Genetic variants in COL2A1, COL11A2, and IRF6 contribute risk to nonsyndromic cleft palate

Tiit Nikopensius; Triin Jagomägi; Kaarel Krjutškov; Veronika Tammekivi; Mare Saag; Inga Prane; Linda Piekuse; Ilze Akota; Biruta Barkane; Astrida Krumina; Laima Ambrozaityte; Aušra Matulevičiene; Zita Aušrele Kučinskiene; Baiba Lace; Vaidutis Kučinskas; Andres Metspalu

doi:10.1002/bdra.20700

Genetic variants in COL2A1, COL11A2, and IRF6 contribute risk to nonsyndromic cleft palate

Tiit Nikopensius, Triin Jagomägi, Kaarel Krjutškov, Veronika Tammekivi, Mare Saag, Inga Prane, Linda Piekuse, Ilze Akota, Biruta Barkane, Astrida Krumina, Laima Ambrozaityte, Aušra Matulevičiene, Zita Aušrele Kučinskiene, Baiba Lace, Vaidutis Kučinskas, Andres Metspalu

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Abstract

BACKGROUND: Orofacial clefts are among the most common birth defects with a strong genetic component. Nonsyndromic cleft palate (NSCP) is a complex malformation determined by the interaction between multiple genes and environmental risk factors. METHODS: We conducted a case-control association study to investigate the role of 40 candidate genes in predisposition to orofacial clefting. Five hundred ninety-one haplotype tagging single nucleotide polymorphism (tagSNPs) were genotyped in a clefting sample from the Baltic region, composed of 104 patients with nonsyndromic cleft palate and 606 controls from an Estonian, Latvian, and Lithuanian population. RESULTS: In case-control comparisons, the minor alleles of IRF6 rs17389541 (p = 5.45 × 10 ^-4) and COL2A1 rs1793949 (p = 7.26 × 10^-4) were associated with increased risk of NSCP. Multiple haplotypes in COL2A1 and COL11A2 and haplotypes in WNT3, FGFR1, and CLPTM1were associated with NSCP. The strongest associations were found for IRF6 haplotype rs17389541/rs9430018 GT (p = 2.23 × 10^-4) and COL2A1 haplotype rs12822608/rs6823 GC (p = 3.68 × 10^-4). The strongest epistatic interactions were observed between MSX1 and BMP2, FGF1 and PVRL2, and COL2A1 and FGF2 genes. CONCLUSIONS: This study provides for the first time evidence of the implication of IRF6, COL2A1, and WNT3 in the occurrence of NSCP. It is likely that variation in cartilage collagen II and XI genes, IRF6, and the Wnt and FGF signaling pathway genes contributes susceptibility to nonsyndromic cleft palate in Northeastern European populations.

Original language	English
Pages (from-to)	748-756
Number of pages	9
Journal	Birth Defects Research Part A - Clinical and Molecular Teratology
Volume	88
Issue number	9
DOIs	https://doi.org/10.1002/bdra.20700
Publication status	Published - Sept 2010

Keywords*

APEX
Case-control association study
Genotyping
Nonsyndromic cleft palate
SNP

Field of Science*

1.6 Biological sciences
3.2 Clinical medicine

Publication Type*

1.1. Scientific article indexed in Web of Science and/or Scopus database

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10.1002/bdra.20700

https://onlinelibrary.wiley.com/doi/epdf/10.1002/bdra.20700

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Nikopensius, T., Jagomägi, T., Krjutškov, K., Tammekivi, V., Saag, M., Prane, I., Piekuse, L., Akota, I., Barkane, B., Krumina, A., Ambrozaityte, L., Matulevičiene, A., Kučinskiene, Z. A., Lace, B., Kučinskas, V., & Metspalu, A. (2010). Genetic variants in COL2A1, COL11A2, and IRF6 contribute risk to nonsyndromic cleft palate. Birth Defects Research Part A - Clinical and Molecular Teratology, 88(9), 748-756. https://doi.org/10.1002/bdra.20700

