TGFβ receptor gene variants in systemic sclerosis-related pulmonary arterial hypertension: results from a multicentre EUSTAR study of European Caucasian patients.
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Koumakis Eugénie, Wipff Julien, Dieudé Philippe, Ruiz Barbara, Bouaziz Matthieu, Revillod Lucile, Guedj Mickaël, Distler Jörg H W, Matucci-Cerinic Marco, Humbert Marc, Riemekasten Gabriella, Airo Paolo, Melchers Inga, Hachulla Eric, Cusi Daniele, Wichmann H-Erich, Hunzelmann Nicolas, Tiev Kiet, Caramaschi Paola, Diot Elisabeth, Kowal-Bielecka Otylia, Cuomo Giovanna, Walker Ulrich, Czirják László, Damjanov Nemanja, Lupoli Sara, Conti Costanza, Müller-Nurasyid Martina, Müller-Ladner Ulf, Riccieri Valeria, Cracowski Jean-Luc, Cozzi Franco, Bournia Vasiliki Kalliopi, Vlachoyiannopoulos P, Chiocchia Gilles, Boileau Catherine, Allanore Yannick
Аннотация
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 first 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.