A Susceptibility Locus for Human Systemic Lupus Erythematosus (hSLE1) on Chromosome 2q

Lindqvist, Anna-Karin; Steinsson, Kristján; Johanneson, Bo; Kristjánsdóttir, Helga; Àrnasson, Alfred; Gröndal, Gerður; Jonasson, Inger; Magnusson, Veronica; Sturfelt, Gunnar; Truedsson, Lennart; Svenungsson, Elisabet; Lundberg, Ingrid E.; Terwilliger, Joseph D.; Gyllensten, Ulf; Alarcón‐Riquelme, Marta E.

doi:10.1006/jaut.1999.0357

Cited by 178 publications

(157 citation statements)

References 43 publications

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“…Genetic linkage of SLE to Ͼ40 unique chromosomal regions has been identified across multiple studies (23,(41)(42)(43)(44). However, results from these 5 genome scans differ widely from each other, and often are not replicated by individual studies.…”

Section: Discussionmentioning

confidence: 99%

Increased prevalence of renal disease in systemic lupus erythematosus families with affected male relatives

Stein

Olson

Gray‐McGuire

et al. 2002

Arthritis & Rheumatism

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Objective. To distinguish familial differences from sex-related differences in the clinical manifestations of systemic lupus erythematosus (SLE).Methods. A total of 372 affected individuals from 160 multiplex SLE pedigrees were analyzed. Twenty-five of these pedigrees contained at least 1 affected male relative. Comparisons of the presence of each of the 11 1982 American College of Rheumatology criteria for SLE were made between female family members with affected male relatives and those without affected male relatives, using Fisher's exact tests.Results. The presence of renal disease was significantly increased in female family members with an affected male relative when compared with those with no affected male relative (68% and 43%, respectively; P ‫؍‬ 0.002). This trend remained after stratifying by race and was most pronounced in European Americans. A familial basis for differences in hematologic and immunologic manifestations was also suggested, while arthritis and dermatologic features appeared to be most influenced by sex.Conclusion. Our results demonstrate that the increased prevalence of renal disease previously reported in men with SLE is, in large part, a familial rather than sex-based difference, at least in multiplex SLE families. Distinguishing familial from sex-related differences may facilitate efforts to understand the genetic and hormonal factors that underlie this complex autoimmune disease.

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Section: Discussionmentioning

confidence: 99%

Increased prevalence of renal disease in systemic lupus erythematosus families with affected male relatives

Stein

Olson

Gray‐McGuire

et al. 2002

Arthritis & Rheumatism

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“…Over the last several years, a number of groups have published genome-wide and targeted linkage analyses in SLE [4][5][6][7] There is considerable heterogeneity within these linkage studies, no doubt reflecting small study sizes, genetic heterogeneity and clinical heterogeneity in SLE. The most consistently mapped lupus susceptibility loci reside in the following regions: 1q23, 1q25-31, 1q41-42, 2q35-37, 4p16-15.2, 6p11-21 (MHC) and 16q12, all of which have been corroborated at least once in an independent cohort.…”

Section: Introductionmentioning

confidence: 99%

Association of LY9 in UK and Canadian SLE families

et al. 2008

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Systemic lupus erythematosus (SLE) is a complex disease trait of unknown aetiology. Genome-wide linkage studies in human SLE identified several linkage regions, including one at 1q23, which contains multiple susceptibility genes, including the members of the signalling lymphocyte activation molecule (SLAM) locus. In mice there is a syntenic linkage region, Sle1. The SLAM genes are functionally related cell-surface receptors, which regulate signal transduction of cells in the immune system. Family-based association study in UK and Canadian SLE families identified variants in the promoter and coding region of SLAMF7 and LY9 contributing to SLE disease susceptibility. The strongest association was from rs509749, in exon 8 of LY9 (P ¼ 0.00209). rs509749 encodes a Val/Met nonsynonymous change in amino acid 602 in the cytoplasmic domain of LY9. In the parents and affected individuals from the Canadian SLE families, the risk allele of rs509049 skews the T-cell population by increasing the number of CD8 þ memory T cells, while decreasing the proportion of CD4 þ naïve T cells and activated T cells. Since rs509749 lies within the consensus binding site for SAP/SH2D1a, which influences downstream signalling events from LY9, the mechanism for increased CD8 þ memory T cells may include differential binding SAP/SH2D1a to the cytoplasmic domain of LY9.

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“…[1][2][3] This is further supported by the identification of genetic associations of candidate gene polymorphisms 4,5 as well as the establishment of linkage to loci in genome-wide scans in SLE. [6][7][8][9][10][11][12] In man, SLE is not often a single gene disorder; the genetic effect generally appears to be conferred by polymorphisms in multiple genes. However, the responsible genes have been difficult to identify since SLE is an unusually heterogeneous disease with a wide range of clinical manifestations among patients.…”

Section: Introductionmentioning

confidence: 99%

Functional promoter haplotypes of the human FAS gene are associated with the phenotype of SLE characterized by thrombocytopenia

et al. 2005

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Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies against intracellular antigens and tissue injury. Defective apoptosis of activated immune cells leads to the development of autoantibodies in SLE. FasL initiated apoptosis is central for peripheral tolerance. Fas deficiencies in humans and mice predispose toward systemic autoimmunity. SLE is conferred by many genes. The genetic effects may be concentrated by familial clustering or by stratifying of subphenotypes. We have tested polymorphisms and haplotypes in FAS and FASL for association to SLE or subphenotypes in 126 multiplex American SLE pedigrees and found association of the FAS codon214 AC C/T as well as the FASÀ670G4A 0 -codon214 AC C/T 0 haplotype to thrombocytopenia in SLE. Furthermore we have functionally characterized the FAS/FASL promoter polymorphisms associated with SLE in other populations and demonstrate that the activity depends on the allelic variants as well as on the haplotype. The presence of FASÀ670G, which affects STAT1 binding, leads to the highest activity. FASLÀ844C activity is modified by the cis acting À478A and, hence, the haplotype and not the individual variant, determines the promoter activity. We conclude that the FAS/FASL promoter haplotypes are functional and that polymorphisms in FAS may contribute to thrombocytopenia in SLE.

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A Susceptibility Locus for Human Systemic Lupus Erythematosus (hSLE1) on Chromosome 2q

Cited by 178 publications

References 43 publications

Increased prevalence of renal disease in systemic lupus erythematosus families with affected male relatives

Increased prevalence of renal disease in systemic lupus erythematosus families with affected male relatives

Association of LY9 in UK and Canadian SLE families

Functional promoter haplotypes of the human FAS gene are associated with the phenotype of SLE characterized by thrombocytopenia

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