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Association Between IRF6 Variants and Nonsyndromic Cleft Lip With or Without Cleft Palate in Chile

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Abstract

The aim of this study was to assess the association between IRF6 single nucleotide polymorphisms and nonsyndromic cleft lip, with or without cleft palate (NSCL/P), in a Chilean population, based on a case-control sample and confirmed in a case-parent trio population. In a sample of 150 Chilean case-parent trios and 164 controls (cohort 1), we evaluated the association between three common IRF6 variants (rs764093, rs2236909, rs2235375) and NSCL/P using odds ratio (OR) for case-control and case-parent trios and in a combined OR of both designs. To confirm associations from the cohort 1, we increased the sample size to 215 triads and 320 controls (cohort 1 + cohort 2). The combined OR for the cohort 1 reveals that the rs2235375 C allele is associated with NSCL/P in Chile (OR 1.34; p = 0.013), which was supported by the results for the two cohorts (OR 1.29; p = 0.006). Bioinformatic prediction showed that this variant, located 27 bp downstream from IRF6 exon 6, potentially alters the splicing process and based on functional annotations is associated with a decrease of gene expression. We propose that the C allele of rs2235375 from IRF6 gene seems to be a risk factor for NSCL/P in a Chilean population. However, we cannot discard a population stratification bias in our findings. On the other hand, further studies are necessary to confirm the biological role of rs2235375 in IRF6 function at craniofacial development level.

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References

  1. Egbe AC. Birth defects in the newborn population: race and ethnicity. Pediatr Neonatol. 2015;56:183–8.

    Article  Google Scholar 

  2. Schutte BC, Murray JC. The many faces and factors of orofacial clefts. Hum Mol Genet. 1999;8:1853–9.

    Article  CAS  Google Scholar 

  3. Nazer HJ, Cifuentes OL. Prevalence of congenital malformations at birth in Chilean maternity hospitals. Rev Med Chil. 2014;142:1150–6.

    Article  Google Scholar 

  4. Dixon MJ, Marazita ML, Beaty TH, Murray JC. Cleft lip and palate: understanding genetic and environmental influences. Nat Rev Genet. 2011;12:167–78.

    Article  CAS  Google Scholar 

  5. Blanco R, Colombo A, Pardo R, Suazo J. Haplotype-based gene-gene interaction of bone morphogenetic protein 4 and interferon regulatory factor 6 in the etiology of non-syndromic cleft lip with or without cleft palate in a Chilean population. Eur J Oral Sci. 2017;125:102–9.

    Article  CAS  Google Scholar 

  6. Watkins SE, Meyer RE, Strauss RP, Aylsworth AS. Classification, epidemiology, and genetics of orofacial clefts. Clin Plast Surg. 2014;41:149–63.

    Article  Google Scholar 

  7. Jugessur A, Murray JC. Orofacial clefting: recent insights into a complex trait. Curr Opin Genet Dev. 2005;15:270–8.

    Article  CAS  Google Scholar 

  8. Kousa YA, Schutte BC. Toward an orofacial gene regulatory network. Dev Dyn. 2016;245:220–32.

    Article  CAS  Google Scholar 

  9. Taniguchi T, Ogasawara K, Takaoka A, Tanaka N. IRF family of transcription factors as regulators of host defense. Annu Rev Immunol. 2001;19:623–55.

    Article  CAS  Google Scholar 

  10. Zucchero TM, Cooper ME, Maher BS, Daack-Hirsch S, Nepomuceno B, Ribeiro L, et al. Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. N Engl J Med. 2004;351:769–80.

    Article  CAS  Google Scholar 

  11. Beaty TH, Murray JC, Marazita ML, Munger RG, Ruczinski I, Hetmanski JB, et al. A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4. Nat Genet. 2010;42:525–9.

    Article  CAS  Google Scholar 

  12. Leslie EJ, O'Sullivan J, Cunningham ML, Singh A, Goudy SL, Ababneh F, et al. Expanding the genetic and phenotypic spectrum of popliteal pterygium disorders. Am J Med Genet A. 2015;167A:545–52.

    Article  Google Scholar 

  13. Moreno-Uribe LM, Fomina T, Munger RG, et al. A population-based study of effects of genetic loci on orofacial clefts. J Dent Res. 2017;96:1322–9.

    Article  CAS  Google Scholar 

  14. Suazo J, Santos JL, Jara L, Blanco R. Linkage disequilibrium between IRF6 variants and nonsyndromic cleft lip/palate in the Chilean population. Am J Med Genet A. 2008;146A:2706–8.

    Article  CAS  Google Scholar 

  15. Santos JL, Pérez F, Carrasco E, Albala C. Use of case-parents trio for epidemiological studies of association between genetic polymorphisms and complex disease. Rev Med Chil. 2002;130:1307–15.

    Article  Google Scholar 

  16. Valenzuela CY. On sociogenetic clines. Ethol Sociobiol. 1988;9:259–68.

    Article  Google Scholar 

  17. Kazeem GR, Farrall M. Integrating case-control and TDT studies. Ann Hum Genet. 2005;69:329–35.

    Article  CAS  Google Scholar 

  18. Martin ER, Kaplan NL. A Monte Carlo procedure for two-stage tests with correlated data. Genet Epidemiol. 2000;18:48–62.

