PAX9 and TGFB3 are linked to susceptibility to nonsyndromic cleft lip with or without cleft palate in the Japanese: population-based and family-based candidate gene analyses

Ichikawa, Eisaburo; Watanabe, Akira; Nakano, Yoko; Akita, Sadanori; Hirano, Akiyoshi; Kinoshita, Akira; Kondo, Shinji; Kishino, Tatsuya; Uchiyama, Takeshi; Niikawa, Norio; Yoshiura, Koh-ichiro

doi:10.1007/s10038-005-0319-8

Cited by 55 publications

(50 citation statements)

References 43 publications

(72 reference statements)

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“…In humans, however, evidence for any involvement of the TGFB3 gene in development of oral clefts has remained inconclusive, with reports of significant (Maestri et al 1997;Lidral et al 1998;Romitti et al 1999;Mitchell et al 2001;Sato et al 2001;Beaty et al 2002;Scapoli et al 2002;Jugessur et al 2003;Kim et al 2003;Slayton et al 2003;Vieira et al 2003;Suzuki et al 2004) as well as negative (Lidral et al 1997;Tanabe et al 2000;Beaty et al 2001;Morkūniené et al 2007) associations among different populations with nonsyndromic orofacial clefts. In this study, we investigated whether the results of Ichikawa et al (2006), who conducted the most comprehensive study of TGFB3 to date, were also apparent in CL/P families of central European descent. We used a case-parent triad design to avoid undetected ethnic stratification as a cause of false positive results.…”

Section: Discussionmentioning

confidence: 99%

“…To test for association, we used three SNPs (IVS1 +2118, IVS1 +5321, and IVS1 -1572), which were significantly associated with CL/P in the study by Ichikawa et al (2006) and which had minor allele frequencies [0.05 in Japanese and central Europeans (see NCBI: http://www.ncbi.nlm. nih.gov/SNP).…”

Section: Genotype Analysismentioning

confidence: 99%

“…single nucleotide polymorphism (SNP) rs3917200] at position -24 relative to intron 4/exon 5 junction to test for involvement of the gene (Lidral et al 1998;Beaty et al 2002). Recently, the study by Ichikawa et al (2006) aimed at a comprehensive coverage of the gene and tested a total of 23 SNP in a Japanese cleft lip and palate (CL/P) population. These authors observed significant association, with P \ 0.01 at four SNPs and P \ 0.05 at an additional five SNPs.…”

Section: Introductionmentioning

confidence: 99%

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TGFB3 displays parent-of-origin effects among central Europeans with nonsyndromic cleft lip and palate

et al. 2008

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Mice with a deletion of Tgf-b3 (-/-) and association studies in humans of different ethnicities support the involvement of TGFB3 in the etiology of orofacial clefts. In this study, we investigated the relevance of TGFB3 in the development of cleft lip and palate (CL/P) among 204 triads of central European origin. Transmission-disequilibrium test (TDT) analysis revealed no significant transmission distortions for each marker alone, and none for any possible haplotypes. However, we found strong evidence for parent-of-origin effects, with lower risk of maternal transmission compared with paternal transmission [I M = 0.38; confidence interval (CI): 0.17-0.86] of the risk allele T to an affected offspring at marker rs2300607. This is also expressed in an increased risk of heterozygous children having the T allele inherited from the father (R P = 3.47; CI: 1.32-9.11). Our data support the involvement of TGFB3 in the development of oral clefts in patients of central European origin.

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Section: Discussionmentioning

confidence: 99%

Section: Genotype Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TGFB3 displays parent-of-origin effects among central Europeans with nonsyndromic cleft lip and palate

et al. 2008

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“…Ichikawa [17] investigated the possible relationship between NCL/P in a Japanese population and multiple polymorphisms of the TGFβ3 gene. The results showed significant association between NCL/P and the TGFβ3 rs2300607 A/T polymorphism.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, another study by Ichikawa and colleagues [17], investigated the relationship between NCL/P and seven candidate genes (TGFβ3, DLX3, PAX9, CLPTM1, TBX10, PVRL1, TBX22), in a Japanese population. The sample consisted of 112 NCL/P cases with their parents and 192 controls.…”

Section: Introductionmentioning

confidence: 99%

Association of TGFβ3 variants with Nonsyndromic Cleft Lip and Palate in Guatemalan Population.

