scholarly journals High incidence and regional distribution of cleft palate in Finns are associated with a functional variant in an IRF6 enhancer

2021 ◽  
Author(s):  
Fedik Rahimov ◽  
Pekka Nieminen ◽  
Priyanka Kumari ◽  
Emma Juuri ◽  
Tiit Nikopensius ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cleft Palate ◽  
Cleft Lip ◽  
Genome Wide Association Study ◽  
Risk Allele ◽  
Regional Distribution ◽  
Orofacial Cleft ◽  
Oral Epithelial Cells ◽  
A Genome ◽  
Oral Epithelial

Abstract In Finland the frequency of isolated cleft palate (CP) is higher than that of isolated cleft lip (CL) or cleft lip with cleft palate (CLP). This trend contrasts to that in other countries but its genetic underpinnings are unknown. We performed a genome-wide association study for orofacial cleft, which includes CL, CLP, and CP in the Finnish population. We identified rs570516915, a single nucleotide polymorphism that is virtually specific to Finns and Estonians, as being strongly associated with orofacial cleft, and predominantly with CP (p = 5.25 x 10-34, OR = 8.65, 95% CI 6.11-12.25). The risk allele frequency for rs570516915 parallels the regional variation of CP prevalence in Finland, and the association was replicated in an independent sample of CP cases from Estonia (p < 1.3 x 10-11). The rs570516915 variant lies in an IRF6 (Interferon Regulatory Factor 6) enhancer active in ectodermal and oral epithelial cells. Other variants in the IRF6 locus, including those in the same enhancer, are associated with orofacial cleft, but predominantly with CL or CLP, suggesting shared mechanisms in the distinct processes of lip and palate development. By luciferase and transgenic mouse reporter assays we found that the risk allele of rs570516915 diminishes the activity of the enhancer. CRISPR-Cas9 edited oral epithelial cells demonstrate that rs570516915 disrupts an IRF6 binding site and decreases the expression of IRF6, suggesting impaired IRF6 autoregulation as the molecular mechanism underlying risk for CP.

scholarly journals Erratum: A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4

2010 ◽  
Vol 42 (8) ◽  
pp. 727-727 ◽  
Author(s):  
Terri H Beaty ◽  
Jeffrey C Murray ◽  
Mary L Marazita ◽  
Ronald G Munger ◽  
Ingo Ruczinski Jacqueline B Hetmanski ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Association Study ◽  
Cleft Lip ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Risk Variants ◽  
Genome Wide ◽  
A Genome

scholarly journals Identification of Copy Number Variation Among Nonsyndromic Cleft Lip and or Without Cleft Palate With Hypodontia: A Genome-Wide Association Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Norliana Ghazali ◽  
Normastura Abd Rahman ◽  
Azlina Ahmad ◽  
Sarina Sulong ◽  
Thirumulu Ponnuraj Kannan
Keyword(s):  
Copy Number Variation ◽  
Cleft Palate ◽  
Copy Number ◽  
Cleft Lip ◽  
Genome Wide Association Study ◽  
Quantitative Polymerase Chain Reaction ◽  
Copy Number Variations ◽  
Genome Wide ◽  
A Genome ◽  
Number Variation

Nonsyndromic cleft lip and or without cleft palate (NSCL/P) with the hypodontia is a common developmental abnormality in humans and animals. This study identified the genetic aberration involved in both NSCL/P and hypodontia pathogenesis. A cross-sectional study using genome-wide study copy number variation-targeted CytoScan 750K array carried out on salivary samples from 61 NSCL/P and 20 noncleft with and without hypodontia Malay subjects aged 7–13 years old. Copy number variations (CNVs) of SKI and fragile histidine triad (FHIT) were identified in NSCL/P and noncleft children using quantitative polymerase chain reaction (qPCR) as a validation analysis. Copy number calculated (CNC) for each gene determined with Applied Biosystems CopyCaller Software v2.0. The six significant CNVs included gains (12q14.3, 15q26.3, 1p36.32, and 1p36.33) and losses (3p14.2 and 4q13.2) in NSCL/P with hypodontia patients compared with the NSCL/P only. The genes located in these regions encoded LEMD3, IGF1R, TP73, SKI, FHIT, and UGT2β15. There were a significant gain and loss of both SKI and FHIT copy number in NSCL/P with hypodontia compared with the noncleft group (p &lt; 0.05). The results supported that CNVs significantly furnish to the development of NSCL/P with hypodontia.

scholarly journals The functional variant of NTN1 contributes to the risk of nonsyndromic cleft lip with or without cleft palate

