-Robert Wood Johnson Medical School, Rutgers State University of New Jersey, New Brunswick, New Jersey
Chi Song - Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
Eric Dean - Sutter Health, Oakland, California
Daniel J Serie - Mayo Clinic, Jacksonville, Florida
Karen Curtin - University of Utah School of Medicine, Salt Lake City, Utah
Xin Sheng - Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
Donglei Hu - University of California at San Francisco, San Francisco, California
Carol Ann Huff - Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, Maryland
Leon Bernal-Mizrachi - Winship Cancer Institute, Emory University, Atlanta, Georgia
Michael H Tomasson - Alvin J. Siteman Cancer Center, Washington University School of Medicine, Washington University, St. Louis, Missouri
Sikander Ailawadhi - Mayo Clinic, Jacksonville, Florida
Seema Singhal - Robert H. Lurie Cancer Center, Northwestern University, Chicago, Illinois
Karen Pawlish - New Jersey State Cancer Registry, New Jersey Department of Health, Trenton, New Jersey
Edward S Peters - Louisiana State University School of Public Health, Louisiana State University, New Orleans, Louisiana
Cathryn H Bock - Karmanos Cancer Institute and Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan
Alex Stram - Genomic Health, Inc., Redwood City, California
David J Van Den Berg - Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
Christopher K Edlund - Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
David V Conti - Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
Todd Zimmerman - University of Chicago, Chicago, Illinois
Amie E Hwang - Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
Scott Huntsman - University of California at San Francisco, San Francisco, California
John Graff - Rutgers-Robert Wood Johnson Medical School, Rutgers State University of New Jersey, New Brunswick, New Jersey
Ajay Nooka - Winship Cancer Institute, Emory University, Atlanta, Georgia
Yinfei Kong - Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
Silvana L Pregja - Karmanos Cancer Institute and Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan
Sonja I Berndt - Division of Cancer Epidemiology and Genetics, National Cancer Institute, U.S. NIH, Bethesda, Maryland
William J Blot - Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee
John Carpten - The Translational Genomics Research Institute, Phoenix, Arizona
Graham Casey - Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
Lisa Chu - Stanford University School of Medicine and Stanford Cancer Institute, Palo Alto, California
W Ryan Diver - American Cancer Society, Atlanta, Georgia
Victoria L Stevens - American Cancer Society, Atlanta, Georgia
Michael R Lieber - Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
Phyllis J Goodman - SWOG Statistical Center, Seattle, Washington
Anselm J M Hennis - Chronic Disease Research Centre and Faculty of Medical Sciences, University of the West Indies, Bridgetown, Barbados
Ann W Hsing - Stanford University School of Medicine and Stanford Cancer Institute, Palo Alto, California
Jayesh Mehta - Robert H. Lurie Cancer Center, Northwestern University, Chicago, Illinois
Rick A Kittles - Department of Surgery, University of Arizona, Tucson, Arizona
Suzanne Kolb - Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
Cristina Leske - Stony Brook University, Stony Brook, New York
Adam B Murphy - Robert H. Lurie Cancer Center, Northwestern University, Chicago, Illinois
Barbara Nemesure - Stony Brook University, Stony Brook, New York
Christine Neslund-Dudas - Henry Ford Hospital, Detroit, Michigan
Sara S Strom - The University of Texas MD Anderson Cancer Center, University of Texas, Houston, Texas
Ravi Vij - Alvin J. Siteman Cancer Center, Washington University School of Medicine, Washington University, St. Louis, Missouri
Benjamin A Rybicki - Henry Ford Hospital, Detroit, Michigan
Janet L Stanford - Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
Lisa B Signorello - Harvard School of Public Health, Harvard University, Boston, Massachusetts
John S Witte - Institute for Human Genetics, University of California, San Francisco, San Francisco, California
Christine B Ambrosone - Roswell Park Cancer Institute, Buffalo, New York
Parveen Bhatti - Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
Esther M John - Stanford University School of Medicine and Stanford Cancer Institute, Palo Alto, California
Leslie Bernstein - Division of Cancer Etiology, Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, California
Wei Zheng - International Epidemiology Institute, Rockville, Maryland
Andrew F Olshan - Gillings School of Global Public Health, and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina
Jennifer J Hu - Sylvester Comprehensive Cancer Center and Department of Epidemiology and Public Health, University of Miami Miller School of Medicine, Miami, Florida
Regina G Ziegler - Division of Cancer Epidemiology and Genetics, National Cancer Institute, U.S. NIH, Bethesda, Maryland
Sarah J Nyante - Gillings School of Global Public Health, and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina
Brenda M Birmann - Harvard School of Public Health, Harvard University, Boston, Massachusetts