    Article  CAS  Google Scholar 

  19. Glaser B, Holmans P. Comparison of methods for combining case-control and family-based association studies. Hum Hered. 2009;68:106–16.

    Article  Google Scholar 

  20. Spielman RS, McGinnis RE, Ewens WJ. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet. 1993;52:506–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Wallace BC, Dahabreh IJ, Trikalinos TA, et al. Closing the gap between methodologists and end-users: R as a computational back-end. J Stat Softw. 2012;49:1–15.

    Article  Google Scholar 

  22. Desmet FO, Hamroun D, Lalande M, Collod-Béroud G, Claustres, Béroud C. Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res. 2009;37:e67.

    Article  Google Scholar 

  23. Scapoli L, Palmieri A, Martinelli M, Pezzetti F, Carinci P, Tognon M, et al. Strong evidence of linkage disequilibrium between polymorphisms at the IRF6 locus and nonsyndromic cleft lip with or without cleft palate, in an Italian population. Am J Hum Genet. 2005;76:180–3.

    Article  CAS  Google Scholar 

  24. Ibarra-Arce A, García-Álvarez M, Cortés-González D, Ortiz de Zarate-Alarcón G, Flores-Peña L, Sánchez-Camacho S, et al. IRF6 polymorphisms in Mexican patients with non-syndromic cleft lip. Meta Gene. 2015;4:8–16.

    Article  Google Scholar 

  25. Huang L, Jia Z, Shi Y, du Q, Shi J, Wang Z, et al. Genetic factors define CPO and CLO subtypes of nonsyndromicorofacial cleft. PLoS Genet. 2019;15:e1008357.

    Article  CAS  Google Scholar 

  26. Price AL, Zaitlen NA, Reich D, Patterson N. New approaches to population stratification in genome-wide association studies. Nat Rev Genet. 2011;11:459–63.

    Article  Google Scholar 

  27. Epstein MP, Veal CD, Trembath RC, Barker JN, Li C, Satten GA. Genetic association analysis using data from triads and unrelated subjects. Am J Hum Genet. 2005;76:592–608.

    Article  CAS  Google Scholar 

  28. Rothhammer F, Lasserre E, Blanco R, Covarrubias E, Dixon M. Microevolution in human Chilean populations. IV. Shovel shape, mesial-palatal version and other dental traits in Pewenche Indians. Z Morphol Anthropol. 1968;60:162–9.

    CAS  PubMed  Google Scholar 

  29. Palomino HM, Palomino H, Cauvi D, Barton SA, Chakraborty R. Facial clefting and Amerindian admixture in populations of Santiago, Chile. Am J Hum Biol. 1997;9:225–32.

    Article  Google Scholar 

  30. Huang Y, Wu J, Ma J, Beaty TH, Sull JW, Zhu L, et al. Association between IRF6 SNPs and oral clefts in West China. J Dent Res. 2009;88(8):715–8.

    Article  CAS  Google Scholar 

  31. Gurramkonda VB, Syed AH, Murthy J, Lakkakula BVKS. IRF6 rs2235375 single nucleotide polymorphism is associated with isolated non-syndromic cleft palate but not with cleft lip with or without palate in south Indian population. Braz J Otorhinolaryngol. 2018;84:473–7.

    Article  Google Scholar 

  32. Maquat LE. Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nat Rev Mol Cell Biol. 2004;5:89–99.

    Article  CAS  Google Scholar 

  33. Zhang D, Cheng L, Badner JA, Chen C, Chen Q, Luo W, et al. Genetic control of individual differences in gene-specific methylation in human brain. Am J Hum Genet. 2010;86:411–9.

    Article  CAS  Google Scholar 

  34. Vieira AR, Modesto A, Meira R, Barbosa AR, Lidral AC, Murray JC. Interferon regulatory factor 6 (IRF6) and fibroblast growth factor receptor 1 (FGFR1) contribute to human tooth agenesis. Am J Med Genet A. 2007;143A:538–45.

    Article  CAS  Google Scholar 

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Acknowledgements

The authors wish to thank the patients, their families, and healthy individuals who voluntarily cooperated with us and the staff members of all cleft children rehabilitation centres and of the Blood Bank of Hospital San Jose.

Funding

This study was supported by the FONDECYT grant 1061078.

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Authors and Affiliations

  1. Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología, Universidad de Chile, Sergio Livingstone # 943, Santiago, Chile

    José Suazo, Andrea S. Recabarren & Nicolás R. Marín

  2. Programa de Genética Humana, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile

    Rafael Blanco

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  1. José Suazo
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  2. Andrea S. Recabarren
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Correspondence to José Suazo.

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Suazo, J., Recabarren, A.S., Marín, N.R. et al. Association Between IRF6 Variants and Nonsyndromic Cleft Lip With or Without Cleft Palate in Chile. Reprod. Sci. 27, 1857–1862 (2020). https://doi.org/10.1007/s43032-020-00203-9

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