2019 ◽  
Vol 28 (4) ◽  
pp. 453-460
Author(s):  
Dandan Li ◽  
Guirong Zhu ◽  
Shu Lou ◽  
Lan Ma ◽  
Chi Zhang ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Cleft Lip ◽  
Genome Wide Association Study ◽  
Case Control Study ◽  
Cleft Lip And Palate ◽  
Case Control ◽  
Orofacial Cleft ◽  
Enhancer Activity ◽  
Increased Risk ◽  
Control Study

AbstractPrevious genome-wide association study of nonsyndromic cleft lip with or without cleft palate (NSCL/P) identified a susceptible variant (rs4791774). We hypothesized that the functional single nucleotide polymorphism (SNP) may be in linkage disequilibrium with this lead SNP. The potential functional SNP (rs4791331) was identified by bioinformatic analysis. A case–control study with 891 orofacial cleft cases and 830 controls was designed to investigate its association with orofacial cleft. The allele-specific DNA-protein binding preference was predicted by JASPAR database. Cell proliferation, cycle and apoptosis, luciferase activity and netrin-1 (NTN1) expression were examined after transfection with the rs4791331 C/T vector in HEK-293 and HEPM cell lines. Forty-six lip tissues of NSCL/P patients were collected to detect NTN1 expression. ntn1a knockout zebrafish models were generated by CRISPR/Cas9 and observed with micro-CT. In the case–control study, the rs4791331-T allele was associated with an increased risk of nonsyndromic orofacial cleft (OR = 1.41, 95% CI = 1.19–1.68), as well as the subgroups cleft lip only (OR = 1.46, 95% CI = 1.14–1.87) and cleft lip and palate (OR = 1.58, 95% CI = 1.27–1.96). The T allele of rs4791331 exhibited anti-apoptotic effects and promoted cell cycle progression at the G1/S transition. Decreased enhancer activity and reduced NTN1 expression following transfection of the T allele were observed. Carriers of the CT/TT genotypes showed significantly lower expression of NTN1 than CC carriers. The ntn1a−/− zebrafish showed relatively wider intermaxillary fissures. These results indicate that rs4791331 (C > T) disrupted motif binding and led to abnormal expression of NTN1, which may be involved in the development of NSCL/P.

scholarly journals Non-Syndromic Cleft Lip with or without Cleft Palate: Genome-Wide Association Study in Europeans Identifies a Suggestive Risk Locus at 16p12.1 and Supports SH3PXD2A as a Clefting Susceptibility Gene

Genes ◽  
2019 ◽  
Vol 10 (12) ◽  
pp. 1023 ◽  
Author(s):  
Iris ALM van Rooij ◽  
Kerstin U Ludwig ◽  
Julia Welzenbach ◽  
Nina Ishorst ◽  
Michelle Thonissen ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Association Study ◽  
Cleft Lip ◽  
Genome Wide Association Study ◽  
Susceptibility Gene ◽  
Small Sample ◽  
Genome Wide Association ◽  
P Value ◽  
Genome Wide ◽  
A Genome

Non-syndromic cleft lip with or without cleft palate (nsCL/P) ranks among the most common human congenital malformations, and has a multifactorial background in which both exogenous and genetic risk factors act in concert. The present report describes a genome-wide association study (GWAS) involving a total of 285 nsCL/P patients and 1212 controls from the Netherlands and Belgium. Twenty of the 40 previously reported nsC/LP susceptibility loci were replicated, which underlined the validity of this sample. SNV-based analysis of the data identified an as yet unreported suggestive locus at chromosome 16p12.1 (p-value of the lead SNV: 4.17 × 10−7). This association was replicated in two of three patient/control replication series (Central European and Yemeni). Gene analysis of the GWAS data prioritized SH3PXD2A at chromosome 10q24.33 as a candidate gene for nsCL/P. To date, support for this gene as a cleft gene has been restricted to data from zebrafish and a knockout mouse model. The present GWAS was the first to implicate SH3PXD2A in non-syndromic cleft formation in humans. In summary, although performed in a relatively small sample, the present GWAS generated novel insights into nsCL/P etiology.

