The FAS -670A>G polymorphism influences susceptibility to systemic sclerosis phenotypes.
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).


CONCLUSIONS
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.
Broen
J
J
Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Gourh
P
P
Rueda
B
B
Coenen
M
M
Mayes
M
M
Martin
J
J
Arnett
F C
FC
Radstake
T R D J
TR
D000241:Adenosine / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006151:Guanosine / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D045743:Scleroderma, Diffuse / Q000235:genetics* / Q000473:pathology; D045745:Scleroderma, Limited / Q000235:genetics* / Q000473:pathology; D019014:fas Receptor / Q000235:genetics*
C491901:FAS protein, human; D019014:fas Receptor; D006151:Guanosine; D000241:Adenosine