Genome-Wide Association Study in Systemic Sclerosis

The Scleroderma Family Registry and DNA Repository (Registry) was initially developed as a registry and bio-specimen repository of patients with systemic sclerosis (scleroderma), family members and unaffected healthy controls. A case-control design was later adopted due to the lack of availability of many parents in this adult-onset disease, which precluded a linkage approach. In addition to collecting demographic data, the registry included the collection of disease-pertinent, cross-sectional, clinical information from medical records of affected participants. Registry participants were >/= 18 years of age at enrollment. On the basis of medical record review, all cases were verified by the principal investigator to meet the eligibility criteria.

800+ blood samples from verified affected cases of European ancestry were selected for a Genome Wide Association Study (GWAS). These genetic data, as well as phenotypic data, are available in dbGaP. DNA, serum and plasma from Registry participants, which are currently being stored in the University of Texas Health Science Center - Houston, Scleroderma Registry Genetic Repository, are available for research purposes. However, not all of the 800+ registry participants who submitted a blood sample currently have DNA available due to depletion of some samples.

In addition to including SNP data from the genome-wide (first study release) and immunochip (second study release) scan on the 800+ samples, the dbGaP database provides a set of data tables with phenotypic information collected from the participants in the registry.

• Study Weblinks:
  • Scleroderma Family Registry and DNA Repository
• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 833
• Subject Sample Telemetry Report (SSTR)

• BioProject
• PubMed
• BioSample
• MeSH
• PMC

Individuals are considered eligible if the diagnosis of systemic sclerosis is confirmed by meeting the 1980 Preliminary Criteria for the Classification of Systemic Sclerosis OR if 3 of the 5 CREST features are documented to be present by medical record review as outlined below.

Inclusion Criteria: 1980 Preliminary Criteria for the Classification of Systemic Sclerosis

The American College of Rheumatology (former American Rheumatism Association - ARA) has defined criteria, that are 97% sensitive and 98% specific for systemic sclerosis (SSc) as follows:

Major criterion:

• Skin thickening (skin sclerosis) involving the fingers and extending proximal to the metacarpal phalangeal (MCP) joints.

Minor criteria:

• Sclerodactyly (skin thickening confined to the fingers and/or toes)
• Digital pitting scars or loss of substance of the digital finger pads (pulp loss)
• Bilateral basilar pulmonary fibrosis

The patient should fulfill the major criterion or two of the three minor criteria.

Subsets of Systemic Sclerosis

In addition, a diagnosis of systemic sclerosis is considered present if at least 3 out of 5 of the CREST features are present. These include: Calcinosis, Raynaud's phenomenon, esophageal dysmotility, Sclerodactyly and Telangiectasias.

Exclusion Criteria:

• <18 years of age
• Unable to provide consent

Scleroderma Family Registry and DNA Repository/Two-Stage Genome Wide Association Study Timeline

• September 2000 - Scleroderma Family Registry and DNA Repository grant awarded (R01-AR-055258)
• August 2000 - IRB approval Wayne State University, Detroit MI
• July 2001 - first patient enrolled, first blood sample obtained
• January 2002 - project relocated to the University of Texas - Houston Medical School
• January 2002 - IRB approval University of Texas - Houston Medical School
• September 2008 - "Two Stage Genome Wide Association Study in Systemic Sclerosis" awarded (R01-AR-055258)
• December 2008 - Genotyping started
• April 2009 - Data analysis and combination with cases from European colleagues
• April 2010 - Publication Nature Genetics
• September 2011 - First dbGaP study release (Illumina 610-Quad array data)
• September 2016 - Second dbGaP study release (Illumina/Infinium Immunobeadchip array data)

• Primary Phenotype: Systemic Sclerosis
• Scleroderma, Systemic

• Principal Investigator (Study Leadership)
  • Maureen D. Mayes, MD, MPH. University of Texas Health Science Center, Houston, TX, USA.
• Co-investigator
  • Frank C. Arnett, MD (now retired). University of Texas Health Science Center, Houston, TX, USA.
• Co-Investigator
  • Filemon Tan, MD, PhD. University of Texas Health Science Center, Houston, TX, USA.
  • Olga Gorlova, PhD. M.D. Anderson Cancer Center, Houston, TX, USA.
• Genetic Repository
  • Maureen D. Mayes, MD, MPH. University of Texas Health Science Center, Houston, TX, USA.
• Genotyping Center: Director and Co-Investigator
  • Peter K. Gregersen, MD. The Robert S. Boas Center for Genomics and Human Genetics of the Feinstein Institute for Medical Research, Manhasset, NY, USA.
• Genotyping Center: Co-Investigator
  • Annette Lee, PhD. The Robert S. Boas Center for Genomics and Human Genetics of the Feinstein Institute for Medical Research, Manhasset, NY, USA.
• Funding Source
  • R01-AR-055258 The Scleroderma Family Registry and DNA Repository. National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
  • N01-AR-0-2251 Two-Stage Genome Wide Association Study in Systemic Sclerosis. National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.