Association of bone morphogenetic proteins with otosclerosis.
We studied the role of polymorphisms in 13 candidate genes on the risk of otosclerosis in two large independent case-control sets. We found significant association in both populations with BMP2 and BMP4, implicating these two genes in the pathogenesis of this disease.


BACKGROUND
Otosclerosis is a progressive disorder of the human temporal bone that leads to conductive hearing loss and in some cases sensorineural or mixed hearing loss. In a few families, it segregates as a monogenic disease with reduced penetrance, but in most patients, otosclerosis is more appropriately considered a complex disorder influenced by genetic and environmental factors.


METHODS
To identify major genetic factors in otosclerosis, we used a candidate gene approach to study two large independent case-control sets of Belgian-Dutch and French origin. Tag single nucleotide polymorphisms (SNPs) in 13 candidate susceptibility genes were studied in a stepwise strategy.


RESULTS
Two SNPs were identified that showed the same significant effect in both populations. The first SNP, rs3178250, is located in the 3' untranslated region of BMP2. Individuals homozygote for the C allele are protected against otosclerosis (combined populations: p = 2.2 x 10(-4); OR = 2.027; 95% CI = 1.380-2.979). The second SNP, rs17563, is an amino acid changing (p.Ala152Val) SNP located in BMP4. The G allele, coding for the amino acid alanine, confers susceptibility in both populations (combined populations: p = 0.002; OR = 1.209; 95% CI: 1.070-1.370).


CONCLUSIONS
These results indicate that polymorphisms in the BMP2 and BMP4 genes, both members of the TGF-beta superfamily, contribute to the susceptibility to otosclerosis and further strengthen the results from the recently reported association of TGFB1 with this disease.
Schrauwen
Isabelle
I
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
Thys
Melissa
M
Vanderstraeten
Kathleen
K
Fransen
Erik
E
Dieltjens
Nele
N
Huyghe
Jeroen R
JR
Ealy
Megan
M
Claustres
Mireille
M
Cremers
Cor R W J
CR
Dhooge
Ingeborg
I
Declau
Frank
F
Van de Heyning
Paul
P
Vincent
Robert
R
Somers
Thomas
T
Offeciers
Erwin
E
Smith
Richard J H
RJ
Van Camp
Guy
G
D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000502:physiology*; D016022:Case-Control Studies; D005260:Female; D034381:Hearing Loss / Q000235:genetics; D006801:Humans; D008297:Male; D010040:Otosclerosis / Q000235:genetics / Q000503:physiopathology*; D020641:Polymorphism, Single Nucleotide; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*
C525718:BMP2 protein, human; C525809:BMP4 protein, human; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D016212:Transforming Growth Factor beta