Osteoprotegerin gene polymorphisms and otosclerosis: an additional genetic association study, multilocus interaction and meta-analysis

Abstract

Background: Otosclerosis (OTSC) is among the most common causes of a late-onset hearing loss in adults and is characterized by an abnormal bone growth in the otic capsule. Alteration in the osteoprotegerin (OPG) expression has been suggested in the implication of OTSC pathogenesis. Methods: A case-control association study of rs2228568, rs7844539, rs3102734 and rs2073618 single nucleotide polymorphisms (SNPs) in the OPG gene was performed in a Tunisian-North African population composed of 183 unrelated OTSC patients and 177 healthy subjects. In addition, a multilocus association and a meta-analysis of existing studies were conducted. Results: Rs3102734 (p = 0.013) and rs2073618 (p = 0.007) were significantly associated with OTSC, which were predominantly detected in females after multiple corrections. Among the OPG studied SNPs, the haplotypes A-A-C-G (p = 0.0001) and A-A-CC (p = 0.0004) were significantly associated with OTSC in females. Multilocus association revealed that the SNPs: rs2073618 in OPG, rs1800472 in TGFβ1, rs39335, rs39350 and rs39374 in RELN, and rs494252 in chromosome 11 showed significant OTSC-associated alleles in Tunisian individuals. In addition, meta-analysis of the rs2073618 SNP in Tunisian, Indian and Italian populations revealed evidence of an association with OTSC (OR of 0.826, 95% CI [0.691-0.987], p = 0.035). Conclusions: Our findings suggest that rs3102734 and rs2073618 variants are associated with OTSC in North African ethnic Tunisian population. Meta-analysis of the rs2073618 in three different ethnic population groups indicated an association with OTSC.

Genetic Association of rs1021188 and DNA Methylation Signatures of TNFSF11 in the Risk of Conductive Hearing Loss

“…Given the critical role of the RANK/RANKL/OPG signaling pathway in maintaining/ regulating proper bone metabolism, SNPs in these pathway genes could also be determinants for bone alterations and the onset of pathological conditions. We provided evidence previously that rs3102734 and rs2073618 variants of the OPG gene are associated with OTSC in a Tunisian North-African ethnic population ( 15 ). To the best of our knowledge, based on a deep literature review and the Mastermind database search, a widely-used bioinformatics platform of a comprehensive genomic association, this is the first study elucidating the roles of genetic association and DNA methylation modifications of TNFSF11 gene in OTSC ( Figure 5 ).…”

“…Nevertheless, case-control, linkage, and association studies have evoked an eventual association of several genes with OTSC in different ethnic populations. These studies reported the possible implications of different genes, including COL1A1, COL1A2 ( 9 ), FGF2 ( 10 ), TGF β 1, BMP2 ( 11 , 12 ), BMP4 ( 11 , 13 ), AGT, ACE ( 14 ), and OPG ( 15 , 16 ). In addition, a genome-wide association study (GWAS) conducted in Belgian-Dutch individuals revealed that a region on chromosome 7q22.1 within the RELN gene is strongly associated with OTSC ( 17 ).…”

Brazilian Society of Otology task force – Otosclerosis: evaluation and treatment

“…OPG has an important anti-osteoclastogenic action and acts indirectly by opposing the anti-TNF-alpha and RAK/RANKL actions. 36 Preliminary studies, not used for clinical practice but in animals, are promising due to the potential action of OPG in the early stage of otosclerotic disease. Therefore, its use should be encouraged in research, initially, only after safety and efficacy have been evaluated in preliminary human studies.…”

“…Compared with normal stapes tissue samples, the mRNA expression of OPG is reduced in patients with otosclerosis. 35 , 36 In addition, homozygous mutations in TNFRSF11B play a role in Paget’s disease, which may also lead to hearing loss, 37 making it an interesting candidate gene for otosclerosis.…”

The risks of RELN polymorphisms and its expression in the development of otosclerosis

“…Despite intensive study on OTSC, till date ten monogenic loci has been mapped but have not yet identified the causal genes [ 4 , 5 ]. Several case-control studies reported a significant association of SNPs in COL1A1 [ 6 , 7 ] , TGF-β1 [ 8 , 9 ] , BMP2 [ 10 ], BMP4 [ 7 , 10 ] and OPG [ 11 , 12 ] genes with OTSC in different populations. Recently, high throughput sequencing has spotted certain pathogenic variants in MEPE , ACAN and SERPINF1 genes with unsettled pathogenicity [ 5 , 13 ].…”