A Genome-Wide Association Study Identifies a Locus for Nonsyndromic Cleft Lip with or without Cleft Palate on 8q24

2009 ◽  
Vol 155 (6) ◽  
pp. 909-913 ◽  
Author(s):  
Struan F.A. Grant ◽  
Kai Wang ◽  
Haitao Zhang ◽  
Wendy Glaberson ◽  
Kiran Annaiah ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Association Study ◽  
Cleft Lip ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome

scholarly journals A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4

2010 ◽  
Vol 42 (6) ◽  
pp. 525-529 ◽  
Author(s):  
Terri H Beaty ◽  
Jeffrey C Murray ◽  
Mary L Marazita ◽  
Ronald G Munger ◽  
Ingo Ruczinski ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Association Study ◽  
Cleft Lip ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Risk Variants ◽  
Genome Wide ◽  
A Genome

scholarly journals A genome-wide scan of cleft lip triads identifies parent-of-origin interaction effects between ANK3 and maternal smoking, and between ARHGEF10 and alcohol consumption

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 960 ◽  
Author(s):  
Øystein Ariansen Haaland ◽  
Julia Romanowska ◽  
Miriam Gjerdevik ◽  
Rolv Terje Lie ◽  
Håkon Kristian Gjessing ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Cleft Lip ◽  
Genome Wide Association Study ◽  
Environmental Exposures ◽  
Future Research ◽  
Maternal Cigarette Smoking ◽  
Genome Wide ◽  
A Genome ◽  
Parent Of Origin ◽  
Genetic And Environmental Factors

Background: Although both genetic and environmental factors have been reported to influence the risk of isolated cleft lip with or without cleft palate (CL/P), the exact mechanisms behind CL/P are still largely unaccounted for. We recently developed new methods to identify parent-of-origin (PoO) interactions with environmental exposures (PoOxE) and applied them to families with children born with isolated cleft palate only. Here, we used the same genome-wide association study (GWAS) dataset and methodology to screen for PoOxE effects in the larger sample of CL/P triads. Methods: Genotypes from 1594 complete triads and 314 dyads (1908 nuclear families in total) with CL/P were available for the current analyses. Of these families, 1024 were Asian, 825 were European and 59 had other ancestries. After quality control, 341,191 SNPs remained from the original 569,244. The exposures were maternal cigarette smoking, use of alcohol, and use of vitamin supplements in the periconceptional period. The methodology applied in the analyses is implemented in the R-package Haplin. Results: Among Europeans, there was evidence of a PoOxSmoke effect for ANK3 with three SNPs (rs3793861, q=0.20, p=2.6e-6; rs7087489, q=0.20, p=3.1e-6; rs4310561, q=0.67, p=4.0e-5) and a PoOxAlcohol effect for ARHGEF10 with two SNPs (rs2294035, q=0.32, p=2.9e-6; rs4876274, q=0.76, p=1.3e-5). Conclusion: Our results indicate that the detected PoOxE effects have a plausible biological basis, and thus warrant replication in other independent cleft samples. Our demonstration of the feasibility of identifying complex interactions between relevant environmental exposures and PoO effects offers new avenues for future research aimed at unravelling  the complex etiology of cleft lip defects.

scholarly journals Novel Aggregation Properties of Candida albicans Secreted Aspartyl Proteinase Sap6 Mediate Virulence in Oral Candidiasis

2015 ◽  
Vol 83 (7) ◽  
pp. 2614-2626 ◽  
Author(s):  
Rohitashw Kumar ◽  
Darpan Saraswat ◽  
Swetha Tati ◽  
Mira Edgerton
Keyword(s):  
Candida Albicans ◽  
Epithelial Cells ◽  
Oral Candidiasis ◽  
Oral Microbiome ◽  
Proteinase Activity ◽  
Adhesion Properties ◽  
Content Type ◽  
Oral Epithelial Cells ◽  
Oral Epithelial ◽  
Cell Cell

Candida albicans, a commensal fungus of the oral microbiome, causes oral candidiasis in humans with localized or systemic immune deficiencies. Secreted aspartic proteinases (Saps) are a family of 10 related proteases and are virulence factors due to their proteolytic activity, as well as their roles in adherence and colonization of host tissues. We found that mice infected sublingually withC. albicanscells overexpressing Sap6 (SAP6OE and a Δsap8strain) had thicker fungal plaques and more severe oral infection, while infection with the Δsap6strain was attenuated. These hypervirulent strains had highly aggregative colony structurein vitroand higher secreted proteinase activity; however, the levels of proteinase activity ofC. albicansSaps did not uniformly match their abilities to damage cultured oral epithelial cells (SCC-15 cells). Hyphal induction in cells overexpressing Sap6 (SAP6OE and Δsap8cells) resulted in formation of large cell-cell aggregates. These aggregates could be produced in germinated wild-type cells by addition of native or heat-inactivated Sap6. Sap6 bound only to germinated cells and increasedC. albicansadhesion to oral epithelial cells. The adhesion properties of Sap6 were lost upon deletion of its integrin-binding motif (RGD) and could be inhibited by addition of RGD peptide or anti-integrin antibodies. Thus, Sap6 (but not Sap5) has an alternative novel function in cell-cell aggregation, independent of its proteinase activity, to promote infection and virulence in oral candidiasis.

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