@article{5e510bb88526472c8d3507e6ba4bc8f6,

title = "Genetic variants in COL2A1, COL11A2, and IRF6 contribute risk to nonsyndromic cleft palate",

abstract = "BACKGROUND: Orofacial clefts are among the most common birth defects with a strong genetic component. Nonsyndromic cleft palate (NSCP) is a complex malformation determined by the interaction between multiple genes and environmental risk factors. METHODS: We conducted a case-control association study to investigate the role of 40 candidate genes in predisposition to orofacial clefting. Five hundred ninety-one haplotype tagging single nucleotide polymorphism (tagSNPs) were genotyped in a clefting sample from the Baltic region, composed of 104 patients with nonsyndromic cleft palate and 606 controls from an Estonian, Latvian, and Lithuanian population. RESULTS: In case-control comparisons, the minor alleles of IRF6 rs17389541 (p = 5.45 × 10 -4) and COL2A1 rs1793949 (p = 7.26 × 10-4) were associated with increased risk of NSCP. Multiple haplotypes in COL2A1 and COL11A2 and haplotypes in WNT3, FGFR1, and CLPTM1were associated with NSCP. The strongest associations were found for IRF6 haplotype rs17389541/rs9430018 GT (p = 2.23 × 10-4) and COL2A1 haplotype rs12822608/rs6823 GC (p = 3.68 × 10-4). The strongest epistatic interactions were observed between MSX1 and BMP2, FGF1 and PVRL2, and COL2A1 and FGF2 genes. CONCLUSIONS: This study provides for the first time evidence of the implication of IRF6, COL2A1, and WNT3 in the occurrence of NSCP. It is likely that variation in cartilage collagen II and XI genes, IRF6, and the Wnt and FGF signaling pathway genes contributes susceptibility to nonsyndromic cleft palate in Northeastern European populations.",

keywords = "APEX, Case-control association study, Genotyping, Nonsyndromic cleft palate, SNP",

author = "Tiit Nikopensius and Triin Jagom{\"a}gi and Kaarel Krjut{\v s}kov and Veronika Tammekivi and Mare Saag and Inga Prane and Linda Piekuse and Ilze Akota and Biruta Barkane and Astrida Krumina and Laima Ambrozaityte and Au{\v s}ra Matulevi{\v c}iene and Ku{\v c}inskiene, {Zita Au{\v s}rele} and Baiba Lace and Vaidutis Ku{\v c}inskas and Andres Metspalu",

year = "2010",

month = sep,

doi = "10.1002/bdra.20700",

language = "English",

volume = "88",

pages = "748--756",

journal = "Birth Defects Research Part A - Clinical and Molecular Teratology",

issn = "1542-0752",

publisher = "Wiley-Liss Inc.",

number = "9",

}

Nikopensius, T, Jagomägi, T, Krjutškov, K, Tammekivi, V, Saag, M, Prane, I , Piekuse, L , Akota, I, Barkane, B, Krumina, A, Ambrozaityte, L, Matulevičiene, A, Kučinskiene, ZA, Lace, B, Kučinskas, V & Metspalu, A 2010, 'Genetic variants in COL2A1, COL11A2, and IRF6 contribute risk to nonsyndromic cleft palate', Birth Defects Research Part A - Clinical and Molecular Teratology, vol. 88, no. 9, pp. 748-756. https://doi.org/10.1002/bdra.20700

TY - JOUR

T1 - Genetic variants in COL2A1, COL11A2, and IRF6 contribute risk to nonsyndromic cleft palate

