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


Kristin A. Rand
Chi Song
Eric Dean
Daniel J. Serie
Karen Curtin
Xin Sheng
Donglei Hu
Carol A. Huff
Leon Bernal-Mizrachi
Michael H. Tomasson
Sikander Ailawadhi
Seema Singhal
Karen Pawlish
Edward S. Peters
Cathryn H. Bock
Alex Stram
David J 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 R. Diver
Victoria L Stevens
Michael R Lieber
Phyllis J Goodman
Anselm J M Hennis
Ann W Hsing
Jayesh Mehta
Rick A Kittles
Suzanne Kolb
Eric A Klein
Cristina Leske
Adam B Murphy
Barbara Nemesure
Christine Neslund-Dudas, Henry Ford Health SystemFollow
Sara S Strom
Ravi Vij
Benjamin A. Rybicki, Henry Ford Health SystemFollow
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
Elisa V Bandera
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, Henry Ford Health System
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

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Cancer epidemiology, biomarkers & prevention


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 x 10(-7)) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-kappaB 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.

Medical Subject Headings

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

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