Association of bone morphogenetic proteins with otosclerosis

Abstract

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.

Introduction: 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.

Materials and 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.

FIG. 1

Bar charts of SNP rs3178250 (BMP2) and rs17563 (BMP4) showing the distribution of genotypes in the Belgian-Dutch and French population. (A) Bar chart of rs3178250 in the Belgian-Dutch population. Number of patients: CC, 23; CT, 207; TT, 378. Number of controls: CC, 44; CT, 189; TT, 371. (B) Bar chart of rs3178250 in the French population. Number of patients: CC, 18; CT, 165; TT, 271. Number of controls: CC, 38; CT, 171; TT, 275. (C) Bar chart of rs17563 in the Belgian-Dutch population. Number of patients: GG, 203; GA, 319; AA, 94. Number of controls: GG, 176; GA, 307; AA, 121. (D) Bar chart of rs17563 in the French population. Number of patients: GG, 114; GA, 243; AA, 94. Number of controls: GG, 105; GA, 247; AA, 129.