Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
SLE-Risk Alleles of SNPs in the NMNAT2/SMG7 Region Are Associated with Lower mRNA Levels of SMG7.
Zhao1, Jian, Sakurai1, Daisuke, Deng1, Yun, Sestak2, Andrea L., Langefeld3, Carl D., Kaufman4, Kenneth M., Kelly5, Jennifer A.
David Geffen School of Medicine University of California Los Angeles, Los Angeles, CA
Divisions of Genetics and Molecular Medicine and Immunology, King's College London, London, United Kingdom
Keck School of Medicine University of Southern California, Los Angeles, CA
Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, University of California San Francisco, San Francisco, CA
Department of Medicine, University of Oklahoma Health Sciences Center and Oklahoma Medical Research Foundation, Oklahoma City, OK
Division of Rheumatologyand Immunology, Medical University of South Carolina, Charleston, SC
Universidad del Rosario-Corporacion para Investigaciones Biologicas, Bogota, Colombia
National Defense Medical Center, Taipei
Seoul National University, Seoul
UCLA David Geffen School of Medicine, Los Angeles, CA
University of Oklahoma Health Sciences Center, Oklahoma City, OK
University of California Los Angeles, Los Angeles, CA
Wake Forest University Health Sciences, Winston-Salem, NC
US Department of Veterans Affairs Medical Center and Oklahoma Medical Research Foundation, Oklahoma City, OK
Oklahoma Medical Research Foundation, Oklahoma City, OK
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK
Cincinnati Children's Hospital Medical Center and the US Department of Veterans Affairs Medical Center, Cincinnati, OH
Hanyang University Hospital for Rheumatic Diseases, Clinical Research Center for Rheumatoid Arthritis (CRCRA), Seoul, South Korea
Within the 1q25 region, rs2022013 located in NMNAT2 (encoding a central enzyme of the NAD biosynthesis pathway expressed mainly in neurons) was associated with SLE in the SLEGEN genome-wide association study (GWAS) and a replication study conducted in subjects of European ancestry, which indicates the NMNAT2 region is a risk locus for SLE. Here we sought to fine map the NMNAT2 region to identify underlying causal variants predisposing to SLE.
We genotyped 34 NMNAT2 SNPs and 347 ancestry informative markers (AIMs) in 15,292 case-control subjects including European Americans (EA, 3438 cases vs. 3417 controls not used in SLEGEN GWAS), African Americans (AA, 1679 vs. 1934), Asians (AS, 1265 vs. 1260) and Hispanics enriched for the Amerindian-European admixture (HS, 1492 vs. 807). AIMs were used to estimate global ancestry for each subject and eliminate genetic outliers. NMNAT2 SNPs were assessed for the association with SLE under a logistic regression model adjusted for sex and global ancestry. We also imputed genotypes for SNPs in the 1000 Genomes Project and assessed them for the association with SLE. In addition, we performed conditional analysis to distinguish independent association signals, meta-analysis to calculate combined P value and RT-PCR to measure gene expression levels.
We detected significant association signals (defined as P<0.05/34=1.5×10-3) in EA and HS but not in AA and AS. Previously reported association of rs2022013 with SLE was confirmed in EA (P=3.9×10-7, OR=0.83). After imputation, 163 SNPs in EA and 10 SNPs in HS, spanning 239 kb from NMNAT2 to SMG7, were significantly associated with SLE, of which 68 SNPs showed consistent association in EA and HS (P<0.05). These association signals could be explained by 4 groups of SNPs (group 1: rs12146097, Pmeta=6.4×10-13, OR=1.40; group 2: proxy SNP rs12410472, Pmeta=1.6×10-6, OR=0.77; group 3: proxy SNP rs2702178, Pmeta=7.9×10-10, OR=1.22; group 4: proxy SNP rs536586, Pmeta=1.5×10-7, OR=1.18). Group 1, 2 and 4 SNPs are all located in intron 1 of NMNAT2 long isoform, but multiple group 3 SNPs are located in the SMG7 region. SMG7 is an ubiquitously expressed key component of the nonsense-mediated mRNA decay (NMD) pathway, which mainly functions in controlling mRNA quality and expression levels and is coupled with alternative splicing to regulate core spliceosomal proteins such as Sm and snRNP. In the Genevar eQTL database, SLE-risk alleles of group 1, 3 and 4 SNPs were associated with lower expression levels of SMG7 rather than NMNAT2 or other genes within 250 kb. We confirmed that the risk allele of group 3 SNPs showed dosage-dependent association with lower mRNA levels of SMG7 in PBMCs of 34 SLE patients and 33 healthy controls of European ancestry (P<1.0×10-4), in which SMG7 levels were negatively associated with known ANA titers of 26 of the 34 SLE patients (r=-0.43, P=0.03).
We identified SLE-associated SNPs, exceeding GWAS significance level of P<5.0×10-8, in the NMNAT2/SMG7 region and showed that these SNPs might confer risk of SLE, at least in part, by influencing the expression of SMG7. These findings implicate a novel mechanism by which the NMD pathway may be involved in the pathogenesis of SLE.
To cite this abstract, please use the following information:
Zhao, Jian, Sakurai, Daisuke, Deng, Yun, Sestak, Andrea L., Langefeld, Carl D., Kaufman, Kenneth M., et al; SLE-Risk Alleles of SNPs in the NMNAT2/SMG7 Region Are Associated with Lower mRNA Levels of SMG7. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :639