The FGF and FGFR gene family and risk of cleft lip with or without cleft palate

Hong Wang, Tianxiao Zhang, Tao Wu, Jacqueline B. Hetmanski, Ingo Ruczinski, Holger Schwender, Kung Yee Liang, Tanda Murray, M. Daniele Fallin, Richard J. Redett, Gerald V. Raymond, Sheng Chih Jin, Yah Huei Wu Chou, Philip Kuo Ting Chen, Vincent Yeow, Samuel S. Chong, Felicia S.H. Cheah, Sun Ha Jee, Ethylin W. Jabs, Alan F. Scott & 1 others Terri H. Beaty

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Background: Isolated, nonsyndromic cleft lip with or without cleft palate is a common human congenital malformation with a complex and heterogeneous etiology. Genes coding for fibroblast growth factors and their receptors (FGF/FGFR genes) are excellent candidate genes. Methods: We tested single-nucleotide polymorphic markers in 10 FGF/FGFR genes (including FGFBP1, FGF2, FGF10, FGF18, FGFR1, FGFR2, FGF19, FGF4, FGF3, and FGF9) for genotypic effects, interactions with one another, and with common maternal environmental exposures in 221 Asian and 76 Maryland case-parent trios ascertained through a child with isolated, nonsyndromic cleft lip with or without cleft palate. Results: Both FGFR1 and FGF19 yielded evidence of linkage and association in the transmission disequilibrium test, confirming previous evidence. Haplotypes of three single-nucleotide polymorphisms in FGFR1 were nominally significant among Asian trios. Estimated odds ratios for individual single-nucleotide polymorphic markers and haplotypes of multiple markers in FGF19 ranged from 1.31 to 1.87. We also found suggestive evidence of maternal genotypic effects for markers in FGF2 and FGF10 among Asian trios. Tests for gene-environment (G × E) interaction between markers in FGFR2 and maternal smoking or multivitamin supplementation yielded significant evidence of G × E interaction separately. Tests of gene-gene (G × G) interaction using Cordell's method yielded significant evidence between single-nucleotide polymorphisms in FGF9 and FGF18, which was confirmed in an independent sample of trios from an international consortium. Conclusion: Our results suggest several genes in the FGF/FGFR family may influence risk for isolated, nonsyndromic cleft lip with or without cleft palate through distinct biological mechanisms.

Original languageEnglish
Pages (from-to)96-103
Number of pages8
JournalCleft Palate-Craniofacial Journal
Volume50
Issue number1
DOIs
Publication statusPublished - Jan 1 2013
Externally publishedYes

Fingerprint

Cleft Lip
Cleft Palate
Genes
Gene-Environment Interaction
Fibroblast Growth Factor 2
Haplotypes
Single Nucleotide Polymorphism
Nucleotides
Maternal Exposure
Fibroblast Growth Factor Receptors
Environmental Exposure
Smoking
Odds Ratio
Mothers

Keywords

  • FGF/FGFR
  • Gene-environment interaction
  • Gene-gene interaction
  • Maternal effects
  • Oral clefts

ASJC Scopus subject areas

  • Oral Surgery
  • Otorhinolaryngology

Cite this

Wang, H., Zhang, T., Wu, T., Hetmanski, J. B., Ruczinski, I., Schwender, H., ... Beaty, T. H. (2013). The FGF and FGFR gene family and risk of cleft lip with or without cleft palate. Cleft Palate-Craniofacial Journal, 50(1), 96-103. https://doi.org/10.1597/11-132

The FGF and FGFR gene family and risk of cleft lip with or without cleft palate. / Wang, Hong; Zhang, Tianxiao; Wu, Tao; Hetmanski, Jacqueline B.; Ruczinski, Ingo; Schwender, Holger; Liang, Kung Yee; Murray, Tanda; Daniele Fallin, M.; Redett, Richard J.; Raymond, Gerald V.; Jin, Sheng Chih; Chou, Yah Huei Wu; Chen, Philip Kuo Ting; Yeow, Vincent; Chong, Samuel S.; Cheah, Felicia S.H.; Jee, Sun Ha; Jabs, Ethylin W.; Scott, Alan F.; Beaty, Terri H.

In: Cleft Palate-Craniofacial Journal, Vol. 50, No. 1, 01.01.2013, p. 96-103.

Research output: Contribution to journalArticle

Wang, H, Zhang, T, Wu, T, Hetmanski, JB, Ruczinski, I, Schwender, H, Liang, KY, Murray, T, Daniele Fallin, M, Redett, RJ, Raymond, GV, Jin, SC, Chou, YHW, Chen, PKT, Yeow, V, Chong, SS, Cheah, FSH, Jee, SH, Jabs, EW, Scott, AF & Beaty, TH 2013, 'The FGF and FGFR gene family and risk of cleft lip with or without cleft palate', Cleft Palate-Craniofacial Journal, vol. 50, no. 1, pp. 96-103. https://doi.org/10.1597/11-132
Wang H, Zhang T, Wu T, Hetmanski JB, Ruczinski I, Schwender H et al. The FGF and FGFR gene family and risk of cleft lip with or without cleft palate. Cleft Palate-Craniofacial Journal. 2013 Jan 1;50(1):96-103. https://doi.org/10.1597/11-132
Wang, Hong ; Zhang, Tianxiao ; Wu, Tao ; Hetmanski, Jacqueline B. ; Ruczinski, Ingo ; Schwender, Holger ; Liang, Kung Yee ; Murray, Tanda ; Daniele Fallin, M. ; Redett, Richard J. ; Raymond, Gerald V. ; Jin, Sheng Chih ; Chou, Yah Huei Wu ; Chen, Philip Kuo Ting ; Yeow, Vincent ; Chong, Samuel S. ; Cheah, Felicia S.H. ; Jee, Sun Ha ; Jabs, Ethylin W. ; Scott, Alan F. ; Beaty, Terri H. / The FGF and FGFR gene family and risk of cleft lip with or without cleft palate. In: Cleft Palate-Craniofacial Journal. 2013 ; Vol. 50, No. 1. pp. 96-103.
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abstract = "Background: Isolated, nonsyndromic cleft lip with or without cleft palate is a common human congenital malformation with a complex and heterogeneous etiology. Genes coding for fibroblast growth factors and their receptors (FGF/FGFR genes) are excellent candidate genes. Methods: We tested single-nucleotide polymorphic markers in 10 FGF/FGFR genes (including FGFBP1, FGF2, FGF10, FGF18, FGFR1, FGFR2, FGF19, FGF4, FGF3, and FGF9) for genotypic effects, interactions with one another, and with common maternal environmental exposures in 221 Asian and 76 Maryland case-parent trios ascertained through a child with isolated, nonsyndromic cleft lip with or without cleft palate. Results: Both FGFR1 and FGF19 yielded evidence of linkage and association in the transmission disequilibrium test, confirming previous evidence. Haplotypes of three single-nucleotide polymorphisms in FGFR1 were nominally significant among Asian trios. Estimated odds ratios for individual single-nucleotide polymorphic markers and haplotypes of multiple markers in FGF19 ranged from 1.31 to 1.87. We also found suggestive evidence of maternal genotypic effects for markers in FGF2 and FGF10 among Asian trios. Tests for gene-environment (G × E) interaction between markers in FGFR2 and maternal smoking or multivitamin supplementation yielded significant evidence of G × E interaction separately. Tests of gene-gene (G × G) interaction using Cordell's method yielded significant evidence between single-nucleotide polymorphisms in FGF9 and FGF18, which was confirmed in an independent sample of trios from an international consortium. Conclusion: Our results suggest several genes in the FGF/FGFR family may influence risk for isolated, nonsyndromic cleft lip with or without cleft palate through distinct biological mechanisms.",
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T1 - The FGF and FGFR gene family and risk of cleft lip with or without cleft palate

AU - Wang, Hong

AU - Zhang, Tianxiao

AU - Wu, Tao

AU - Hetmanski, Jacqueline B.

