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

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, Fcgamma receptors (FcgammaR) IIA and IIIA, and hereditary complement component deficiencies, as well as familial aggregation, monozygotic twin concordance >20%, lambdas > 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 FcgammaRIIA 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.

Figure 1

Summary of genome-wide scan. Maximum two-point lod scores ≥1.0 obtained by using six screening models for each marker are indicated. Each ○ along the abscissa represents a genotyped marker from the version 8 Weber Screening Set. Markers from this set that have not been evaluated are indicated (Ø). Approximate locations of centromeres are represented by ■.

Figure 2

Screening lod scores for chromosome 1. Six inheritance models were evaluated for linkage at 39 loci from chromosome 1. The maximum lod score for each model is plotted as indicated against each marker positioned according to genetic map distances in cM (total of 291 cM). Additional genotyped markers not included in the version 8 Weber Screening Set are shown in bold. Analysis of (a) 31 African-American pedigrees containing 72 affecteds of 166 subjects, (b) 55 European-American pedigrees containing 129 affecteds of 320 subjects, and (c) the entire collection of 94 pedigrees containing 533 individuals, including eight pedigrees of predominantly Hispanic, Asian, Middle Eastern, or Native American origin.