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.


Fine Mapping of Xq28: Both MECP2/IRAK1 and NAA10/RENBP Contribute to Risk for SLE in Multiple Ancestral Groups.

Kaufman1,  Kenneth M., Kelly2,  Jennifer A., Hughes2,  Travis, Adler2,  Adam, Sanchez2,  Elena, Ojwang2,  Joshua O., Langefeld3,  Carl D.

Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation and US Department of Veterans Affairs Medical Center, Oklahoma City, OK
Division of Rheumatologyand Immunology, Medical University of South Carolina, Charleston, SC
University of Chicago, Chicago, IL
Hanyang University Hospital for Rheumatic Diseases, Clinical Research Center for Rheumatoid Arthritis (CRCRA), Seoul, South Korea
Oklahoma Medical Research Foundation and Centro de Genómica e Investigación Oncológica Pfizer-Universidad de Granada-Junta de Andalucía (GENYO), Granada, Spain, on behalf of the BIOLUPUS and GENLES netwo
Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA
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
David Geffen School of Medicine University of California Los Angeles, Los Angeles, CA
Oklahoma Medical Research Foundation, Oklahoma City, OK
Wake Forest University Health Sciences, Winston-Salem, NC
Oklahoma Medical Research Foundation and Oklahoma University Health Sciences Center, Oklahoma City, OK
Department of Medicine and Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL
University of Alabama at Birmingham, Birmingham, AL
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL
University of California San Francisco, San Francisco, CA
National Defense Medical Center, Taipei

Objectives:

Previous studies have identified genetic associations of SLE with IRAK1 (interleukin-1 receptor associated kinase-1) and its adjacent gene, MECP2 (Methyl-CpG-binding protein 2) located on chromosome Xq28. To further our understanding of Xq28, we assessed a 215 kb region, including IRAK1, MECP2, and 6 other genes, in a trans-ancestral approach using >15,000 case-control samples of European, African, Asian and Hispanic descent.

Methods:

We genotyped 55 SNPs spanning 8 genes on Xq28 and 347 ancestry informative markers (AIMs) using a customized Illumina array on the iSCAN instrument. Association tests were calculated using logistic regression, as implemented in PLINK, while adjusting for the four admixture proportions (west African, Indigenous American, Asian and European) using AIMs. Standard haplotype analyses were performed using Haploview 4.2. A trans-ancestral meta-analysis was conducted on the 23 SNPs that produced clean data for the European, Asian and Hispanic samples using METAL. Conditional haplotype-based likelihood ratio test statistics were calculated to localize genetic effects observed at Xq28.

Results:

Stratification based on gender identified association in Xq28 in both males and females, however the number of males analyzed was smaller due to lupus being a predominately female disease. Robust associations of SNPs located in genomic region containing NAA10, RENBP, HCFC1, TMEM187, IRAK1, and MECP2 with SLE in samples of European (4248 cases vs. 3818 controls), Asian (1328 vs. 1348) and Hispanic (961 vs. 336) populations surpassing genome wide significance were detected (p<5×10-8; n=7, 12, and 4 SNPs, respectively), but no association after adjustment for multiple testing was detected in African descent (1569 vs. 1893). Located ~70 kb upstream of the IRAK1/MECP2 locus, the NAA10 (N-alpha-acetyltransferase 10)/RENBP (rennin binding protein) locus also exhibited strong linkage disequilibrium between the two neighboring genes, and the strongest association was observed at rs5945377 of RENBP in the European samples (p=1.58×10-9, OR= 1.35) and supported in both Asian and Hispanic samples (p=1.76×10-5and 7.36×10-5, OR=1.32 and 1.30, respectively). A trans-ancestral meta-analysis of European, Asian, and Hispanic derived samples showed pmeta=5.85×10-17, pmeta=1.95×10-22 and =2.68×10-21 at NAA10/RENBP, MECP2 and IRAK1, respectively. In the largest dataset of Europeans, haplotype-based likelihood ratio test statistics showed that the NAA10/RENBP effect (proxy SNP rs2071129) appeared to be independent of IRAK1 (rs7061789) and MECP2 (rs1734787), and the MECP2 association was stronger than that of IRAK1 in lupus susceptibility (Figure 1).

Conclusion:

We confirmed strong association of MECP2 and IRAK1 with SLE in European, Asian, and Hispanic ancestries, and identified the NAA10/RENBP region as a novel lupus susceptibility locus within Xq28.

To cite this abstract, please use the following information:
Kaufman, Kenneth M., Kelly, Jennifer A., Hughes, Travis, Adler, Adam, Sanchez, Elena, Ojwang, Joshua O., et al; Fine Mapping of Xq28: Both MECP2/IRAK1 and NAA10/RENBP Contribute to Risk for SLE in Multiple Ancestral Groups. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :642
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