Sue A Ingles - Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
Michael F Press - Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
Djordje Atanackovic - University of Utah School of Medicine, Salt Lake City, Utah
Martha J Glenn - University of Utah School of Medicine, Salt Lake City, Utah
Lisa A Cannon-Albright - University of Utah School of Medicine, Salt Lake City, Utah
Brandt Jones - University of Utah School of Medicine, Salt Lake City, Utah
Guido Tricot - University of Iowa, Iowa City, Iowa
Thomas G Martin - University of California at San Francisco, San Francisco, California
Shaji K Kumar - Mayo Clinic, Rochester, Minnesota
Jeffrey L Wolf - University of California at San Francisco, San Francisco, California
Sandra L Deming Halverson - International Epidemiology Institute, Rockville, Maryland
Nathaniel Rothman - Division of Cancer Epidemiology and Genetics, National Cancer Institute, U.S. NIH, Bethesda, Maryland
Angela R Brooks-Wilson - BC Cancer Agency, Vancouver, Canada
S Vincent Rajkumar - Mayo Clinic, Rochester, Minnesota
Laurence N Kolonel - University of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii
Stephen J Chanock - Division of Cancer Epidemiology and Genetics, National Cancer Institute, U.S. NIH, Bethesda, Maryland
Susan L Slager - Mayo Clinic, Rochester, Minnesota
Richard K Severson - Karmanos Cancer Institute and Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan
Nalini Janakiraman - Henry Ford Hospital, Detroit, Michigan
Howard R Terebelo - Providence Hospital, Southfield, Michigan
Elizabeth E Brown - University of Alabama at Birmingham, Birmingham, Alabama
Anneclaire J De Roos - School of Public Health, Drexel University, Philadelphia, Pennsylvania
Ann F Mohrbacher - Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
Graham A Colditz - Alvin J. Siteman Cancer Center, Washington University School of Medicine, Washington University, St. Louis, Missouri
Graham G Giles - Monash University, Melbourne, Melbourne, Victoria, Australia
John J Spinelli - School of Population and Public Health, University of British Columbia, Vancouver, Canada
Brian C Chiu - University of Chicago, Chicago, Illinois
Nikhil C Munshi - Dana Farber Cancer Institute, Harvard School of Medicine, Harvard University, Boston, Massachusetts
Kenneth C Anderson - Dana Farber Cancer Institute, Harvard School of Medicine, Harvard University, Boston, Massachusetts
Joan Levy - Multiple Myeloma Research Foundation, Norwalk, Connecticut
Jeffrey A Zonder - Karmanos Cancer Institute and Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan
Robert Z Orlowski - The University of Texas MD Anderson Cancer Center, University of Texas, Houston, Texas
Sagar Lonial - Winship Cancer Institute, Emory University, Atlanta, Georgia
Nicola J Camp - University of Utah School of Medicine, Salt Lake City, Utah
Celine M Vachon - Mayo Clinic, Rochester, Minnesota
Elad Ziv - University of California at San Francisco, San Francisco, California
Daniel O Stram - Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
Dennis J Hazelett - Center for Bioinformatics and Computational Biology, Cedars Sinai Medical Center, Los Angeles, California. wcozen@usc.edu haiman@usc.edu Dennis.Hazelett@csmc.edu
Christopher A Haiman - 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
Wendy Cozen - 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
Publication Details: Cancer epidemiology, biomarkers & prevention, Vol.25(12), pp.1609-1618
Date published: 12/2016
Grant note: U10 CA037429 / NCI NIH HHS U58 DP000807 / NCCDPHP CDC HHS R01 ES011126 / NIEHS NIH HHS R01 CA054281 / NCI NIH HHS P50 CA186781 / NCI NIH HHS R01 CA196671 / NCI NIH HHS U54 CA118948 / NCI NIH HHS R01 CA100504 / NCI NIH HHS R01 CA100374 / NCI NIH HHS K24 CA169004 / NCI NIH HHS U01 CA069417 / NCI NIH HHS R01 CA088164 / NCI NIH HHS R01 CA092579 / NCI NIH HHS P30 ES010126 / NIEHS NIH HHS P50 CA142509 / NCI NIH HHS UG1 CA189974 / NCI NIH HHS UM1 CA164973 / NCI NIH HHS R01 CA073629 / NCI NIH HHS P30 ES007784 / NIEHS NIH HHS R01 CA134786 / NCI NIH HHS R01 CA184464 / NCI NIH HHS R01 CA063464 / NCI NIH HHS U01 CA127298 / NCI NIH HHS U01 CA063464 / NCI NIH HHS R01 CA068578 / NCI NIH HHS R21 CA191896 / NCI NIH HHS K05 CA136967 / NCI NIH HHS R01 CA186646 / NCI NIH HHS P50 CA058223 / NCI NIH HHS HHSN261201300021C / NCI NIH HHS R37 CA054281 / NCI NIH HHS R01 CA134674 / NCI NIH HHS P30 CA042014 / NCI NIH HHS R01 CA082664 / NCI NIH HHS R21 CA152336 / NCI NIH HHS RC2 CA148085 / NCI NIH HHS P50 CA140388 / NCI NIH HHS R35 GM118009 / NIGMS NIH HHS P50 CA100707 / NCI NIH HHS U01 HG004726 / NHGRI NIH HHS R21 CA155951 / NCI NIH HHS U58 DP003931 / NCCDPHP CDC HHS P30 CA068485 / NCI NIH HHS U19 CA148065 / NCI NIH HHS R01 CA100598 / NCI NIH HHS P30 CA013148 / NCI NIH HHS R01 CA056678 / NCI NIH HHS N01PC35139 / NCI NIH HHS P30 CA086862 / NCI NIH HHS UM1 CA182883 / NCI NIH HHS P01 CA151135 / NCI NIH HHS P30 CA014089 / NCI NIH HHS R25 CA076023 / NCI NIH HHS HHSN261201000026C / NCI NIH HHS
Academic Unit: Cancer Epidemiology and Health Outcomes
Language: English
Resource Type: Journal article
Identifiers: 991031665344704646