-238 and +489 TNF-alpha along with TNF-RII gene polymorphisms associate with the diffuse phenotype in patients with Systemic Sclerosis

Objective: To investigate possible associations of TNF-alpha and TNF-RII gene polymorphisms with diffuse or limited-skin involvement phenotype in a cohort of Systemic Sclerosis (SSc) patients. Methods : One-hundred and fourteen consecutive SSc patients attending the referral centres of three academic hospitals in Italy (University of Naples, Pavia and Udine), 56 with the diffuse (dcSSc) and 58 with limited (lcSSc) skin involvement subsets. and 170 healthy blood donors (HBDs) were included in the study. The extracted DNA was genotyped for the following polymorphisms: TNF-alpha (-238. + 489) and TNF-RII (+196), using the polymerase chain reaction (PCR) and the restriction enzymes BamHI, HpyCH4 IV and NlaIII, respectively. Results : The AG/AA (presence of allele A) genotypes in position -238 and the AG genotype in position +489 of the TNT-alpha gene were found significantly increased in SSc, as a whole, when compared with healthy blood donors (x(v)(=2)(2) = 4.48,p=0.03 for -238 and x(v)(=2)(2) = 7.82 p = 0.02 for +489, respectively). The rare GG genotype in exon 6 (codon 196) of the TNF-RII gene was also found increased in SSc compared to HBDs, even though the difference did not show statistical significance (x(v)(=2)(2) = 3.56,p = 0.17) . The strength of the association was mainly due to the dcSSc phenotype (Fisher test, p = 0.04 for -238, X-v(m2)2 = 10.07 p < 0.01 for +489 and x(v)(2) = 6.25, p = 0.04 for the +196 TNF-RII respectively). Conclusions : TNF-alpha and TNF-RII gene polyrnorphisms seem to contribute to the development of SSc and in parficular to the diffuse phenotype.