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Familial aggregation and linkage analysis of autoantibody traits in pedigrees multiplex for systemic lupus erythematosus

Genes & Immunity volume 7, pages 417–432 (2006)Cite this article

Abstract

Autoantibodies are clinically relevant biomarkers for numerous autoimmune disorders. The genetic basis of autoantibody production in systemic lupus erythematosus (SLE) and other autoimmune diseases is poorly understood. In this study, we characterized autoantibody profiles in 1506 individuals from 229 multiplex SLE pedigrees. There was strong familial aggregation of antinuclear antibodies (ANAs), anti-double-stranded DNA (dsDNA), anti-La/SSB, anti-Ro/SSA, anti-Sm, anti-nRNP (nuclear ribonucleoprotein), IgM antiphospholipid (aPL) antibodies (Abs) and rheumatoid factor (RF) across these families enriched for lupus. We performed genome-wide linkage analyses in an effort to map genes that contribute to the production of the following autoantibodies: Ro/SSA, La/SSB, nRNP, Sm, dsDNA, RF, nuclear and phospholipids. Using an approach to minimize false positives and adjust for multiple comparisons, evidence for linkage was found to anti-La/SSB Abs on chromosome 3q21 (adjusted P=1.9 × 10−6), to anti-nRNP and/or anti-Sm Abs on chromosome 3q27 (adjusted P=3.5 × 10−6), to anti-Ro/SSA and/or anti-La/SSB Abs on chromosome 4q34–q35 (adjusted P=3.4 × 10−4) and to anti-IgM aPL Abs on chromosome 13q14 (adjusted P=2.3 × 10−4). These results support the hypothesis that autoantibody production is a genetically complex trait. Identification of the causative alleles will advance our understanding of critical molecular mechanisms that underlie SLE and perhaps other autoimmune diseases.

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Acknowledgements

We thank the families and their referring physicians for their participation in this study. We gratefully acknowledge Dr Jane Olson for making a substantial contribution to the study design and statistical analyses, as well as insightful discussions. Some of the results in this report were obtained using the program package SAGE, which is supported by a US Public Health Service Resource Grant (RR03655) from the National Center for Research Resources. Some pedigrees (cohorts A, B, C and D) were obtained from the Lupus Multiplex Registry and Repository (http://omrf.ouhsc.edu/lupus), supported by NIH contract N01 AR12253. PSR was supported by a fellowship from the Fundação para a Ciência e Tecnologia (SFRH/BD/1090/2000). This study was supported by NIH Grants AI24717, AI31584, AI053747, AR42460, AR048940, RR020143 (to JBH) and AR46405 (to KLM).

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Authors and Affiliations

  1. Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA

    P S Ramos, A N Leiran, C M Meyer, K J Espe, W A Ortmann, P M Gaffney, T W Behrens & K L Moser

  2. Department of Arthritis and Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

    J A Kelly, G R Bruner, B Namjou, M Reichlin, J A James & J B Harley

  3. Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA

    C Gray-McGuire

  4. Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    C D Langefeld

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  1. P S Ramos
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  2. J A Kelly
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  16. K L Moser
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Correspondence to K L Moser.

Additional information

URLS

Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim

Statistical Analysis for Genetic Epidemiology (SAGE) software, http://darwin.cwru.edu/sage/index.php

StatView software for Windows version 5.0, Cary, NC, http://www.statview.com

GraphPad Instat software version 3.0 for Windows XP, San Diego, CA, http://www.graphpad.com

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Ramos, P., Kelly, J., Gray-McGuire, C. et al. Familial aggregation and linkage analysis of autoantibody traits in pedigrees multiplex for systemic lupus erythematosus. Genes Immun 7, 417–432 (2006). https://doi.org/10.1038/sj.gene.6364316

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  • DOI: https://doi.org/10.1038/sj.gene.6364316

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