Genome-Wide Screen for Systemic Lupus Erythematosus Susceptibility Genes in Multiplex Families

Shai, Ruty Mehrian; Fp, Quismorio; L, Li; Oj, Kwon; Morrison, John L.; Wallace, DJ; Cm, Neuwelt; Brautbar, Chaim; Wj, Gauderman; Jacob, Claire

doi:10.1093/hmg/8.4.639

Cited by 286 publications

(250 citation statements)

References 30 publications

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“…Chromosome region 1q31 has been implicated in linkage studies in lupus and multiple sclerosis (22)(23)(24). Multiple investigations have suggested linkage for chromosome region 1p36 in lupus (24)(25)(26), celiac disease (27), inflammatory bowel disease (28), and RA (29,30). This region was delineated further in adult RA using a case-control association design of single-nucleotide polymorphisms, resulting in a functional haplotype associated with RA that includes the gene PADI4 (31).…”

Section: Discussionmentioning

confidence: 99%

A genome‐wide scan for juvenile rheumatoid arthritis in affected sibpair families provides evidence of linkage

Thompson¹,

Moroldo²,

Guyer³

et al. 2004

Arthritis & Rheumatism

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Methods. Genotype data collected for HLA-DR and 386 microsatellite markers were subjected to multipoint nonparametric linkage analysis. Following analysis of the entire set of families, additional analyses were performed after a priori stratification by disease onset type, age at onset, disease course, and selected HLA-DRB1 alleles. Conclusion. These data support the hypothesis that multiple genes, including at least 1 in the HLA region, influence susceptibility to JRA. These findings for JRA are consistent with findings for other autoimmune diseases and support the notion that common genetic regions contribute to an autoimmune phenotype.Collectively, the varied conditions that constitute juvenile rheumatoid arthritis (JRA) represent the most common chronic rheumatic inflammatory conditions of childhood. Current estimates indicate that as many as 50,000 children in the US have been diagnosed with some form of JRA (1). The diagnosis of JRA is complicated by the heterogeneous nature of the clinical phenotypes and has broadly been defined by the American College of Rheumatology (ACR) (2) based on systemic involvement (fevers, rash, and involvement of other organ systems besides the musculoskeletal system) and mode of disease onset (pauciarticular [Յ4 joints] versus polyarticular [Ն5 joints]).Evidence suggests that JRA is a complex genetic disorder that is influenced by multiple genetic and environmental factors. The sibling risk ratio for a full sibling of a child with JRA is estimated to be 15 (3). These results are consistent with other autoimmune disorders, such as type 1 diabetes (4).

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Section: Discussionmentioning

confidence: 99%

A genome‐wide scan for juvenile rheumatoid arthritis in affected sibpair families provides evidence of linkage

Thompson¹,

Moroldo²,

Guyer³

et al. 2004

Arthritis & Rheumatism

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show abstract

“…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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“…[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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Genome-Wide Screen for Systemic Lupus Erythematosus Susceptibility Genes in Multiplex Families

Cited by 286 publications

References 30 publications

A genome‐wide scan for juvenile rheumatoid arthritis in affected sibpair families provides evidence of linkage

A genome‐wide scan for juvenile rheumatoid arthritis in affected sibpair families provides evidence of linkage

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

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

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