Top

Published in:

01-12-2020 | Otosclerosis | Research article

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

Authors: Amal Bouzid, Adel Tekari, Fida Jbeli, Amine Chakroun, Kirtal Hansdah, Amal Souissi, Neha Singh, Mohamed Ali Mosrati, Imen Achour, Abdelmonem Ghorbel, Ilhem Charfeddine, Puppala Venkat Ramchander, Saber Masmoudi

Published in: BMC Medical Genetics | Issue 1/2020

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-C-C (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.

Ealy M, Smith RJH. The genetics of otosclerosis. Hear Res. 2010;266:70–4.PubMedCrossRef

Harada S, Rodan GA. Control of osteoblast function and regulation of bone mass. Nature. 2003;423:349–55.PubMedCrossRef

Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat Rev Genet. 2003;4:638–49.PubMedCrossRef

Rodan GA. Introduction to bone biology. Bone. 1992;13(Suppl 1):S3–6.PubMedCrossRef

Feng X, McDonald JM. Disorders of bone remodeling. Annu Rev Pathol. 2011;6:121–45.PubMedPubMedCentralCrossRef

Fowler EP. Otosclerosis in identical twins. A study of 40 pairs. Arch Otolaryngol. 1966;83:324–8.PubMedCrossRef

Morrison AW. Genetic factors in otosclerosis. Ann R Coll Surg Engl. 1967;41:202–37.PubMedPubMedCentral

Mowat AJ, Crompton M, Ziff JL, Aldren CP, Lavy JA, Saeed SR, et al. Evidence of distinct RELN and TGFB1 genetic associations in familial and non-familial otosclerosis in a British population. Hum Genet. 2018;137:357–63.PubMedPubMedCentralCrossRef

Schrauwen I, Van Camp G. The etiology of otosclerosis: a combination of genes and environment. Laryngoscope. 2010;120:1195–202.PubMedCrossRef

10.

Schrauwen I, Ealy M, Huentelman MJ, Thys M, Homer N, Vanderstraeten K, et al. A genome-wide analysis identifies genetic variants in the RELN gene associated with otosclerosis. Am J Hum Genet. 2009;84:328–38.PubMedPubMedCentralCrossRef

11.

Ziff JL, Crompton M, Powell HR, Lavy JA, Aldren CP, Steel KP, et al. Mutations and altered expression of SERPINF1 in patients with familial otosclerosis. Hum Mol Genet. 2016;25:2393–403.PubMedPubMedCentral

12.

Schrauwen I, Valgaeren H, Tomas-Roca L, Sommen M, Altunoglu U, Wesdorp M, et al. Variants affecting diverse domains of MEPE are associated with two distinct bone disorders, a craniofacial bone defect and otosclerosis. Genet Med. 2019;21:1199–208.PubMedCrossRef

13.

Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997;89:309–19.PubMedCrossRef

14.

Emery JG, McDonnell P, Burke MB, Deen KC, Lyn S, Silverman C, et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem. 1998;273:14363–7.PubMedCrossRef

15.

Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A. 1998;95:3597–602.PubMedPubMedCentralCrossRef

16.

Tsuda E, Goto M, Mochizuki S, Yano K, Kobayashi F, Morinaga T, et al. Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis. Biochem Biophys Res Commun. 1997;234:137–42.PubMedCrossRef

17.

Yasuda H, Shima N, Nakagawa N, Mochizuki SI, Yano K, Fujise N, et al. Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology. 1998;139:1329–37.PubMedCrossRef

18.

Kang JH, Ko HM, Moon JS, Yoo HI, Jung JY, Kim MS, et al. Osteoprotegerin expressed by osteoclasts: an autoregulator of osteoclastogenesis. J Dent Res. 2014;93:1116–23.PubMedPubMedCentralCrossRef

19.

Ney JT, Fehm T, Juhasz-Boess I, Solomayer EF. RANK, RANKL and OPG expression in breast Cancer – influence on osseous metastasis. Geburtshilfe Frauenheilkd. 2012;72:385–91.PubMedPubMedCentralCrossRef

20.

Boyce BF, Xing L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys. 2008;473:139–46.PubMedPubMedCentralCrossRef

21.