AU - Ruczinski, Ingo

AU - Schwender, Holger

AU - Liang, Kung Yee

AU - Murray, Tanda

AU - Daniele Fallin, M.

AU - Redett, Richard J.

AU - Raymond, Gerald V.

AU - Jin, Sheng Chih

AU - Chou, Yah Huei Wu

AU - Chen, Philip Kuo Ting

AU - Yeow, Vincent

AU - Chong, Samuel S.

AU - Cheah, Felicia S.H.

AU - Jee, Sun Ha

AU - Jabs, Ethylin W.

AU - Scott, Alan F.

AU - Beaty, Terri H.

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N2 - Background: Isolated, nonsyndromic cleft lip with or without cleft palate is a common human congenital malformation with a complex and heterogeneous etiology. Genes coding for fibroblast growth factors and their receptors (FGF/FGFR genes) are excellent candidate genes. Methods: We tested single-nucleotide polymorphic markers in 10 FGF/FGFR genes (including FGFBP1, FGF2, FGF10, FGF18, FGFR1, FGFR2, FGF19, FGF4, FGF3, and FGF9) for genotypic effects, interactions with one another, and with common maternal environmental exposures in 221 Asian and 76 Maryland case-parent trios ascertained through a child with isolated, nonsyndromic cleft lip with or without cleft palate. Results: Both FGFR1 and FGF19 yielded evidence of linkage and association in the transmission disequilibrium test, confirming previous evidence. Haplotypes of three single-nucleotide polymorphisms in FGFR1 were nominally significant among Asian trios. Estimated odds ratios for individual single-nucleotide polymorphic markers and haplotypes of multiple markers in FGF19 ranged from 1.31 to 1.87. We also found suggestive evidence of maternal genotypic effects for markers in FGF2 and FGF10 among Asian trios. Tests for gene-environment (G × E) interaction between markers in FGFR2 and maternal smoking or multivitamin supplementation yielded significant evidence of G × E interaction separately. Tests of gene-gene (G × G) interaction using Cordell's method yielded significant evidence between single-nucleotide polymorphisms in FGF9 and FGF18, which was confirmed in an independent sample of trios from an international consortium. Conclusion: Our results suggest several genes in the FGF/FGFR family may influence risk for isolated, nonsyndromic cleft lip with or without cleft palate through distinct biological mechanisms.

AB - Background: Isolated, nonsyndromic cleft lip with or without cleft palate is a common human congenital malformation with a complex and heterogeneous etiology. Genes coding for fibroblast growth factors and their receptors (FGF/FGFR genes) are excellent candidate genes. Methods: We tested single-nucleotide polymorphic markers in 10 FGF/FGFR genes (including FGFBP1, FGF2, FGF10, FGF18, FGFR1, FGFR2, FGF19, FGF4, FGF3, and FGF9) for genotypic effects, interactions with one another, and with common maternal environmental exposures in 221 Asian and 76 Maryland case-parent trios ascertained through a child with isolated, nonsyndromic cleft lip with or without cleft palate. Results: Both FGFR1 and FGF19 yielded evidence of linkage and association in the transmission disequilibrium test, confirming previous evidence. Haplotypes of three single-nucleotide polymorphisms in FGFR1 were nominally significant among Asian trios. Estimated odds ratios for individual single-nucleotide polymorphic markers and haplotypes of multiple markers in FGF19 ranged from 1.31 to 1.87. We also found suggestive evidence of maternal genotypic effects for markers in FGF2 and FGF10 among Asian trios. Tests for gene-environment (G × E) interaction between markers in FGFR2 and maternal smoking or multivitamin supplementation yielded significant evidence of G × E interaction separately. Tests of gene-gene (G × G) interaction using Cordell's method yielded significant evidence between single-nucleotide polymorphisms in FGF9 and FGF18, which was confirmed in an independent sample of trios from an international consortium. Conclusion: Our results suggest several genes in the FGF/FGFR family may influence risk for isolated, nonsyndromic cleft lip with or without cleft palate through distinct biological mechanisms.

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