A Genome-wide Analysis Identifies Genetic Variants in the RELN Gene Associated with Otosclerosis

Schrauwen, Isabelle; Ealy, Megan; Huentelman, Matthew J.; Thys, Melissa; Homer, Nils; Vanderstraeten, Kathleen; Fransén, Erik; Corneveaux, Jason J.; Craig, David W.; Claustres, Mireille; Cremers, C.W.R.J.; Dhooge, Ingeborg; Heyning, Paul Van de; Vincent, Robert; Offeciers, Erwin; Smith, Richard J.H.; Camp, Guy Van

doi:10.1016/j.ajhg.2009.01.023

Cited by 64 publications

(120 citation statements)

References 41 publications

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“…In the Caucasian population, it has been observed that each minor allele (C) at rs3914132 in RELN gene is acting as a protective allele and decreases the risk of otosclerosis by 1.54 times. In the same study, expression of reelin was also detected in human stapedial footplate samples without OTSC (Schrauwen et al, 2009a). The exact role of RELN in the bone remodeling of the otic capsule is not yet known.…”

Section: Discussionmentioning

confidence: 51%

“…It is not clear whether the reelin acts as such in the otic capsule of the ear. Although reelin has been shown to be expressed in the human stapedial footplate samples, human inner ear and mouse inner ear, the exact role in pathogenesis of OTSC is not yet known (Schrauwen et al, 2009a).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, a genome-wide association study reported a novel loci (7q22.1) showing a strong association between intron 1-4 of the RELN gene and found a causative single-nucleotide polymorphism (SNP) rs3914132 for OTSC in intron 2 at contig position 2923439 (Schrauwen et al, 2009a). Reelin is a secreted extracellular matrix glycoprotein that plays an important role in neuronal migration during embryonic development of the brain (Rice and Curran, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Lack of association between SNP rs3914132 of the RELN gene and otosclerosis in India

Priyadarshi

Panda²,

Panda³

et al. 2010

Genet. Mol. Res.

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ABSTRACT. Otosclerosis (MIM 166800) is primarily a metabolic bone disorder of the otic capsule, which leads to bony fixation of the stapedial footplate in the oval window; it is among the most common causes of acquired hearing loss. The etiology of this disease is largely unknown, although epidemiological studies suggest the involvement of both genetic and environmental factors. Recently, a reelin gene, SNP rs3914132, located in intron 2, was shown to be associated with otosclerosis in a European population. When we sequenced blood DNA samples of 85 individuals with otosclerosis and 85 controls, four SNPs of this gene: rs3914131 (P = 0.6463), rs3914132 (P = 0.1822), rs9641319 (P = 0.7371), and rs10227303 (P = 0.5669) were not significantly associated with this disease. In one familial case, a novel variant (C/T) at contig position 2923488 was found to be inherited by the proband and affected family members.

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Section: Discussionmentioning

confidence: 51%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lack of association between SNP rs3914132 of the RELN gene and otosclerosis in India

Priyadarshi

Panda²,

Panda³

et al. 2010

Genet. Mol. Res.

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“…Several association studies reveal the implication of COL1A1 (McKenna et al, 1998), TGFB1 (Thys et al, 2007a), BMP2, BMP4 , ACE and AGT (Imauchi et al, 2008) in the development of the disease, although the evidence for association with COL1A1, ACE and AGT is controversial (Rodriguez et al, 2004;Schrauwen et al, 2009c). A recent genome wide association study (GWAS) in a population of European origin identified two new regions associated with otosclerosis (Schrauwen et al, 2009b). The first region, on chr7q22.1, is located in the Reelin (RELN) gene.…”

Section: Introductionmentioning

confidence: 99%

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

Khalfallah¹,

Schrauwen

Mnaja

et al. 2010

Annals of Human Genetics

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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.

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“…For the complex form of otosclerosis, several association studies were performed to identify genes. [9][10][11][12] Many different hypotheses for the etiology of otosclerosis have been proposed, including several theories involving a role for the immune system. It has been suggested that disease pathology can be induced by an autoimmune reaction to type II collagen present in embryonic cartilaginous remnants in the endochondral layer of the otic capsule.…”

Section: Introductionmentioning

confidence: 99%

Involvement of T-cell receptor-β alterations in the development of otosclerosis linked to OTSC2

et al. 2010

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Otosclerosis is a common form of hearing loss, characterized by disordered bone remodeling in the otic capsule. Within the otosclerotic foci, several immunocompetent cells and immune-modulating factors can be found. Different etiological theories involving the immune system have been suggested. However, a genetic component is clearly present. In large otosclerosis families, seven autosomal-dominant loci have been found, but none of the disease-causing genes has been identified. This study focused on the exploration of the second otosclerosis locus on chromosome 7q34-36 (OTSC2), holding the T-cell receptor beta locus (TRB locus). A significantly lower T-cell receptor-b (TCR-b) mRNA expression and percentage of blood circulating TCR-ab þ T cells was detected in OTSC2 patients compared with controls and patients with the complex form of the disease. Further analysis illustrated more significant disturbances in specific T-cell subsets, including an increased CD28 null cell population, suggesting a disturbed T-cell development and ageing in OTSC2 patients. These disturbances could be associated with otosclerotic bone remodeling, given the known effects of immunocompetent cells on bone physiology. These data implicate the TRB locus as the causative gene in the OTSC2 region and represent an important finding in the elucidation of the disease pathology.

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A Genome-wide Analysis Identifies Genetic Variants in the RELN Gene Associated with Otosclerosis

Cited by 64 publications

References 41 publications

Lack of association between SNP rs3914132 of the RELN gene and otosclerosis in India

Lack of association between SNP rs3914132 of the RELN gene and otosclerosis in India

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

Involvement of T-cell receptor-β alterations in the development of otosclerosis linked to OTSC2

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