Zehnder AF, Kristiansen AG, Adams JC, Kujawa SG, Merchant SN, McKenna MJ. Osteoprotegrin knockout mice demonstrate abnormal remodeling of the otic capsule and progressive hearing loss. Laryngoscope. 2006;116:201–6.PubMedPubMedCentralCrossRef

22.

Zehnder AF, Kristiansen AG, Adams JC, Merchant SN, McKenna MJ. Osteoprotegerin in the inner ear may inhibit bone remodeling in the otic capsule. Laryngoscope. 2005;115:172–7.PubMedCrossRef

23.

Iossa S, Morello G, Esposito T, Corvino V, Giannini P, Salvato R, et al. Exclusion of TNFRSF11B as candidate gene for Otosclerosis in Campania population. Indian J Otolaryngol Head Neck Surg. 2014;66:297–301.PubMedPubMedCentralCrossRef

24.

Priyadarshi S, Ray CS, Biswal NC, Nayak SR, Panda KC, Desai A, et al. Genetic association and altered gene expression of osteoprotegerin in otosclerosis patients. Ann Hum Genet. 2015;79:225–37.PubMedCrossRef

25.

Khalfallah A, Schrauwen I, Mnejja M, HadjKacem H, Dhouib L, Mosrati MA, et al. Association of COL1A1 and TGFB1 polymorphisms with otosclerosis in a Tunisian population. Ann Hum Genet. 2011;75:598–604.PubMedCrossRef

26.

Khalfallah A, Schrauwen I, Mnaja M, Fransen E, Lahmar I, Ealy M, et al. Genetic variants in RELN are associated with otosclerosis in a non-European population from Tunisia. Ann Hum Genet. 2010;74:399–405.PubMedCrossRef

27.

Ugozzoli L, Wallace RB. Allele-specific polymerase chain reaction. Methods. 1991;2:42–8.CrossRef

28.

Rodriguez S, Gaunt TR, Day IN. Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol. 2009;169:505–14.PubMedPubMedCentralCrossRef

29.

Armitage P, Berry G, Matthews JNS. Statistical methods in medical research: Wiley; 2001. https://www.wiley.com/en-au/Statistical+Methods+in+Medical+Research%2C+4th+Edition-p-9780632052578.

30.

Borenstein M, Hedges LV, Higgins JP, Rothstein HR. A basic introduction to fixed-effect and random-effects models for meta-analysis. Res Synth Methods. 2010;1:97–111.PubMedCrossRef

31.

Huedo-Medina TB, Sanchez-Meca J, Marin-Martinez F, Botella J. Assessing heterogeneity in meta-analysis: Q statistic or I2 index? Psychol Methods. 2006;11:193–206.PubMedCrossRef

32.

Jin C, Hu Y, Chen XC, Zheng FY, Lin F, Zhou K, et al. Laparoscopic versus open myomectomy--a meta-analysis of randomized controlled trials. Eur J Obstet Gynecol Reprod Biol. 2009;145:14–21.PubMedCrossRef

33.

Bedi U, Singh M, Singh P, Molnar J, Khosla S, Arora R. Effects of statins on progression of coronary artery disease as measured by intravascular ultrasound. J Clin Hypertens (Greenwich). 2011;13:492–6.CrossRef

34.

Jiang K, Lepak DP, Hu J, Baer JC. How does human resource management influence organizational outcomes? A meta-analytic investigation of mediating mechanisms. Acad Manag J. 2012;55:1264–94.CrossRef

35.

Vyas A, Swaminathan PD, Zimmerman MB, Olshansky B. Are treatments for vasovagal syncope effective? A meta-analysis. Int J Cardiol. 2013;167:1906–11.PubMedCrossRef

36.

Woolf AD, Akesson K. Understanding the burden of musculoskeletal conditions. The burden is huge and not reflected in national health priorities. BMJ. 2001;322:1079–80.PubMedPubMedCentralCrossRef

37.

DALYs GBD, Collaborators H. Global, regional, and national disability-adjusted life-years (DALYs) for 333 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2016: a systematic analysis for the global burden of disease study 2016. Lancet. 2017;390:1260–344.CrossRef

38.

Briggs AM, Woolf AD, Dreinhofer K, Homb N, Hoy DG, Kopansky-Giles D, et al. Reducing the global burden of musculoskeletal conditions. Bull World Health Organ. 2018;96:366–8.PubMedPubMedCentralCrossRef

39.

