Stratification of pedigrees multiplex for systemic lupus erythematosus and for self‐reported rheumatoid arthritis detects a systemic lupus erythematosus susceptibility gene (SLER1) at 5p15.3

Abstract

Objective. Arthritis is a common manifestation in systemic lupus erythematosus (SLE), appearing in ϳ85% of patients. Often, the polyarthritis at presentation of SLE cannot be distinguished from rheumatoid arthritis (RA) by physical examination or history. Indeed, physicians initially tell many SLE patients that they have RA (one source of "self-reported RA"), only to have SLE established later. In addition, RA aggregates in families with an SLE proband. We predicted that pedigrees multiplex for both SLE and for self-reported RA would better isolate particular genetic effects. If this proved to be true, we would then use the increased genetic homogeneity to more easily reveal genetic linkage.Methods. From a collection of 160 pedigrees multiplex for SLE, we selected 36 pedigrees that also contained >2 members with self-reported RA (19 pedigrees were African American, 14 were European American, and 3 were of other ethnic origin). Data from a genome scan of 307 microsatellite markers were evaluated for SLE linkage by contemporary genetic epidemiologic techniques.Results. The most significant evidence of linkage to SLE was obtained at 5p15.3 in the European American pedigrees by both parametric (logarithm of odds [LOD] score 6.2, P ‫؍‬ 9.3 ؋ 10 ؊8) and nonparametric (LOD score 6.9, P ‫؍‬ 1.7 ؋ 10 ؊8 ) methods. The bestfitting model for this putative SLE gene in this region was a recessive gene with a population frequency of 5% and with 50% penetrance in females and 15% penetrance in males at virtually 100% homogeneity.Conclusion. For a genetically complex disease phenotype, an unusually powerful linkage has been found with SLE at 5p15.3 in European American pedigrees multiplex for SLE and for self-reported RA. This result predicts the presence of a gene at the top of chromosome 5 in this subset of patients that is important for the pathogenesis of SLE.Strong evidence exists for a genetic component in systemic lupus erythematosus (SLE). Familial aggregation, high sibling recurrence rates ( s ϭ 10-40) (1), increased monozygotic twin concordance rates compared with those for dizygotic twins and other full siblings (2), and the discovery of genetic linkages and associations all support the existence of susceptibility genes for SLE. Indeed, a number of genetic associations have been clearly established with SLE. Examples include alleles at multiple genes in the HLA region, including HLA-DR3 and various complement components, and the Fc␥ region of 1q23.1 (3-5). More recent investigations have also established multiple genetic linkages with SLE, including effects at 1q21. 3, 1q41, 2q37, 4p16, 6p21, and 16q13 (6-8).Rheumatoid arthritis (RA) is related to SLE on

Linkage analysis of SLE susceptibility: confirmation of SLER1 at 5p15.3

“…In our previous study, 1 we found the peak linkage at D5S2505, which is approximately 8.2 cM away from the current peak ( Figure 1). The Zlr score at this marker (D5S2505) in the replication sample is 2.3 (P ¼ 0.01, LOD ¼ 1.15).…”

“…The highly significant linkage to SLE with the SLE-ARA was found in European-American families, 1 although linkage in remaining 19 African-American families used in the previous analysis could not be excluded (LOD ¼ 0.77). In the present study, the strongest evidence for linkage in this region came from the African-American SLE-ARA families.…”

“…However, the present study was a replication study and our a priori hypothesis was set at 5p13.3. All the genome screening models previously reported 1 were not performed in this group of 88 additional SLE-ARA pedigrees. We only tested the best-fitted genetic model from the previous study, consequently, no correction for multiple testing was made.…”

“…In our previous study, 1 we performed a genome-wide linkage screen on a set of 36 SLE families, multiplex for both SLE and self-reported or 'alleged rheumatoid arthritis' (SLE-ARA). We used the number of alleged RA diagnoses in pedigrees as a measure of the tendency for polyarthritis in the pedigree and not as an indication of the relationship of RA to SLE.…”

The genetic etiology of systemic lupus erythematosus: a short dispatch from the combat zone

“…Using another approach, Hal Scofield, 12 Swapan Nath, Ana Quintero, Amr Sawalha, Jennifer Kelly 13 and their Oklahoma colleagues presented work stratifying pedigrees by racial background and clinical characteristics (Table 1). [14][15][16][17][18][19] In this approach, one assumes that the clinical variation in lupus has either a genetic or environmental (or both) origin.…”