Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Fine Mapping of NMNAT2 for Association with SLE Susceptibility: A Multiethnic Case-Control Study.
Zhao13, Jian, Langefeld16, Carl D., Kaufman2, Kenneth M., Kelly1, Jennifer A., Gaffney1, Patrick M., Moser1, Kathy L., Networks3, Marta E. Alarcón-Riquelme on Behalf of the BIOLUPUS and GENLES
Arthritis and Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK
The Ohio State University, Columbus, OH
University of Alabama, Birmingham, AL
University of California
University of California, Los Angeles, CA
University of Southern California, Los Angeles, CA
US Department of Veterans Affairs Medical Center, Oklahoma City, OK
Wake Forest University Health Sciences, NC
Arthritis and Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK; US Department of Veterans Affairs Medical Center, Oklahoma City, OK
Center for Genomics and Oncological Research, Granada, Spain
Cincinnati Children's Hospital Medical Center and US Department of Veterans Affairs Medical Center, Cincinnati, OH
Imperial College London, Hammersmith Hospital, London, United Kingdom
National Defense Medical Center, Taipei, Taiwan
Rosalind Russell Medical Research Center for Arthritis, University of California, San Francisco, CA
Sanatorio Parque, Rosario, Argentina
Seoul National University, Seoul, Korea
NMNAT2, one of the three Nicotinamide mononucleotide adenylyl transferases, is a central enzyme of the NAD biosynthesis pathway mainly expressed in Golgi-complex with a known function of delaying axon degeneration. In this study, we sought to replicate a putative association at rs2022013 in NMNAT2 from the SLEGEN genome-wide association study (GWAS) conducted in women of European ancestry (Harley et at, 2008) not yet exceeding the stringent threshold for genome-wide significance (typically P<5×10-8).
A total of 24 SNPs, spanning the genomic region of NMNAT2, were genotyped on a customized Illumina array. Additionally, ~400 ancestry informative markers were used to control population admixture and to eliminate genetic outliers. The association of NMNAT2 SNPs with SLE was tested in a collection of 15,424 case-control samples consisting of European Americans (EA), African Americans and Gullahs (AA&Gullah), Asians and Hispanic and Native Americans (Hisp&NA). We performed Chi-square test to compare the allelic difference between cases and controls, likelihood ratio test to distinguish independent signals from associated SNPs, and Mantel-Haenszel test to conduct the trans-ethnic meta-analysis.
Among the 16 association signals observed in EA (3477 vs. 3470 case-control samples independent of SLEGEN GWAS), we replicated the association of rs2022013 (P=9.5×10-7, OR=0.84) and identified 4 independent SLE-associated SNPs located in intron 1 of NMNAT2 (long isoform) with the strongest signal at rs12146097 (P=1.6×10-9, OR=1.34). Allelic association detected in EA was partially extended to Hisp&NA (5 SNPs with allelic P from 0.018 to 7.8×10-4, 1508 vs. 812) but not to AA&Gullah (1680 vs. 1953). Rs607332 (within intron 6) exhibited the strongest signal in AA&Gullah (P=0.0013, OR=0.9) and Hisp&NA (P=2.9×10-4, OR=0.8) but had no association in EA, which indicated specific associations of NMNAT2 SNPs in various populations. No SNP showed significant association with SLE in Asians (1272 vs. 1270). The most significant meta-analysis P value of 4 ethnic groups was detected at rs12146097 (P=1.25×10-9, OR=1.29).
We provided independent evidence that NMNAT2 predisposes to susceptibility to SLE with genome-wide significance. Trans-ethnic fine mapping showed NMNAT2 SNPs had different association patterns among multiple ethnic groups. Our data suggested the novel role of NAD biosynthesis in the pathogenesis of SLE.
To cite this abstract, please use the following information:
Zhao, Jian, Langefeld, Carl D., Kaufman, Kenneth M., Kelly, Jennifer A., Gaffney, Patrick M., Moser, Kathy L., et al; Fine Mapping of NMNAT2 for Association with SLE Susceptibility: A Multiethnic Case-Control Study. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1595