AU - Nikopensius, Tiit

AU - Jagomägi, Triin

AU - Krjutškov, Kaarel

AU - Tammekivi, Veronika

AU - Saag, Mare

AU - Prane, Inga

AU - Piekuse, Linda

AU - Akota, Ilze

AU - Barkane, Biruta

AU - Krumina, Astrida

AU - Ambrozaityte, Laima

AU - Matulevičiene, Aušra

AU - Kučinskiene, Zita Aušrele

AU - Lace, Baiba

AU - Kučinskas, Vaidutis

AU - Metspalu, Andres

PY - 2010/9

Y1 - 2010/9

N2 - BACKGROUND: Orofacial clefts are among the most common birth defects with a strong genetic component. Nonsyndromic cleft palate (NSCP) is a complex malformation determined by the interaction between multiple genes and environmental risk factors. METHODS: We conducted a case-control association study to investigate the role of 40 candidate genes in predisposition to orofacial clefting. Five hundred ninety-one haplotype tagging single nucleotide polymorphism (tagSNPs) were genotyped in a clefting sample from the Baltic region, composed of 104 patients with nonsyndromic cleft palate and 606 controls from an Estonian, Latvian, and Lithuanian population. RESULTS: In case-control comparisons, the minor alleles of IRF6 rs17389541 (p = 5.45 × 10 -4) and COL2A1 rs1793949 (p = 7.26 × 10-4) were associated with increased risk of NSCP. Multiple haplotypes in COL2A1 and COL11A2 and haplotypes in WNT3, FGFR1, and CLPTM1were associated with NSCP. The strongest associations were found for IRF6 haplotype rs17389541/rs9430018 GT (p = 2.23 × 10-4) and COL2A1 haplotype rs12822608/rs6823 GC (p = 3.68 × 10-4). The strongest epistatic interactions were observed between MSX1 and BMP2, FGF1 and PVRL2, and COL2A1 and FGF2 genes. CONCLUSIONS: This study provides for the first time evidence of the implication of IRF6, COL2A1, and WNT3 in the occurrence of NSCP. It is likely that variation in cartilage collagen II and XI genes, IRF6, and the Wnt and FGF signaling pathway genes contributes susceptibility to nonsyndromic cleft palate in Northeastern European populations.

AB - BACKGROUND: Orofacial clefts are among the most common birth defects with a strong genetic component. Nonsyndromic cleft palate (NSCP) is a complex malformation determined by the interaction between multiple genes and environmental risk factors. METHODS: We conducted a case-control association study to investigate the role of 40 candidate genes in predisposition to orofacial clefting. Five hundred ninety-one haplotype tagging single nucleotide polymorphism (tagSNPs) were genotyped in a clefting sample from the Baltic region, composed of 104 patients with nonsyndromic cleft palate and 606 controls from an Estonian, Latvian, and Lithuanian population. RESULTS: In case-control comparisons, the minor alleles of IRF6 rs17389541 (p = 5.45 × 10 -4) and COL2A1 rs1793949 (p = 7.26 × 10-4) were associated with increased risk of NSCP. Multiple haplotypes in COL2A1 and COL11A2 and haplotypes in WNT3, FGFR1, and CLPTM1were associated with NSCP. The strongest associations were found for IRF6 haplotype rs17389541/rs9430018 GT (p = 2.23 × 10-4) and COL2A1 haplotype rs12822608/rs6823 GC (p = 3.68 × 10-4). The strongest epistatic interactions were observed between MSX1 and BMP2, FGF1 and PVRL2, and COL2A1 and FGF2 genes. CONCLUSIONS: This study provides for the first time evidence of the implication of IRF6, COL2A1, and WNT3 in the occurrence of NSCP. It is likely that variation in cartilage collagen II and XI genes, IRF6, and the Wnt and FGF signaling pathway genes contributes susceptibility to nonsyndromic cleft palate in Northeastern European populations.

KW - APEX

KW - Case-control association study

KW - Genotyping

KW - Nonsyndromic cleft palate

KW - SNP

UR - http://www.scopus.com/inward/record.url?scp=77956936282&partnerID=8YFLogxK

U2 - 10.1002/bdra.20700

DO - 10.1002/bdra.20700

M3 - Article

C2 - 20672350

AN - SCOPUS:77956936282

SN - 1542-0752

VL - 88

SP - 748

EP - 756

JO - Birth Defects Research Part A - Clinical and Molecular Teratology

JF - Birth Defects Research Part A - Clinical and Molecular Teratology

IS - 9

ER -

Genetic variants in COL2A1, COL11A2, and IRF6 contribute risk to nonsyndromic cleft palate

Abstract

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