Aljabeiti¹,

Salahuddin²,

Tolar³

et al. 2017

J Den Craniofac Res

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Introduction: Nonsyndromic cleft lip with or without cleft palate (NCL/P) is a common orofacial anomaly with a multifactorial etiology. The genetic component of NCL/P etiology is complex with multiple genes involved. The transforming growth factor beta 3 (TFGβ3) is among the strong susceptibility genes that have been shown to be involved in morphogenesis of lip and palate. Materials and Methods:Case-control study design was used in this study. Cases (n=237) were patients affected with NCL/P identified at the Roosevelt Hospital in Guatemala City, Guatemala. Controls (n=168) were individuals with no history of NCL/P from the same hospital. Genotypes were established by PCR and PAGE for TGFβ3 rs2300607 A/T SNP and by PCR and sequencing for TGFβ3 rs2268625 C/T SNP.Results: For rs2300607A/T, a proportion of TT homozygotes was significantly higher (p=0.029) in cases than in controls (13.92% vs 5.36%). T allele frequency was 0.340 in cases and 0.274 in controls. Also for rs2268625 C/T, a significantly higher proportion of TT homozygotes was found among cases than among controls (p=0.041; 54.0% vs. 48.98%). Frequency of mutated T allele was 0.744 in cases and 0.694 in controls. Conclusion:The results of our study showed for the first time the association between TGFβ3 rs2268625 C/T polymorphism and NCL/P and confirmed for Guatemalan population the association between TGFβ3 rs2300607 A/T polymorphism and NCL/P found by Ichikawa in Japanese by Ichikava et al. in 2006. Thus, our findings suggest that rs2268625 C/T and rs2300607 A/T mutations in the TGFβ3 gene are associated with NCL/P in Guatemalan population. Keywords Nonsyndromic cleft lip and palate TFGβ3;TGFβ3 rs2300607 A/T; TGFβ3 rs2268625; C/T Guatemala; Casecontrol study IntroductionOrofacial clefts (OFC) are among the most common craniofacial malformations in humans. The prevalence rates vary between 0.5 and 3 per 1000 total births, with considerable variations between populations, genders and geographic regions [1].In general, Asian and Amerindian populations have the highest frequencies of OFC, often at 1/500, and Africanderived populations have the lowest frequencies at 1/2500 [2]. Tolarova and Cervenka [3] analyzed the occurrence of OFC in an ethnically diverse population in California. The non-Hispanic whites had the highest birth prevalence of isolated clefts, followed by Asians and blacks who had the lowest values.In the USA, twenty infants are born with an orofacial cleft on an average day, or 7500 every year. Children who have an OFC require several surgical procedures and complex medical treatments and, together with their families, often suffer serious psychological problems. The estimated lifetime medical cost for each child with an OFC is $100,000, amounting to $750 million for all children with OFC born each year in the USA [4].Recently, over 30 potential candidate loci and candidate genes throughout the human genome were identified as strong susceptibility genes for OFC. The MSX1 (4p16.1), TGFα (2p13), TGFβ1 (19q13.1), TGFβ2 (1q41), TGFβ3 (1...

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MTHFR, TGFB3, and TGFA polymorphisms and their association with the risk of non‐syndromic cleft lip and cleft palate in China

Zhu

Lü

et al. 2010

American J of Med Genetics Pt A

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Our previous results indicated a moderate association between the methylenetetrahydrofolate reductase (MTHFR) gene 677C-T variant and an increased risk of non-syndromic cleft lip with or without cleft palate (nsCL/P) among the northern but not southern population in China, suggesting possible genetic heterogeneity in the etiology of nsCL/P between these two populations. It remains unknown whether the transforming growth factor alpha (TGFA) gene TaqI polymorphism and transforming growth factor beta 3 (TGFB3) gene CA repeats influence the risk of nsCL/P differently between the northern and southern Chinese populations. In this study of 188 Chinese case-parent triads, we found an independent association between the TGFB3 variant and risk of nsCL/P (OR = 2.10, 95% CI: 1.25-3.54 for heterozygotes; OR = 1.78, 95% CI: 0.83-3.83 for homozygotes). The MTHFR variant was associated with an increased risk of nsCL/P among children in the north (OR = 3.11, 95% CI: 1.18-8.23 for heterozygotes; OR = 3.36, 95%CI: 1.14-9.93 for homozygotes) and appear to interact marginally with the TGFB3 variant in the occurrence of nsCL/P among southern subjects (OR = 0.26, 95% CI: 0.06-1.07). No association was found between the TGFA variant and risk of nsCL/P in our data. Our results suggest that the TGFB3 gene variant may be an important genetic risk factor for nsCL/P occurrence in Chinese children, and we found no evidence of heterogeneity between northern and southern Chinese populations in the associations between TGFB3 and TGFA variants and risk of nsCL/P, but these results warrant further investigation.

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PAX9 and TGFB3 are linked to susceptibility to nonsyndromic cleft lip with or without cleft palate in the Japanese: population-based and family-based candidate gene analyses

Cited by 55 publications

References 43 publications

TGFB3 displays parent-of-origin effects among central Europeans with nonsyndromic cleft lip and palate

TGFB3 displays parent-of-origin effects among central Europeans with nonsyndromic cleft lip and palate

Association of TGFβ3 variants with Nonsyndromic Cleft Lip and Palate in Guatemalan Population.

MTHFR, TGFB3, and TGFA polymorphisms and their association with the risk of non‐syndromic cleft lip and cleft palate in China

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