Koumakis, E. Wipff, J. Dieudé, P. Ruiz, B. Bouaziz, M. Revillod, L. Guedj, M. Distler, J.H.W. Matucci-Cerinic, M. Humbert, M. Riemekasten, G. Airo, P. Melchers, I. Hachulla, E. Cusi, D. Wichmann, H.-E. Hunzelmann, N. Tiev, K. Caramaschi, P. Diot, E. Kowal-Bielecka, O. Cuomo, G. Walker, U. Czirják, L. Damjanov, N. Lupoli, S. Conti, C. Müller-Nurasyid, M. Müller-Ladner, U. Riccieri, V. Cracowski, J.-L. Cozzi, F. Bournia, V.K. Vlachoyiannopoulos, P. Chiocchia, G. Boileau, C. Allanore, Y.
Introduction: Systemic sclerosis (SSc)-related pulmonary arterial hypertension (PAH) has emerged as a major mortality prognostic factor. Mutations of transforming growth factor beta (TGFβ) receptor genes strongly contribute to idiopathic and familial PAH. Objective: To explore the genetic bases of SSc-PAH, we combined direct sequencing and genotyping of candidate genes encoding TGFβ receptor family members. Materials and methods: TGFβ receptor genes, BMPR2, ALK1, TGFR2 and ENG, were sequenced in 10 SSc-PAH patients, nine SSc and seven controls. In addition, 22 single-nucleotide polymorphisms (SNP) of these four candidate genes were tested for association in a fi rst set of 824 French Caucasian SSc patients (including 54 SSc-PAH) and 939 controls. The replication set consisted of 1516 European SSc (including 219 SSc-PAH) and 3129 controls from the European League Against Rheumatism Scleroderma Trials and Research group network. Results: No mutation was identified by direct sequencing. However, two repertoried SNP, ENG rs35400405 and ALK1 rs2277382, were found in SSc-PAH patients only. The genotyping of 22 SNP including the latter showed that only rs2277382 was associated with SSc-PAH (p=0.0066, OR 2.13, 95% CI 1.24 to 3.65). Nevertheless, this was not replicated with the following result in combined analysis: p=0.123, OR 0.79, 95% CI 0.59 to 1.07. Conclusions: This study demonstrates the lack of association between these TGFβ receptor gene polymorphisms and SSc-PAH using both sequencing and genotyping methods.