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

Citation

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., et al. (2016). A Meta-Analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci. Cancer Epidemiology, Biomarkers & Prevention, 25(12), 1609-1618. PMCID: PMC5524541

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 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.

URL

http://dx.doi.org/10.1158/1055-9965.epi-15-1193

Reference Type

Journal Article

Year Published

2016

Journal Title

Cancer Epidemiology, Biomarkers & Prevention

Author(s)

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, Alexander
Van Den Berg, David J.
Edlund, Christopher K.
Conti, David V.
Zimmerman, Todd
Hwang, Amie E.
Huntsman, Scott
Graff, John
Nooka, Ajay K.
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.
Hsing, Ann W.
Mehta, Jayesh
Kittles, Rick A.
Kolb, Suzanne
Klein, Eric A.
Leske, M. 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 Ann
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-H.
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

PMCID

PMC5524541