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Review Article Association Between IRF6 Rs642961 Polymorphism and Non-Syndromic Cleft Lip with Or Without a Cleft Palate: a Systematic Review and Meta-Analysis

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Review Article Association Between IRF6 Rs642961 Polymorphism and Non-Syndromic Cleft Lip with Or Without a Cleft Palate: a Systematic Review and Meta-Analysis Int J Clin Exp Med 2018;11(4):3033-3042 www.ijcem.com /ISSN:1940-5901/IJCEM0066579 Review Article Association between IRF6 rs642961 polymorphism and non-syndromic cleft lip with or without a cleft palate: a systematic review and meta-analysis Tzu-Hui Lee1*, Tsung-Ta Liu2*, Chih-Wei Sung3,4*, Ju-Chi Ou5, Jui-Ju Yeh6, Yung-Ting Kuo1,7, Yuan-Hung Wang8,9 Departments of 1Pediatrics, 5Emergency Medicine, 6Family Medicine, 8Medical Research, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan; 2Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; 3Department of Emergency Medicine, National Taiwan Univer- sity Hospital Hsin-Chu Branch, Hsinchu, Taiwan; 4Department of Emergency Medicine, National Taiwan University Hospital, Taipei, Taiwan; 7Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; 9Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan. *Equal contributors. Received October 2, 2017; Accepted January 29, 2018; Epub April 15, 2018; Published April 30, 2018 Abstract: Non-syndromic cleft lip with or without a cleft palate (NSCL/P) is one of the most common newborn malformations. sPrevious studies have reported that genetic variations of interferon regulatory factor 6 (IRF6) poly- morphisms are associated with NSCL/P. However, the effect sizes of individual studies still vary. Our present study is a meta-analysis to investigate the association of IRF6 rs642961 polymorphism with NSCL/P. A literature search in PubMed was performed to select eligible literatures including observational studies which evaluated association between IRF6 polymorphisms and NSCL/P. We conducted a systematic review and a meta-analysis on all qualified eight case-control studies that included 1,899 cases and 3,458 controls to investigate the association between NSCL/P and IRF6 rs642961 polymorphism. We found that the A allele had a higher risk of NSCL/P (odds ratio (OR)=1.64, 95% confidence interval (CI)=1.37-1.97) in comparison to the G allele of IRF6 rs642961 polymorphism. The rs642961 A allele in the Asian population had an increased risk of NSCL/P (OR=2.12, 95% CI=1.66-2.71). Un- der various genetic models, the A allele of IRF6 rs642961 polymorphism in Asian population showed a significantly increased risk of NSCL/P under the dominant model (OR=2.19, 95% CI=1.64-2.91), recessive model (OR=4.49, 95% CI=2.26-8.92), homozygous model (OR=5.86, 95% CI=2.90-11.8), and heterozygous model (OR=1.91, 95% CI=1.42-2.57). Our major findings suggest that association of IRF6 rs642961 polymorphism and NSCL/P is pre- dominant in an Asian population rather than non-Asian populations, which might be useful in clinical diagnoses and treatment of patients with NSCL/P. Keywords: IRF6, meta-analysis, non-syndromic cleft lip and palate, polymorphism Introduction live births). In Taiwan, the annual rate of in- cidence of CL/P was approximately 1.48 in Non-syndromic cleft lip with or without a cleft 1000 live births with a 2.9% annual decline in palate (NSCL/P) is characterized by an incom- the rate [4]. Patients with NSCL/P are vulnera- plete separation between the nasal and oral ble to speech and communication problems cavities. It is a birth craniofacial abnormality, which result in delayed development, low self- the incidence of which varies with geographic confidence, and a poor quality of life repre- origin and ethnicity [1-3]. Prevalence of NSCL/P senting challenges to clinical care. The etiology in Asian and Amerindian populations appear of NSCL/P is multifactorial and includes both to have the highest frequencies (~2 in 1000 genetic and environmental components [5]. Ex- live births), with European populations being posure to smoking, drugs, infections, and/or intermediate (~1 in 1000 live births), and nutrient deficiencies may contribute to the risk African populations the lowest (~0.4 in 1000 of NSCL/P [6]. In addition, specific gene muta- IRF6 and nonsyndromic cleft lip with or without a cleft palate tions may also play a role in the development of for NSCL/P [19]. Those findings were then fur- NSCL/P. Several studies have identified specif- ther pooled by meta-analyses [20, 21]. How- ic genes associated with NSCL/P, which may ever, meta-analyses pooled only allele effects shed light on the etiology of the condition and rather than genetic model analyses. There facilitate efforts to prevent this disease [7, 8]. are more pooled studies targeting the IRF6 rs2235371 polymorphism than those targeting The interferon regulatory factor-6 (IRF6) gene, the rs642961 polymorphism. Therefore, we located on chromosome 1q32.3-q41, encodes conducted an updated meta-analysis of the a protein that plays