The hypothesis to be tested in this proposal is that systemic sclerosis (SSC) is a more aggressive disease in non-Caucasians who manifest a higher occurrence of critical organ involvement and a worse prognosis, and that reasons for this may include both genetic factor factors as well as sociodemographic or behavioral determinants. To ascertain this we have established a multi-ethic cohort of 175 patients with SSC of relatively recent onset (
Our specific aims are: 1) To continue followup of the GENISOS cohort of Caucasians, Hispanics and African Americans with SSc of five years of less duration at the University of Texas Health Science Center at Houston, the University of Texas Medical Branch at Galveston and the University of Texas Health Science Center at San Antonio in order to follow their course and outcome at regular intervals for a period of five to seven years and to enroll 80 new cases at the three centers, focusing especially on African American patients. 2) To determine the HLA class II genotypes (HLA-DRB1, DQA1, DQB1 and DPB1 alleles) as well as disease-associated alleles of other candidate genes found to be associated with SSc in ongoing studies in our Division and elsewhere (e.g. fibrillin, SPARC, and others). 3) To determine the sociodemographic parameters (income, education, insurance status) and behavioral features (illness behavior, health care utilization and attitudes, compliance) of these patients. 4) To determine pertinent clinical and laboratory parameters, including disease manifestations (e.g. extent of organ system involvement and co- morbidities), laboratory features (CBC, urinalysis, serum creatinine, serial pulmonary function tests, high resolution CT(HRCT), chest Xray and selected SSc-associated autoantibodies (anti-centromere antibodies (ACA), anti-topoisomerase I (anti-topo I), anti-fibrillin (anti-fib, etc) whose expression has been shown to e associated with specific clinical features of SSc as well as with certain HLA class II alleles. 5) To follow disease progression to outcomes manifested by: a) the development of end-stage pulmonary fibrosis (manifested by a forced vital capacity of < 50% predicted, resting arterial PO2 of < 65n mm Hg of pulmonary hypertension, or lung transplant; b) end-stage scleroderma- related renal disease (defined as """"""""scleroderma renal cris"""""""" or serum creatinine > 3.0 mg/dl not transplant; b) end-stage scleroderma-related renal disease (defined as """"""""scleroderma renal crisis"""""""" or a serum creatinine>3.0 mg/dl not drug related; c) scleroderma heart disease, defined as either congestive heart failure (defined as a left ventricular ejection fraction of <40%) or malignant arrhythmias requiring therapy; d) functional disability (determined by the SF36 and the mHAQ); e) skin score; f) cumulative disease damage (as measured by the Disease Severity Scale proposed by Medsger et al (1) or death. 6) To examine how gene expression (of fibroblasts from involved and uninvolved skin and from peripheral blood leukocytes) at one point early in disease course predict disease progression (using the outcomes stated above). 7) To examine the relative contributions and interactions of genetic, demographic, socioeconomic, cultural, family history and initial and followup clinical and laboratory features on the course and outcome of early SSc through time dependent statistical analytic approaches including proportional hazard Cox-regression models and longitudinal analysis methods. By elucidating the sociodemographic, behavioral and genetic contributions to morbidity and mortality in SSC, interventions would be possible that could improve the course and outcome of this disease.
