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Systemic sclerosis (SSc), a multisystem immunologic disease of unknown etiology, is commonly manifested in the lung as fibrosing alveolitis (FASSc). There is evidence to support the role of genetic factors in the predisposition to pulmonary fibrosis in SSc (HLA DR3/DR52a). This association is not complete and other candidate genes are likely involved. Of these, fibronectin is a growth factor known to play a crucial role in lung fibrosis. Our study investigated whether polymorphisms of the fibronectin gene are associated with lung fibrosis in SSc. Using the polymerase chain reaction and the restriction enzymes HaeIII, MspI, HindIII, and TaqI, we assessed the restriction fragment length polymorphisms (RFLPs) in 161 patients with SSc and 253 healthy control subjects from the United Kingdom. For each restriction enzyme, three genotypes were possible corresponding to the presence of the cutting site on neither, one, or both chromosomes (HaeIII AA, AB, BB; MspI CC, CD, DD; HindIII EE, EF, FF; TaqI GG, GH, HH). There was a significant decrease of genotype BB (FASSc: 17%, control: 34%; Pcorr = 0.006) with a reciprocal increase of genotype AB (FASSc: 62%, control: 46%; Pcorr = 0.022) in FASSc with the HaeIII RFLP. A significant decrease of genotype DD was observed in FASSc (FASSc: 28%, control: 41%; Pcorr = 0.038) with the MspI RFLP. The coassociation of genotypes AB (HaeIII RFLP) and CD (MspI RFLP) was present in 45% of the FASSc group (P = 0.0059), with an increased relative risk of developing fibrosing alveolitis of 1.988. We conclude that genotypes of the fibronectin gene are useful prognostic factors in SSc, helping to predict individuals likely to develop pulmonary fibrosis.