The FAS −670A>G polymorphism influences susceptibility to systemic sclerosis phenotypes

• Published in: Arthritis and rheumatism Vol. 60; no. 12; pp. 3815 - 3820
• Main Authors: Broen, J., Gourh, P., Rueda, B., Coenen, M., Mayes, M., Martin, J., Arnett, F. C., Radstake, T. R. D. J.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.12.2009
• Subjects: Adenosine - genetics; fas Receptor - genetics; Female; Genetic Predisposition to Disease; Genotype; Guanosine - genetics; Humans; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Scleroderma, Diffuse - genetics; Scleroderma, Diffuse - pathology; Scleroderma, Limited - genetics; Scleroderma, Limited - pathology
• ISSN: 0004-3591; 1529-0131
• DOI: 10.1002/art.24964

Objective To investigate the possible role of the FAS −670A>G functional polymorphism in the genetic predisposition to systemic sclerosis (SSc) susceptibility or clinical phenotype. Methods A total of 2,900 SSc patients and 3,186 healthy controls were included in this study. We analyzed the genotype and allele frequencies of the FAS −670A>G polymorphism in 9 distinct ethnic cohorts, including 6 cohorts of European ancestry (a Spanish cohort of 228 SSc patients and 265 controls, a Dutch cohort of 203 SSc patients and 277 controls, a German cohort of 313 SSc patients and 247 controls, an Italian cohort of 323 SSc cases and 89 controls, a British cohort of 269 SSc patients, and a Swedish cohort of 182 patients) and 3 distinct ethnic cohorts from the US (a cohort of 1,047 white patients and 692 controls, a cohort of 159 Hispanic patients and 137 controls, and a cohort of 176 black SSc patients and 194 controls). Genotyping was performed using a TaqMan 5′ allelic discrimination assay. Results In the British, Italian, and American white cohorts we observed an association of the FAS −670G allele with limited cutaneous SSc (lcSSc) (odds ratios [ORs] 1.25, 1.43, and 1.18, respectively). A meta‐analysis comprising all 9 cohorts revealed an association of both the FAS −670G allele (OR 1.10) and the FAS −670GG genotype (OR 1.13) with the lcSSc phenotype. In a meta‐analysis including only white subjects, both the FAS −670G allele and the FAS −670GG genotype remained associated with lcSSc (allele OR 1.12; genotype OR 1.16). In addition, a recessive model of the −670GG genotype exhibited a strong association with SSc, lcSSc, and anticentromere antibody–positive lcSSc (OR 1.23, OR 1.33, and OR 1.45, respectively). Conclusion Our data show that the FAS −670A>G polymorphism plays a role in lcSSc susceptibility. A similar trend has been observed in other autoimmune diseases.