Abstract
Genetic Susceptibility Markers of Multiple Myeloma in African-Americans
Blood, Vol.124(21), pp.2030-2030
12/06/2014
DOI: 10.1182/blood.V124.21.2030.2030
Abstract
Abstract
Multiple myeloma (MM) is 2-3 times more common among African-Americans compared to non-Hispanic whites. The 2-3-fold increased risk among family members of cases suggests a genetic contribution to risk. Genome-wide association studies (GWAS) in populations of European ancestry have identified seven novel risk loci at 2p23.3 (rs6746082), 3q26.2 (rs10936599), 3p22.1 (rs1052501), 6p21.32 (rs2285803), 7p15.3 (rs4487645), 17p11.2 (rs4273077) and 22q13.1 (rs877529) (Broderick, et al. Nat Genet, 2011, Chubb, et al. Nat Genet, 2013), three of which were replicated in another European series (Martino et al., Br J Haematol, 2012). Here we examined the index signals and conducted fine-mapping for each locus in a case-control study of 1,049 multiple myeloma cases and 7,084 controls of African ancestry to identify better markers of risk and novel independent loci in seven previously reported regions in this high risk population.
Incident cases were recruited from 10 clinical centers and SEER cancer registries from 2011 to 2013 and genotyped using the Illumina HumanCore GWAS array. Control data were obtained from previous genome-wide studies of breast and prostate cancer, genotyped using the Illumina 1M-Duo in 4425 male controls from the African Ancestry Prostate Cancer Consortium (consisting of 14 independent studies) and 2632 female controls from a breast cancer GWAS of African-American women (consisting of 9 independent studies). Imputation to 1000 Genomes (March 2012 release) was conducted for regions around six of the previously identified single nucleotide polymorphisms [SNPs] (the HLA region harboring rs2285803 is still being imputed, results will be presented). A case-control analysis of SNPs/indels >1% frequency within 250 kb of each index variant was conducted using unconditional multivariable logistic regression adjusting for age, sex and five leading principal components. Region-specific alpha levels were determined through permutation tests. The minimum alpha level across the six regions was α=0.002.
All previously reported risk variants were common in African-Americans (minor allele frequency [MAF] >0.05). For five of the six SNPs, we had ≥94% power to detect the same effect observed in non-Hispanic whites, and 64% power for the less common variant rs10936599 (MAF=0.07). We observed directionally consistent effects (odds ratio [OR]>1) for the six risk variants tested, with three replicating at p≤0.05 (7p15.3, p=1.4x10-7; 17p11.2, p=0.05; 22q13.1, p=0.02). For three of the six regions, we observed better markers of risk in African-Americans that were correlated with the index SNP in Europeans (7p15.3, rs56333627, p=1.5x10-5, r2=0.89; 17p11.2, rs34562254, p=2.9x10-3, r2=0.90; 22q13.1, rs2092410, p=1.1x10-4 r2=.71). The missense variant identified in the 17p11.2 region (rs34562254, Pro251Leu) is located in TNFRSF13B, which encodes the protein TACI, a B cell surface receptor which plays a role in B cell maturation, apoptosis and antibody production by inducing activation of transcription factors including NFAT and NFκβ. In addition, there is evidence suggesting that TACI is involved in MM pathogenesis.
Our results demonstrate that many of the risk loci for MM found in European ancestry populations are also risk loci in men and women of African ancestry and that by fine-mapping, we are able to identify variants that better capture risk in populations of African ancestry.
Disclosures
Terebelo: Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Lonial:Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.
Details
- Title: Subtitle
- Genetic Susceptibility Markers of Multiple Myeloma in African-Americans
- Creators
- Kristin A Rand - University of Southern CaliforniaChi Song - University of Southern CaliforniaAmie E. Hwang - University of Southern CaliforniaCarol A. Huff - Johns Hopkins UniversityLeon Bernal-Mizrachi - Emory UniversityMichael H Tomasson - Washington University in St. LouisSikander Ailawadhi - Mayo Clinic in ArizonaDavid J. Van Den Berg - University of Southern CaliforniaXin Sheng - University of Southern CaliforniaJohn J. Graff - Rutgers, The State University of New JerseyDavid V. Conti - University of Southern CaliforniaTodd Zimmerman - University of ChicagoEdward Peters - Louisiana State UniversitySeema Singhal - Northwestern UniversityCathryn H. Bock - Wayne State UniversityKaren Pawlish - New Jersey Department of HealthGraham A Colditz - Washington University in St. LouisAlexander Stram - Norris Comprehensive Center, Keck School of Medicine of USC, University of Southern California, Los Angeles, CASara S. Strom - The University of Texas MD Anderson Cancer CenterBenjamin Rybicki - Henry Ford HospitalRick Kittles - University of ArizonaHoward TerebeloJanet Stanford - University of WashingtonPhyllis J. Goodman - University of WashingtonSonja I Berndt - National Institutes of HealthJohn Carpten - Translational Genomics Research InstituteAnselm JM Hennis - University of the West Indies SystemLisa Chu - Cancer Prevention Institute of CaliforniaGraham Casey - University of Southern CaliforniaW R Driver - American Cancer SocietyEric A. Klein - Cleveland ClinicM. Christina Leske - Stony Brook University HospitalEsther John - Cancer Prevention Institute of CaliforniaAdam Bryant Murphy - Northwestern UniversityChristine Neslund-Dudas - Henry Ford Health SystemVictoria L. Stevens - American Cancer SocietyCurtis Pettaway - The University of Texas MD Anderson Cancer CenterWei Zheng - Vanderbilt UniversitySuh-Yuh Wu - Stony Brook UniversityJohn Witte - University of California, San FranciscoSiqun Lilly Zheng - Wake Forest UniversityJianfeng Xu - Wake Forest UniversityNikhil C. Munshi - Harvard UniversityAnn Hsing - Cancer Prevention Institute of CaliforniaSue Ingles - University of Southern CaliforniaJayesh Mehta - Northwestern UniversityLisa B. Signorello - Harvard UniversityStephen Jacob Chanock - National Institutes of HealthBarbara Nemesure - Stony Brook UniversityAnn M Mohrbacher - University of Southern CaliforniaNalini Janakiraman - Henry Ford HospitalWilliam J Blot - Vanderbilt UniversityBrian E. Henderson - University of Southern CaliforniaLaurence N. Kolonel - University of Hawaii SystemKenneth C. Anderson - Harvard UniversityBrian C-H Chiu - University of ChicagoJeffrey Zonder - The Barbara Ann Karmanos Cancer InstituteRobert Z. Orlowski - The University of Texas MD Anderson Cancer CenterSagar Lonial - Emory UniversityDaniel O. Stram - University of Southern CaliforniaChristopher Haiman - University of Southern CaliforniaWendy Cozen - University of Southern California
- Resource Type
- Abstract
- Publication Details
- Blood, Vol.124(21), pp.2030-2030
- DOI
- 10.1182/blood.V124.21.2030.2030
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Language
- English
- Date published
- 12/06/2014
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Health, Sport, and Human Physiology ; Internal Medicine
- Record Identifier
- 9984363554502771
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