Association of common variants, not rare mutations, in <i>IRF6</i> With nonsyndromic clefts in a honduran population

Larrabee, Yuna C.; Birkeland, Andrew C.; Kent, David T.; Flores, Carlos; Su, Gloria H.; Lee, Joseph H.; Haddad, Joseph

doi:10.1002/lary.21870

Cited by 19 publications

(16 citation statements)

References 15 publications

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“…In contrast to other studies [6], [8]–[22], all of which showed association of IRF6 comparing only the three major cleft categories (cleft lip, cleft lip/palate and cleft palate), we only found positive association when comparing cleft subphenotypes with controls. Maybe IRF6 is not a strong risk factor for clefting in Brazil, or maybe it has specific contributions, e.g.…”

Section: Discussioncontrasting

confidence: 99%

“…Attributable risk calculations suggested IRF6 could contribute to as much as 12% of all cleft cases [6]. Intriguingly, additional studies with different populations have consistently shown positive association between markers in IRF6 and cleft lip/palate [8]–[22]. The frequency of the V274I risk allele is over 97% in European and African populations making it an unlikely candidate for the etiological mutation.…”

Section: Introductionmentioning

confidence: 99%

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Interaction between IRF6 and TGFA Genes Contribute to the Risk of Nonsyndromic Cleft Lip/Palate

et al. 2012

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Previous evidence from tooth agenesis studies suggested IRF6 and TGFA interact. Since tooth agenesis is commonly found in individuals with cleft lip/palate (CL/P), we used four large cohorts to evaluate if IRF6 and TGFA interaction contributes to CL/P. Markers within and flanking IRF6 and TGFA genes were tested using Taqman or SYBR green chemistries for case-control analyses in 1,000 Brazilian individuals. We looked for evidence of gene-gene interaction between IRF6 and TGFA by testing if markers associated with CL/P were overtransmitted together in the case-control Brazilian dataset and in the additional family datasets. Genotypes for an additional 142 case-parent trios from South America drawn from the Latin American Collaborative Study of Congenital Malformations (ECLAMC), 154 cases from Latvia, and 8,717 individuals from several cohorts were available for replication of tests for interaction. Tgfa and Irf6 expression at critical stages during palatogenesis was analyzed in wild type and Irf6 knockout mice. Markers in and near IRF6 and TGFA were associated with CL/P in the Brazilian cohort (p<10−6). IRF6 was also associated with cleft palate (CP) with impaction of permanent teeth (p<10−6). Statistical evidence of interaction between IRF6 and TGFA was found in all data sets (p = 0.013 for Brazilians; p = 0.046 for ECLAMC; p = 10−6 for Latvians, and p = 0.003 for the 8,717 individuals). Tgfa was not expressed in the palatal tissues of Irf6 knockout mice. IRF6 and TGFA contribute to subsets of CL/P with specific dental anomalies. Moreover, this potential IRF6-TGFA interaction may account for as much as 1% to 10% of CL/P cases. The Irf6-knockout model further supports the evidence of IRF6-TGFA interaction found in humans.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interaction between IRF6 and TGFA Genes Contribute to the Risk of Nonsyndromic Cleft Lip/Palate

et al. 2012

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“…The distance between the upper lip point and lower lip point (ULipP-LLipP) also suggested potential shape difference between the CC and TT groups (nominal p value = 0.0023, Table 2). The suggestive involvement of this SNP with mouth shape is consistent with the known role the host gene IRF6 plays in NSCL/P [17], [23], [44], [45]. SNP rs6180 and rs6184 both showed some signals in males, which seemed to mainly involve the two lip corners and their relative positions to the middle line landmarks such as Pronasale, Nasion, Subnasale, lower lip point and chin (Table 2).…”

