Evidence for a Susceptibility Gene, SLEV1, on Chromosome 17p13 in Families with Vitiligo-Related Systemic Lupus Erythematosus

Abstract

Both systemic lupus erythematosus (SLE) and vitiligo are autoimmune disorders that have strong evidence of complex genetic contributions to their etiology, but, to date, efforts using genetic linkage to find the susceptibility genes for either phenotype have met with limited success. Since autoimmune diseases are thought to share at least some of their genetic origins, and since only a small minority (16 of 92) of the European-American pedigrees multiplex for SLE in our collection have one or more affected members with vitiligo, we hypothesized that these pedigrees might be more genetically homogeneous at loci important to both SLE and vitiligo and, hence, have increased power for detection of linkage. We therefore evaluated genomewide microsatellite-marker-scan data for markers at an average marker density of approximately 11 cM in these 16 European-American pedigrees and identified a significant linkage at 17p13, where the maximum multipoint parametric LOD score was 3.64 (P<4.3x10(-5)) and the nonparametric linkage score was 4.02 (P<2.8x10(-5)), respectively. The segregation behavior of this linkage suggests a recessive mode of inheritance with a virtually homogeneous genetic effect in these 16 pedigrees. These results support the hypotheses that SLE and vitiligo may share important genetic effects and that sampling on the basis of clinical covariates dramatically improves power to identify genetic effects.

A genetic marker within the CD44 gene confirms linkage at 11p13 in African-American families with lupus stratified by thrombocytopenia, but genetic association with CD44 is not present

“…This manifestation of SLE is strongly associated with an increased mortality. 10,12 In our families with SLE, the presence of thrombocytopenia in one member of a family is associated with severe disease in other members of the family, despite the fact that these other SLE affected members do not tend to have thrombocytopenia (Scofield et al, submitted) Thus, thrombocytopenia identifies not just individual patients, but entire families with severe SLE. Therefore, our effort in which SLE families are stratified by thrombocytopenia is likely to identify genes associated with severe disease.…”

“…[5][6][7][8][9] We have hypothesized that the use of the clinical variation found among patients with SLE can be used in studies of the genetics of the disease, and this approach has proved useful so far. 10 Thrombocytopenia is a manifestation of SLE that is of particular clinical interest because of its strong association with mortality. 11 Low platelet count is part of the diagnostic criteria for SLE 1 and occurs in 10-20% of SLE patients.…”

“…Expected and observed counts of transmitted and non-transmitted alleles were evaluated using: (1) trios and, (2) 15 Six tandem repeats that had a period size of 2, 3 or 4, a copy number greater than 10 and a percent match greater than 90% were found either within or near the CD44 gene with three of these regions polymorphic (see above). The 78 participants DNA samples were genotyped by polymerase chain reaction and separated the PCR products by size as described elsewhere 5,10 at the three polymorphic tandem repeat markers. One of the tandem repeat markers located near the middle of the gene showed linkage to lupus with a LOD score of 2.721 and is shown above.…”

A genome screen of systemic lupus erythematosus using affected-relative-pair linkage analysis with covariates demonstrates genetic heterogeneity

“…In a recent report of results obtained using 16 of these pedigrees that were of EA ancestry and had one or more members with vitiligo, Nath et al 22 reported a maximum lod score of 4.0 at D17S974-D17S1303, about 12 cM from our peak at D17S1298. As vitiligo was not among the criteria we analyzed, we fit a model using as a covariate an indicator variable denoting the presence or absence of vitiligo in any family member and observed an effect of vitiligo (lod score = 1.53, P = 0.008) at D17S974-D17S1303 but no improvement at D17S1298.…”

Genetic linkage of systemic lupus erythematosus with chromosome 11q14 (SLEH1) in African-American families stratified by a nucleolar antinuclear antibody pattern

“…9 In previously published studies, significant linkages with a LOD у 3.3 have been established at 1q22-23, 1q41, 2q37, 4p16, 6p21-11, 16q13, and 17p13. 7,[10][11][12][13][14][15] In this study, we selected SLE pedigrees based on the presence of antinucleolar antibodies and found evidence for linkage at 11q14, where SLEH1 was already known to reside 1 (http://www.gene. ucl.ac.uk/cgi-bin/nomenclature/choose.pl?match=SLEH1).…”