BMP4 rs17563 polymorphism and nonsyndromic cleft lip with or without cleft palate

Abstract

Background:Previous studies have investigated the relationship between human bone morphogenetic protein 4 gene (BMP4) rs17563 polymorphism and nonsyndromic cleft lip with or without cleft palate (NSCL/P). However, the results remained inconsistent. Therefore, we conducted a meta-analysis to assess the effect of BMP4 rs17563 polymorphism on NSCL/P.Methods:Electronic searches in 5 databases were conducted to select all eligible studies up to March 2017. Odds ratios (ORs) with the corresponding 95% confidence intervals (CIs) were calculated to estimate the association. Sensitivity analysis was performed to evaluate the results stability by excluding each study in turn. Publication bias was assessed by Begg funnel plots and Egger test.Results:A total of 11 case–control studies were included in the meta-analysis. The pooled frequency of the minor allele C for BMP4 rs17563 was lower in Asians (pooled frequency = 0.33, 95% CI: 0.29–0.37) than in Brazilian population (pooled frequency = 0.47, 95% CI: 0.40–0.54). The overall results showed no significant association of BMP4 rs17563 polymorphism with NSCL/P risk. However, the results turned out to be different when stratified by ethnicity. BMP4 rs17563 polymorphism was associated with a higher risk of NSCL/P among Asian ethnicity (C vs T: OR = 1.33, 95% CI: 1.02–1.73; CC vs TT: OR = 2.10, 95% CI: 1.28–3.43; CC vs TT + TC: OR = 2.16, 95% CI: 1.34–3.47) and among Caucasian population (TC vs TT: OR = 3.36, 95% CI: 2.03–5.54; TC + CC vs TT: OR = 3.71, 95% CI: 2.43–5.69). Among Brazilian population, BMP4 rs17563 polymorphism exerted a significantly protective effect on NSCL/P (C vs T: OR = 0.70, 95% CI: 0.58–0.84; CC vs TT: OR = 0.54, 95% CI: 0.33–0.88; TC vs TT: OR = 0.55, 95% CI: 0.44–0.69; TC + CC vs TT: OR = 0.56, 95% CI: 0.45–0.69).Conclusion:The results suggest that the C allele of BMP4 rs17563 may be a risk factor for NSCL/P among Asians and Caucasians, and may be a protective factor for NSCL/P in Brazilian population. Future large-sample studies with appropriate designs among specific populations are warranted to evaluate the association.

Potential genetic markers for nonsyndromic oral clefts in the Brazilian population: A systematic review and meta‐analysis

“…For the Chinese population, rs17563 increased risk for NSCL ± P whereas a protective effect was found in the Brazilian population (Hu, Qin, Deng, Niu, & Long, ). In the second meta‐analysis (Li et al, ), five more case‐control studies were included, confirming the risk effect of C variant allele in the Chinese population and the protective effect in Brazilians. This recent meta‐analysis also revealed that BMP4 rs17563 was associated with a higher risk among Caucasians, represented in the meta‐analysis by populations from India and Iran (Li et al, ).…”

“…In the second meta‐analysis (Li et al, ), five more case‐control studies were included, confirming the risk effect of C variant allele in the Chinese population and the protective effect in Brazilians. This recent meta‐analysis also revealed that BMP4 rs17563 was associated with a higher risk among Caucasians, represented in the meta‐analysis by populations from India and Iran (Li et al, ). The current meta‐analysis, involving 446 patients with NSCL ± P and 682 controls, suggests that rs17563 in BMP4 is a protective factor for developing NSCL ± P in the Brazilian population, but the conclusions on BMP4 were based in only two studies, and as revealed by Tau 2 and I 2 values, the effects were heterogeneous, deserving further studies to determine the real association of this marker with the susceptibility of NSCL ± P in the Brazilian population.…”

“…While IRF6 rs2235371 showed a protective effect among Asians, with no effects in Caucasians, 8q24 rs987525 increased the risk for NOC among Caucasians but not among Asians (Wang et al, ). The effects of bone morphogenetic protein 4 ( BMP4 ) gene are also influenced by ethnicity, since the C allele of BMP4 rs17563 is a risk factor for NOC in Asians and Caucasians, but demonstrates a protective effect in the Brazilian population (Li et al, ). The population of Brazil is highly admixed, with each individual showing variable ancestry proportions of Amerindians, Europeans and sub‐Saharan Africans, which has been shown to affect the specific genetic susceptibility of genes and loci previously associated with NOC in other populations (Bagordakis et al, ; Brito, Paranaiba, & Bassi, ; de Aquino et al, a; do Rego Borges et al, ).…”

The PAX1 locus at 20p11 is a modifier for bilateral cleft lip only

“…There is also evidence that PAX1 is upregulated by SHH, and in turn, upregulates SOX5 and BMP4 (41)(42)(43). There is only a limited literature describing PAX1 expression in the developing face (38) and it has not been previously associated with risk to nonsyndromic OFCs, but PAX1 is in a pathway with other genes known to be associated with nonsyndromic OFCs (44)(45)(46)(47)(48)(49). Additionally, recent studies have shown mutations in PAX1 cause otofaciocervical syndrome (OTFCS, MIM#615560) which presents with facial dysmorphisms (50,51), and studies of normal facial variation have found this locus has also been associated with nasal width (the distance between left and right cartilaginous nasal ala) in people of European descent (52) and in people of Latin American descent (53).…”

Polymorphic Variants of V-Maf Musculoaponeurotic Fibrosarcoma Oncogene Homolog B (rs13041247 and rs11696257) and Risk of Non-Syndromic Cleft Lip/Palate: Systematic Review and Meta-Analysis

“…The live-birth prevalence of NSCL/P changes by the geographical region and ethnicity (1/2500 in African, 1/1000 in European, and 1/500 in Asian and American Indian populations) [4]. However, the NSCL/P etiology is unknown, and its underlying molecular mechanisms remain poorly understood, but some recent meta-analyses showed the association of genetics with the development of NSCL/P [2,5,6,7]. The 20q12 locus includes the V-Maf musculoaponeurotic fibrosarcoma oncogene homolog B ( MAFB ) encoded by the MAFB gene [8].…”