Weegerink NJ, Schrauwen I, Huygen PL, Pennings RJ, Cremers CW, Van Camp G, et al. Phenotype of the first otosclerosis family linked to OTSC10. Laryngoscope. 2011;121:838–45.PubMedCrossRef

40.

Ealy M, Smith RJH. Otosclerosis. Adv Otorhinolaryngol. 2011;70:122–9.PubMed

41.

Boyce BF, Xing L. The RANKL/RANK/OPG pathway. Curr Osteoporos Rep. 2007;5:98–104.PubMedCrossRef

42.

Karosi T, Csomor P, Szalmas A, Konya J, Petko M, Sziklai I. Osteoprotegerin expression and sensitivity in otosclerosis with different histological activity. Eur Arch Otorhinolaryngol. 2011;268:357–65.PubMedCrossRef

43.

Lehnerdt G, Unkel C, Metz KA, Jahnke K, Neumann A. Immunohistochemical evidence of BMP-2, −4 and −7 activity in otospongiosis. Acta Otolaryngol. 2008;128:13–7.PubMedCrossRef

44.

Frenz DA, Liu W, Capparelli M. Role of BMP-2a in otic capsule chondrogenesis. Ann N Y Acad Sci. 1996;785:256–8.PubMedCrossRef

45.

Liu W, Oh SH, Kang Yk Y, Li G, Doan TM, Little M, et al. Bone morphogenetic protein 4 (BMP4): a regulator of capsule chondrogenesis in the developing mouse inner ear. Dev Dyn. 2003;226:427–38.PubMedCrossRef

46.

Sommen M, Van Camp G, Liktor B, Csomor P, Fransen E, Sziklai I, et al. Genetic association analysis in a clinically and histologically confirmed otosclerosis population confirms association with the TGFB1 gene but suggests an association of the RELN gene with a clinically indistinguishable otosclerosis-like phenotype. Otol Neurotol. 2014;35:1058–64.PubMedCrossRef

47.

Iossa S, Corvino V, Giannini P, Salvato R, Cavaliere M, Panetti M, et al. The rs39335 polymorphism of the RELN gene is not associated with otosclerosis in a southern Italian population. Acta Otorhinolaryngol Ital. 2013;33:320–3.PubMedPubMedCentral

48.

Sheng X, Cai G, Gong X, Yao Z, Zhu Y. Common variants in OPG confer risk to bone mineral density variation and osteoporosis fractures. Sci Rep. 2017;7:1739.PubMedPubMedCentralCrossRef

49.

Nava-Valdivia CA, Saldana-Cruz AM, Corona-Sanchez EG, Murillo-Vazquez JD, Moran-Moguel MC, Salazar-Paramo M, et al. Polymorphism rs2073618 of the TNFRSF11B (OPG) gene and Bone mineral density in Mexican women with rheumatoid arthritis. J Immunol Res. 2017;2017:7680434.PubMedPubMedCentralCrossRef

Title: Osteoprotegerin gene polymorphisms and otosclerosis: an additional genetic association study, multilocus interaction and meta-analysis
Authors: Amal Bouzid
Adel Tekari
Fida Jbeli
Amine Chakroun
Kirtal Hansdah
Amal Souissi
Neha Singh
Mohamed Ali Mosrati
Imen Achour
Abdelmonem Ghorbel
Ilhem Charfeddine
Puppala Venkat Ramchander
Saber Masmoudi
Publication date: 01-12-2020
Publisher: BioMed Central
Keyword: Otosclerosis
Published in: BMC Medical Genetics / Issue 1/2020
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/s12881-020-01036-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2020

Association of preeclampsia with infant APOL1 genotype in African Americans

Copy number variation of IL17RA gene and its association with the ankylosing spondylitis risk in Iranian patients: a case-control study

Genetic variation in toll like receptors 2, 7, 9 and interleukin-6 is associated with cytomegalovirus infection in late pregnancy

A novel VPS13B mutation in Cohen syndrome: a case report and review of literature

The genome-wide supported CACNA1C gene polymorphisms and the risk of schizophrenia: an updated meta-analysis

Mucopolysaccharidosis type VI: case report with first neonatal presentation with ascites fetalis and rapidly progressive cardiac manifestation