Genetic variants in RELN are associated with otosclerosis in a non‐European population from Tunisia

Abstract

SummaryOtosclerosis is a common form of conductive hearing loss, caused by an abnormal bone remodelling in the otic capsule. Both environmental and genetic factors have been implicated in the etiology of this disease. A recent genome wide association study identified two regions associated with otosclerosis, one on chr7q22.1, located in the RELN gene, and one on chr11q13.1. A second study in four European populations has replicated the association of the RELN gene with otosclerosis. To investigate the association of these loci with otosclerosis in a non-European population, we tested 11 SNPs from the two regions in 149 unrelated Tunisian patients and 152 controls. Four SNPs were significantly associated with otosclerosis. Three SNPs are located in the RELN region and the last one is located in the region on chromosome 11. We also observed a significant interaction with gender for rs3914132. This suggests an influence of sex on the association of RELN with otosclerosis. A meta-analysis showed that the disease-associated alleles in the Tunisian sample are the same as in all previously reported associations. Our study provides additional evidence implicating RELN in the development of otosclerosis. Additional functional studies should determine the role of RELN in the physiopathology of this disease.

Controversies in RELN/reelin expression in otosclerosis

“…In conjunction with previous results, Khalfallah et al [29] have found the same associations in a smaller Tunisian population with clinical otosclerosis. They have also described a novel statistical SNP association located to the 11q13.1 region with unknown signiWcance [29]. Furthermore, authors have observed a signiWcant interaction with gender for rs3914132 SNP of RELN suggesting an inXuence of sex on the association of RELN with otosclerosis [29].…”

“…The main power of this study is the relative large number of samples (1.141) obtained from patients with stapes Wxation [28]. In conjunction with previous results, Khalfallah et al [29] have found the same associations in a smaller Tunisian population with clinical otosclerosis. They have also described a novel statistical SNP association located to the 11q13.1 region with unknown signiWcance [29].…”

“…They have also described a novel statistical SNP association located to the 11q13.1 region with unknown signiWcance [29]. Furthermore, authors have observed a signiWcant interaction with gender for rs3914132 SNP of RELN suggesting an inXuence of sex on the association of RELN with otosclerosis [29].…”

Genetic Association and Altered Gene Expression of Osteoprotegerin in Otosclerosis Patients

“…Scanning these loci has not identified any causative genes to date. In parallel, genetic association studies were carried out and showed the association of OTSC with polymorphisms in the COL1A1, TGFB1, BMP2, BMP4, and RELN genes in multiple populations (McKenna et al, 1998;Thys et al, 2007a;Schrauwen et al, 2008;Schrauwen et al, 2009;Khalfallah et al, 2010;Khalfallah et al, 2011;Priyadarshi et al, 2013). Gene expression profiling of disease tissue compared to controls has been suggested as a method to investigate the genetic basis of complex disorders (Xiong et al, 2012).…”

“…Several association studies have been performed to determine the genetic contributors for sporadic forms of OTSC. These studies have shown the association of OTSC with polymorphisms in the COL1A1 (MIM 120150), TGFB1 (MIM 190180), BMP2 (MIM 112261), BMP4 (MIM 112262), and RELN (MIM 600514) genes (McKenna et al, 1998;Thys et al, 2007a;Schrauwen et al, 2008;Schrauwen et al, 2009;Khalfallah et al, 2010;Khalfallah et al, 2011;Priyadarshi et al, 2013;Ealy et al, 2014). Some of the studies failed to replicate these associations due to small sample size or different ethnicity (Tshifularo & Joseph, 2008;Priyadarshi et al, 2010;Iossa et al, 2013).…”