Section: Resultssupporting

confidence: 79%

“…The Interferon regulatory factor 6 ( IRF6 ) plays a critical role in keratinocyte development. Genetic variants of IRF6 , especially SNP rs642961, were found consistently associated to NSCL/P throughout many candidate gene and GWAS studies [17], [23], [44], [45] As the genetic risk factors of NSCL/P may also contribute to normal facial variation in healthy carriers [16], we enrolled rs642961 into our study. We further included the SNP rs2236907 of IRF6 , which seems to have a particularly strong signal in Han Chinese [23], [46].…”

Section: Resultsmentioning

confidence: 99%

Detecting Genetic Association of Common Human Facial Morphological Variation Using High Density 3D Image Registration

Peng¹,

Tan

Hu³

et al. 2013

PLoS Comput Biol

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Human facial morphology is a combination of many complex traits. Little is known about the genetic basis of common facial morphological variation. Existing association studies have largely used simple landmark-distances as surrogates for the complex morphological phenotypes of the face. However, this can result in decreased statistical power and unclear inference of shape changes. In this study, we applied a new image registration approach that automatically identified the salient landmarks and aligned the sample faces using high density pixel points. Based on this high density registration, three different phenotype data schemes were used to test the association between the common facial morphological variation and 10 candidate SNPs, and their performances were compared. The first scheme used traditional landmark-distances; the second relied on the geometric analysis of 15 landmarks and the third used geometric analysis of a dense registration of ∼30,000 3D points. We found that the two geometric approaches were highly consistent in their detection of morphological changes. The geometric method using dense registration further demonstrated superiority in the fine inference of shape changes and 3D face modeling. Several candidate SNPs showed potential associations with different facial features. In particular, one SNP, a known risk factor of non-syndromic cleft lips/palates, rs642961 in the IRF6 gene, was validated to strongly predict normal lip shape variation in female Han Chinese. This study further demonstrated that dense face registration may substantially improve the detection and characterization of genetic association in common facial variation.

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“…Nonetheless, one European and two non-European studies did not identify any association between this variant and nsCL/P (ref. [25][26][27] ). Another finding of our study was an association of the SNP located at the 8q24 locus with nsCL/P.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms at 1q32, 8q24, and 17q22 loci are associated with nonsyndromic cleft lip with or without cleft palate risk in the Slovak population

Salagovic¹,

Klimčáková²,

Zabavnikova³

et al. 2017

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Background. Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is the most common orofacial birth defect with an aetiology involving both genetic and environmental factors. Genome-wide association studies (GWAS) have identified several genomic susceptibility regions for nsCL/P. In the present study, the three well established single nucleotide polymorphisms (SNPs) identified by GWAS (rs987525 at 8q24, rs7078160 at 10q25, and rs227731 at 17q22 loci) and one SNP identified by candidate gene study (rs642961 in IRF6 gene at 1q32 locus) were analysed for an association with nsCL/P in Slovak population. Methods. Nucleotide variants were genotyped in 165 nsCL/P patients and 326 unaffected controls. All variants of interest were genotyped using high-resolution melting analysis after real-time PCR. Results. We found significant differences between patient and control groups with respect to the allele and genotype frequencies for the SNPs at the 1q32, 8q24, and 17q22 loci. SNP at the 10q25 locus showed a trend toward association with nsCL/P risk. Conclusions.The results suggest that SNPs at the 1q32, 8q24 and 17q22 loci may contribute to the nsCL/P risk in Slovak population.

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Association of common variants, not rare mutations, in IRF6 With nonsyndromic clefts in a honduran population

Cited by 19 publications

References 15 publications

Interaction between IRF6 and TGFA Genes Contribute to the Risk of Nonsyndromic Cleft Lip/Palate

Interaction between IRF6 and TGFA Genes Contribute to the Risk of Nonsyndromic Cleft Lip/Palate

Detecting Genetic Association of Common Human Facial Morphological Variation Using High Density 3D Image Registration

Polymorphisms at 1q32, 8q24, and 17q22 loci are associated with nonsyndromic cleft lip with or without cleft palate risk in the Slovak population

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