Genome scan of human systemic lupus erythematosus: Evidence for linkage on chromosome 1q in African-American pedigrees

Genome scan of human systemic lupus erythematosus: Evidence for linkage on chromosome 1q in African-American pedigrees

^aArthritis and Immunology Program and ^dProtein Studies Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104; Departments of ^bBiostatistics and Epidemiology and ^jMedicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; ^cDivision of Rheumatic Diseases, Hospital for Special Surgery, New York, NY 10021; ^fDepartment of Medicine/Rheumatology, University of Chicago, Chicago, IL 60637; ^gMcBride Clinic, Edmond, OK 73013; ^hDivision of Rheumatology, Johns Hopkins Hospital, Baltimore, MD 21205; ⁱDivision of Rheumatology, East Carolina University School of Medicine, Greenville, NC 27858; ^kU.S. Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104; and ^eCenter for Rheumatic Disease, Kansas City, MO 64111

Communicated by Richard M. Krause, National Institutes of Health, Bethesda, MD (received for review July 2, 1998)

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies against intracellular antigens including DNA, ribosomal P, Ro (SS-A), La (SS-B), and the spliceosome. Etiology is suspected to involve genetic and environmental factors. Evidence of genetic involvement includes: associations with HLA-DR3, HLA-DR2, Fcγ receptors (FcγR) IIA and IIIA, and hereditary complement component deficiencies, as well as familial aggregation, monozygotic twin concordance >20%, λ_s > 10, purported linkage at 1q41–42, and inbred mouse strains that consistently develop lupus. We have completed a genome scan in 94 extended multiplex pedigrees by using model-based linkage analysis. Potential [log₁₀ of the odds for linkage (lod) > 2.0] SLE loci have been identified at chromosomes 1q41, 1q23, and 11q14–23 in African-Americans; 14q11, 4p15, 11q25, 2q32, 19q13, 6q26–27, and 12p12–11 in European-Americans; and 1q23, 13q32, 20q13, and 1q31 in all pedigrees combined. An effect for the FcγRIIA candidate polymorphism) at 1q23 (lod = 3.37 in African-Americans) is syntenic with linkage in a murine model of lupus. Sib-pair and multipoint nonparametric analyses also support linkage (P < 0.05) at nine loci detected by using two-point lod score analysis (lod > 2.0). Our results are consistent with the presumed complexity of genetic susceptibility to SLE and illustrate racial origin is likely to influence the specific nature of these genetic effects.

Footnotes

↵ l To whom reprint requests should be addressed at: University of Oklahoma, Oklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City, OK 73104. e-mail: john-harley{at}omrf.ouhsc.edu.
↵ m Referring physicians were: Eugene Arthur, Jon W. Blaschke, and Robert MacArthur, McBride Clinic, Oklahoma City, OK 73013; Christine E. Codding, Oklahoma City, OK 73109; Kelly K. Cole, Division of Rheumatology, University of Kentucky Medical Center, Lexington, KY 40503; Thomas R. Cupps, Division of Rheumatology, Georgetown University Hospital, Washington, DC 20007; Ralph J. DeHoratius, Division of Rheumatology, Thomas Jefferson Medical College, Philadelphia, PA 19107; Frederick C. Delafield, Oklahoma City, OK 73120; Ellen M. Ginzler, Department of Medicine, State University of New York Downstate Medical Center, Brooklyn, NY 11203; Patrina A. Joslin, Muskogee, OK 74401; Robert P. Kimberly, Clinical Immunology and Rheumatology, University of Alabama, Birmingham, AL 35294; Robert G. Lahita, Division of Rheumatology, St. Lukes/Roosevelt Hospital, New York, NY 10019; Kevin McKown, Department of Medicine, University of Tennessee, Memphis, TN 38163; Allan Metzger and Daniel J. Wallace, Los Angeles, CA 90048; Thomas T. Provost, Department of Dermatology, Johns Hopkins Hospital, Baltimore, MD 21205; Rosalind Ramsey-Goldman, Division of Rheumatology, Northwestern University Medical School, Chicago, IL 60611; Morris Reichlin, R. Hal Scofield, Haraldine Stafford, and Ira Targoff, Arthritis and Immunology Program, Oklahoma Medical Research Foundation and Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; Paul D. Schneider, Louisville, KY 40207; Sandra L. Sessoms, Division of Rheumatology, Baylor College of Medicine, Houston, TX 77030; David B. Staub, Davenport, IA 52804; Michael A. Weitz, Miami, FL 33143; James G. Wilson, Division of Rheumatology, University of Mississippi Medical Center, Jackson, MS 39216; and Robert E. Wolf, Department of Medicine, Louisiana State University Medical Center, Shreveport, LA 71130.
ABBREVIATIONS:

SLE,

systemic lupus erythematosus, FcγR, Fc γ receptor;

lod,

log10 of the odds for linkage