Mutations of the cystic fibrosis gene in patients with bronchiectasis associated with rheumatoid arthritis.
OBJECTIVE
In cystic fibrosis, mutations of the CFTR gene lead to diffuse bronchiectasis (DB). DB is also associated with other diseases including rheumatoid arthritis (RA) in which the role of genetic factors in the predisposition to DB remains unclear.


METHODS
A family-based association study was carried out to determine whether the frequency of CFTR mutations was higher in patients with RA-associated DB and to determine whether a causal relationship could be established between the variant and the disease by evaluating its cosegregation with DB within families. Families of probands with RA-DB were included if one first-degree relative had RA and/or DB. The controls comprised healthy subjects requesting genetic counselling because their partner had cystic fibrosis.


RESULTS
The frequency of CFTR mutations was higher in family members with RA-DB or DB only than in unaffected relatives (p<0.005 for each comparison) and in unrelated healthy controls (p<0.001 for each comparison) but not in family members with RA only. CFTR mutations were more frequent in family members with RA-DB than in those with RA only (OR 5.30, 95% CI 2.48 to 11.33; p<5×10(-5)). They cosegregated with RA-DB in the families (sib-TDT=10.82, p=0.005).


CONCLUSIONS
RA-DB should be added to the list of phenotypes in which CFTR mutations are pathogenic. CFTR mutation is the first genetic defect linked to an extra-articular feature of RA to be described. CFTR mutations in patients with RA appear to be an important marker of the risk of associated DB, which has been linked to a less favourable prognosis.
Center for Rare Systemic Auto-immune Diseases, Department of Rheumatology, Centre Hospitalier du Mans, 194 avenue Rubillard, 72000 Le Mans, France. xpuechal@ch-lemans.fr
Xavier
X
Puéchal
Thierry
T
Bienvenu
Emmanuelle
E
Génin
Jean-Marie
JM
Berthelot
Jean
J
Sibilia
Philippe
P
Gaudin
Christian
C
Marcelli
Sandra
S
Lasbleiz
Laëtitia
L
Michou
François
F
Cornélis
André
A
Kahan
Daniel J
DJ
Dusser
D001172:Arthritis, Rheumatoid / Q000150:complications / Q000235:genetics*; D001987:Bronchiectasis / Q000209:etiology / Q000235:genetics*; D016022:Case-Control Studies; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies / Q000379:methods; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D009154:Mutation; D010641:Phenotype
D019005:Cystic Fibrosis Transmembrane Conductance Regulator