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Localization and replication of the systemic lupus erythematosus linkage signal at 4p16: interaction with 2p11, 12q24 and 19q13 in European Americans

Abstract

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by both population and phenotypic heterogeneity. Our group previously identified linkage to SLE at 4p16 in European Americans (EA). In the present study we replicate this linkage effect in a new cohort of 76 EA families multiplex for SLE by model-free linkage analysis. Using densely spaced microsatellite markers in the linkage region, we have localized the potential SLE susceptibility gene(s) to be telomeric to the marker D4S2928 by haplotype construction. In addition, marker D4S394 showed marginal evidence of linkage disequilibrium with the putative disease locus by the transmission disequilibrium test and significant evidence of association using a family-based association approach as implemented in the program ASSOC. We also performed both two-point and multipoint model-based analyses to characterize the genetic model of the potential SLE susceptibility gene(s), and the lod scores both maximized under a recessive model with penetrances of 0.8. Finally, we performed a genome-wide scan of the total 153 EA pedigrees and evaluated the possibility of interaction between linkage signals at 4p16 and other regions in the genome. Fourteen regions on 11 chromosomes (1q24, 1q42, 2p11, 2q32, 3p14.2, 4p16, 5p15, 7p21, 8p22, 10q22, 12p11, 12q24, 14q12, 19q13) showed evidence of linkage, among which, signals at 2p11, 12q24 and 19q13 also showed evidence of interaction with that at 4p16. These results provide important additional information about the SLE linkage effect at 4p16 and offer a unique approach to uncovering susceptibility loci involved in complex human diseases.

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Acknowledgments

We extend our thanks to all the patients and family members who participated in this study, as well as the many referring physicians and the US Department of Veterans Affairs. This work was supported by the National Institutes of Health grants AR42460, AI24717, AR12253, AI31584, AR049084, DE015223, RR020143, AI062629, and AI53747, by the National Institutes of Health, National Center for Research Resources, General Clinical Research Center Grant M01 RR-14467, Kirkland Scholar Award, US Department of Veterans Affaires, Alliance for lupus research. Some of the results of this paper were obtained by using the program package SAGE, which is supported by a US Public Health Service Resource Grant (RR03655) from the National Center for Research Resources. Chao Xing is supported by a fellowship from the Merck foundation.

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Correspondence to Courtney Gray-McGuire.

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Xing, C., Sestak, A.L., Kelly, J.A. et al. Localization and replication of the systemic lupus erythematosus linkage signal at 4p16: interaction with 2p11, 12q24 and 19q13 in European Americans. Hum Genet 120, 623–631 (2007). https://doi.org/10.1007/s00439-006-0248-4

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Keywords

  • Systemic Lupus Erythematosus
  • Linkage Signal
  • Transmission Disequilibrium Test
  • European American
  • Systemic Lupus Erythematosus Susceptibility