TGFβ receptor gene variants in systemic sclerosis-related pulmonary arterial hypertension: results from a multicentre EUSTAR study of European Caucasian patients.
BACKGROUND
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.


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.
Paris Descartes University, INSERM U1016, Institut Cochin, Sorbonne Paris Cité, Paris, France.
Eugénie
E
Koumakis
Julien
J
Wipff
Philippe
P
Dieudé
Barbara
B
Ruiz
Matthieu
M
Bouaziz
Lucile
L
Revillod
Mickaël
M
Guedj
Jörg H W
JH
Distler
Marco
M
Matucci-Cerinic
Marc
M
Humbert
Gabriella
G
Riemekasten
Paolo
P
Airo
Inga
I
Melchers
Eric
E
Hachulla
Daniele
D
Cusi
H-Erich
HE
Wichmann
Nicolas
N
Hunzelmann
Kiet
K
Tiev
Paola
P
Caramaschi
Elisabeth
E
Diot
Otylia
O
Kowal-Bielecka
Giovanna
G
Cuomo
Ulrich
U
Walker
László
L
Czirják
Nemanja
N
Damjanov
Sara
S
Lupoli
Costanza
C
Conti
Martina
M
Müller-Nurasyid
Ulf
U
Müller-Ladner
Valeria
V
Riccieri
Jean-Luc
JL
Cracowski
Franco
F
Cozzi
Vasiliki Kalliopi
VK
Bournia
P
P
Vlachoyiannopoulos
Gilles
G
Chiocchia
Catherine
C
Boileau
Yannick
Y
Allanore
D004252:DNA Mutational Analysis; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D020641:Polymorphism, Single Nucleotide; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D012595:Scleroderma, Systemic / Q000150:complications / Q000235:genetics* / Q000473:pathology; D044465:White People / Q000235:genetics*
D018125:Receptors, Transforming Growth Factor beta