Genetic associations of LYN with systemic lupus erythematosus

Abstract

We targeted LYN, a src-tyosine kinase involved in B-cell activation, in case-control association studies using populations of European-American, African-American and Korean subjects. Our combined European-derived population, consisting of 2463 independent cases and 3131 unrelated controls, shows significant association with rs6983130 in a female-only analysis with 2254 cases and 2228 controls (P = 1.1 x 10(-4), odds ratio (OR) = 0.81 (95% confidence interval: 0.73-0.90)). This single nucleotide polymorphism ( SNP) is located in the 50 untranslated region within the first intron near the transcription initiation site of LYN. In addition, SNPs upstream of the first exon also show weak and sporadic association in subsets of the total European-American population. Multivariate logistic regression analysis implicates rs6983130 as a protective factor for systemic lupus erythematosus (SLE) susceptibility when anti-dsDNA, anti-chromatin, anti-52 kDa Ro or anti-Sm autoantibody status were used as covariates. Subset analysis of the European-American female cases by American College of Rheumatology classification criteria shows a reduction in the risk of hematological disorder with rs6983130 compared with cases without hematological disorders (P = 1.5 x 10(-3), OR = 0.75 (95% CI: 0.62-0.89)). None of the 90 SNPs tested show significant association with SLE in the African American or Korean populations. These results support an association of LYN with European-derived individuals with SLE, especially within autoantibody or clinical subsets. Genes and Immunity (2009) 10, 397-403; doi: 10.1038/gene.2009.19; published online 16 April 2009We thank the participants, both patients and controls, who graciously agreed to take part in these studies by donating samples to the various collections, including the Lupus Family Registry and Repository (http://lupus.omrf.org), PROFILE, BIOLUPUS and many other individual or multicenter collaborator initiated collections. We also thank the recruitment and technical teams at each of the sample procurement sites for their important contributions. We thank the Wake Forest University Health Sciences Center for Public Health Genomics for support of the data analysis efforts of our Wake Forest University collaborators. Finally, we thank the various funding sources as outlined on the title page for their continued support for the collection of samples and the conduct of this research.; Members of BIOLUPUS who have provided samples to this study are: Peter Junker, Ann Voss and Helle Laustrup (Odense, Denmark), Bernard Lawerys and Fredric Houssieau (Louvain, Belgium), Carlos Vasconcelos and Berta Martins Da Silva (Porto, Portugal), Carmen Gutierrez and Ana Suarez (Oviedo, Spain), Torsten Witte (Hannover, Germany), Sandra D'Alfonso, Sergio Migliaresi, Mauro Galeazzi and Gian Domenico Sebastiani (Novara, Naples, Siena and Rome, Italy), Bernardo Pons-Estel and the members of GENLES (Rosario, Argentina) and Emoke Endreffy (Szeged, Hungary). Peter K Gregersen from the Feinstein Institute of Medical Research and Jorge R Oksenberg from the University of California at San Francisco graciously provided controls used in this study. Members of PROFILE who have provided samples to this study are Graciela S Alarcon, Elizabeth E Brown, Robert P Kimberly, Jeffery C Edberg and Gerald McGwin, Jr (University of Alabama Birmingham, Birmingham, AL, USA), Rosalind Ramsey-Goldman (Northwestern University Feinberg School of Medicine, Chicago, IL, USA), John D Reveille (University Texas Health Science Center, Houston, TX, USA), Luis M Vila (University of Puerto Rico Medical Sciences Campus, San Juan, PR, USA) and Michelle A Petri (Johns Hopkins Hospital, Baltimore, MD, USA). This project was funded by National Institutes of Health RR020143 (JMG and JBH), RR015577 (JMG, JBH, JAJ), NIAID-HHSN266200500026C (JMG and JAJ), AI031584 (JBH, JMG, JAJ), AR053483 (JMG, SKN and JAJ), AR48940 (JBH, JAJ), AI063622 (SKN), Kirkland Scholar awards (JBH and JAJ), AR049084 (SKN, JBH, RPK, RRG, JDR, MAP, LMV, GSA, JCE, GMcG Jr), AR42460 (JBH), AR12253 (JBH), AR62277 (JBH), AI24717 (JBH), AI063274 (PMG), AR052125 (PMG), AR043247 (KLM), DEO15223 (JBH), Alliance for Lupus Research (JBH), the US Department of Veterans Affairs (JBH), Swedish Research Council (MEAR), the Korea Healthcare technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea. (A010252, A080588) (SCB), the Torsten & Ragnar Soderbergs Foundation (MEAR), the Swedish Foundation Against Rheumatism (MEAR), the Gustaf Vth-80th-Year Foundation (MEAR), Plan Nacional de I+D, Spain (SAF06-00398) (JM), the Junta de Andalucia, grupo CTS-180 (JM) and OHRS award # HR08-037 from the Oklahoma Center for the Advancement of Science & Technology (JMG). Dr Harley has received consulting fees, speaking fees and/or director's fees from Bio-Rad Laboratories, Merck, UCB Inc., ImmunoVision Inc., IVAX Diagnostics and JK Autoimmunity and owns stock or stock options in IVAX Diagnostics