an important role in de- association between IRF6 rs642961 polymor- velopment of the maxillofacial region. IRF6 phism and the risk of NSCL/P, aiming to as- mutations may produce a nonfunctional pro- sess both variant effects and possible genetic tein leading to haplo-insufficiency, affecting models. the DNA-binding domain, causing a dominant negative effect, and resulting in severe phe- Methods notypes [9]. In animal models, IRF6-knockout mice exhibited abnormal skin, limb, and cranio- The methodology and reporting of the present facial development due to defects in the kerati- meta-analysis were based on the recommen- nocyte proliferation-differentiation switch [10]. dations of the Cochrane Collaboration, the Pre- The IRF6 gene is involved in the proliferation- ferred Reporting Items for Systematic Reviews differentiation of keratinocytes [11]. In humans, and Meta-Analyses (PRISMA) statement, and mutations in IRF6 gene were first identified as the Moose group [22-24]. A systematic search an etiologic factor in the autosomal-dominant was performed of PubMed, Web of Science, Van der Woude’s syndrome (VWS), which in- EMBASE, and the Cochrane Libraries to iden- cludes NSCL/P along with dental anomalies tify all eligible studies. References of all rele- as well as lip fistulas [12]. Association of vant articles were also searched for additional NSCL/P with the single-nucleotide polymor- studies. The search strategy included the fol- phism (SNP) rs642961 in the IRF6 gene locat- lowing key words: “interferon regulatory factor ed in chromosomal region 1q32 was confirmed 6 gene”, “IRF-6”, “polymorphism”, “rs642961”, in candidate genes and genome-wide associa- “SNP”, “NSCL/P”, “non-syndromic cleft”, “cleft tion studies (GWAS) [13, 14]. lip”, and “cleft palate only (CPO)”. Two authors (C.W. Sung and T.H. Lee) performed the litera- Several studies have investigated the effects ture review and searched independently. The of polymorphisms in the IRF6 gene (at rs22- search included papers published by Decem- 35371 (G>A) and rs642961 (G>A)) and the ber 2014. Any human population-based asso- 8q24 region (at rs987525 (C>A)) on NSCL/P. ciation study published in English was included The risky A allele disrupts the binding site of if it also met the following criteria: 1) the out- the AP-2-α transcription factor and an expres- come of interest was NSCL/P or CPO; and 2) sion analysis of the mouse localized the en- the studied polymorphisms included IRF6 rs- hancer activity to craniofacial and limb struc- 642961 with sufficient data for analysis in- tures [15]. Currently, the biological mecha- cluding the allele/genotype frequency between nisms of newly identified SNPs of IRF6 gene cases and controls. remain unclear. Grant et al. conducted a GWAS and identified a locus for non-syndromic cleft Two independent authors extracted the data lip with or without cleft palate on 8q24 [16]. of eligible studies using a standardized data Beaty et al. replicated the GWAS in Asian popu- extraction form. The following terms were ex- lation and found that rs987525 polymorphism tracted: the first author, country of study, eth- was another significant SNP [17]. Shi investi- nicity, source, and number of cases and con- gated two identified SNPs of IRF6 gene and trols, frequencies of IRF6 rs642961 genotyp- three transcription factor AP-2a tag SNPs and ing, and year of publication. Ethnic descent observed a significant correlation between the was categorized into Asian and non-Asian sub- IRF6 rs642961 polymorphism and NSCL/P groups. Our study focused on NSCL/P as the [18]. Kousa found that of the several SNPs outcome of interest, which was diagnosed in located within the IRF6 gene, rs2235371 and accordance with the original studies. The SNP rs642961 variants existed in over 30% of the of interest was a polymorphism within the IRF6 world’s population and contributed to the risk gene (rs642961 G>A). The data was computer- 3034 Int J Clin Exp Med 2018;11(4):3033-3042 IRF6 and nonsyndromic cleft lip with or without a cleft palate the OR of the selected out- comes and Egger’s test [26]. An asymmetrical funnel plot and a p value of <0.05 sug- gested possible publication bias. Some of the included studies presented several re- sults using different adjust- ments for covariates and de- sign elements. We also per- formed a sensitivity analysis to explore the effects of using differently adjusted results for these studies. All statistical analyses were performed us- ing Software R version 3.2.2 (The R Foundation for Sta- tistical Computing). Results The search located 29 rele- Figure 1. Flow diagram of the eligible vant studies from Medline by study selection. means of the PubMed and Web of Science databases. Among these studies, seven ized by two independent authors (T.H. Lee and of them were excluded because of no full text M.C. Chang) and compared to identify disa- (two studies) or being family-based studies greement. Discrepancies were further resolved (five studies).
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