The OVERALL GOAL of this project is to identify genes that influence susceptibility to systemic sclerosis (SSc). Our HYPOTHESES are that there are susceptibility genes that predispose to autoimmunity in general and to SSc in particular;and that each of the unique autoantibody subtypes of SSc has its own set of distinct or incompletely overlapping susceptibility genes. In order to obtain an adequate sample size, we propose to use a 10 scleroderma centers to enroll SSc cases to supplement the 998 current cases in the Scleroderma Family Registry and DNA Repository.
The SPECIFIC AIMS are: 1) To establish a case-control sample of 3,000 systemic sclerosis (SSc) patients and 6,000 controls, frequency matched on age, gender, and ethnicity;2) To identify candidate gene regions by performing a genome wide association analysis using a two-phase design;3) To estimate disease risk associated with identified significant SNPs;4) To analyze the data by autoantibody subsets which define the phenotypes of SSc;5) (exploratory)To perform fine mapping studies of the most strongly associated genes;and 6) To make the data and specimens available for the scientific community. Our preliminary data and that of others indicate that particular gene polymorphisms and HLA class II alleles are more strongly associated with SSc subtypes based on autoantibody expression than with SSc as a single disease entity. Our METHOD OF APPROACH is a 2-phase study initially utilizing the Illumina Human Hap550K Genotyping BeadChip which enables whole-genome genotyping of over 550,000 tagged SNP markers from the HapMap Project on 1,500 cases, then directed SNP genotyping of approximately15,000 most significant SNPs identified in the first stage on 1,500 additional cases and controls. Data on 3,000 age-, gender-, and ethnicity-matched controls for the first and the second stage will be obtained from the NYCP, a longitudinal cohort study (P. Gregersen, Principal Investigator). POWER CALCULATIONS show that we will have adequate power to detect an effect size of OR 1.5-2 at the 10-4 significance level in joint analysis of cases from the two stages. We propose a combination of traditional statistical methods as well as novel methods as ANALYTICAL STRATEGY.
. Scleroderma (systemic sclerosis) is an autoimmune disease characterized by fibrosis and blood vessel damage in the skin and in internal organs which interfere with normal function. The cause is unknown but there is a genetic component, such that only those individuals with the right set of genes are likely to develop this disease. This study will perform a genome-wide scan of DNA from 3,000 scleroderma cases and 6,000 controls in order to find areas of the genome that are different in the cases than in the controls;using this approach, we hope to learn what genes are responsible for susceptibility to scleroderma and which biological pathways are used to cause organ damage in this disease.
|López-Isac, Elena; Bossini-Castillo, Lara; Guerra, Sandra G et al. (2014) Identification of IL12RB1 as a novel systemic sclerosis susceptibility locus. Arthritis Rheumatol 66:3521-3|
|López-Isac, Elena; Bossini-Castillo, Lara; Simeon, Carmen P et al. (2014) A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility. Arthritis Res Ther 16:R6|
|Liu, Xiaochun; Mayes, Maureen D; Tan, Filemon K et al. (2013) Correlation of interferon-inducible chemokine plasma levels with disease severity in systemic sclerosis. Arthritis Rheum 65:226-35|
|Wang, Jiucun; Assassi, Shervin; Guo, Gang et al. (2013) Clinical and serological features of systemic sclerosis in a Chinese cohort. Clin Rheumatol 32:617-21|
|Bossini-Castillo, Lara; Martin, Jose Ezequiel; Broen, Jasper et al. (2013) Confirmation of TNIP1 but not RHOB and PSORS1C1 as systemic sclerosis risk factors in a large independent replication study. Ann Rheum Dis 72:602-7|
|Diaz-Gallo, Lina-Marcela; Simeon, Carmen P; Broen, Jasper C et al. (2013) Implication of IL-2/IL-21 region in systemic sclerosis genetic susceptibility. Ann Rheum Dis 72:1233-8|
|Martin, Jose-Ezequiel; Assassi, Shervin; Diaz-Gallo, Lina-Marcela et al. (2013) A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci. Hum Mol Genet 22:4021-9|
|Elhaj, Mona; Charles, Julio; Pedroza, Claudia et al. (2013) Can serum surfactant protein D or CC-chemokine ligand 18 predict outcome of interstitial lung disease in patients with early systemic sclerosis? J Rheumatol 40:1114-20|
|Dharamsi, Jennifer Warner; Victor, Sandra; Aguwa, Nancy et al. (2013) Morphea in adults and children cohort III: nested case-control study--the clinical significance of autoantibodies in morphea. JAMA Dermatol 149:1159-65|
|Carmona, F David; Gutala, Ramana; Simeon, Carmen P et al. (2012) Novel identification of the IRF7 region as an anticentromere autoantibody propensity locus in systemic sclerosis. Ann Rheum Dis 71:114-9|
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