BMP2 and BMP4 variations and risk of non-syndromic cleft lip and palate

Saket, Mitra; Saliminejad, Kioomars; Kamali, Koorosh; Moghadam, Fatemeh Aghakhani; Anvar, Nazanin Esmaeili; Khorshid, Hamid Reza Khorram

doi:10.1016/j.archoralbio.2016.08.019

Cited by 21 publications

(20 citation statements)

References 20 publications

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“…Thus, a total of 11 eligible publications were finally included in the present meta-analysis. [ 13 – 15 , 19 – 26 ] The characteristics of the included studies are presented in Table 1 . Of these studies, seven were hospital-based case–control designs, and 4 were population-based case–control designs.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, more relevant human genetic association studies have been published among different populations since then, and the association results are not consistent. [ 12 – 15 ] We, therefore, conducted an updated meta-analysis to assess the association between BMP4 rs17563 polymorphism and NSCL/P risk. The allele frequencies of BMP4 rs17563 among groups were also pooled in the current meta-analysis, which, to our knowledge, have not been investigated before.…”

Section: Introductionmentioning

confidence: 99%

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

Yang²,

Zhang³

et al. 2017

Medicine

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Yang²,

Zhang³

et al. 2017

Medicine

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“…Recent other studies of BMP2 gene rs235768 A> T on orofacial cleft has been taken place. A previous study in Tehran, Iran 16 , with a total sample of 107 orofacial cleft and 186 controls showed that BMP2 gene rs235768 A> T genotype was significantly higher (p = 0.009, OR = 3.95%) between both groups. At the same time, the allele distribution was also significantly higher than the control group, which indicated the T allele as a risk factor, with OR = 2.2%.…”

Section: Discussionmentioning

confidence: 86%

Association of rs235768 A>T polymorphism of the bone morphogenetic protein 2 gene on non-syndromic orofacial cleft in an Indonesian population

et al. 2020

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Introduction: Orofacial cleft is one of the many congenital malformations that often occur in human, leaving it at the fourth level of the most common orofacial birth defect findings. The incident rate is one in 700-1000 deliveries, where without therapeutic and surgical interventions, children with an orofacial cleft may have problems with speech, nutrition intake, and growth. Bone morphogenetic protein 2 (BMP-2) gene play essential roles in the migration and proliferation of neural crest cell of the early head formation and regulate mineralised tissues such as maxillary, mandible, palate and teeth. This study was aimed to analyse the BMP-2 polymorphism and its potential association with orofacial cleft in an Indonesian population. Methods: Cross-sectional study was conducted towards 128 samples, 32 samples of orofacial cleft patients and 96 samples of control. Extracted genotype and allele was determined with PCR-RFLP method using stored DNA samples from 32 orofacial cleft patients, and 96 healthy control. Results: The TT genotype was showing the p-value = 0.001, OR = 2.43% in orofacial samples (71.4%), which was significantly higher than in control groups (28.6%). The allele distribution was also considered statistically significant (p = 0.036, OR =1.89%. Conclusion: There is a significant association of rs235768 A>T polymorphism of the BMP-2 gene on non-syndromic orofacial cleft patients in Indonesia.

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

Curtis

Chang

Lee

et al. 2020

Preprint

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Nonsyndromic orofacial clefts (OFCs) are the most common craniofacial birth defect in humans and, like many complex traits, OFCs are phenotypically and etiologically heterogenous. The phenotypic heterogeneity of OFCs extends beyond the structures affected by the cleft (e.g., cleft lip (CL) and cleft lip and palate (CLP) to other features, such as the severity of the cleft. Here, we focus on bilateral and unilateral clefts as one dimension of OFC severity. Unilateral clefts are more frequent than bilateral clefts for both CL and CLP, but the genetic architecture of these subtypes is not well understood, and it is not known if genetic variants predispose for the formation of one subtype over another. Therefore, we tested for subtype-specific genetic associations in 44 bilateral CL (BCL) cases, 434 unilateral CL (UCL) cases, 530 bilateral CLP cases (BCLP), 1123 unilateral CLP (UCLP) cases, and unrelated controls (N = 1626), using the mixed-model approach implemented in GENESIS. While no novel loci were found in subtype-specific analyses comparing cases to controls, the genetic architecture of UCL was distinct compared to BCL, with 43.8% of suggestive loci (p < 1.0×10-5) having non-overlapping confidence intervals between the two subtypes. To further understand the genetic risk factors for severity differences, we then performed a genome-wide scan for modifiers using a similar mixed-model approach and found one genome-wide significant modifier locus on 20p11 (p = 7.53×10-9), 300kb downstream of PAX1, associated with higher odds of BCL compared to UCL, which also replicated in an independent cohort (p = 0.0018) and showed no effect in BCLP (p>0.05). We further found that SNPs at this locus were associated with normal human nasal shape. Taken together, these results suggest bilateral and unilateral clefts may have differences in their genetic architecture, especially between CL and CLP. Moreover, our results suggest BCL, the rarest form of OFC, may be genetically distinct from the other OFC subtypes. This expands our understanding of genetic modifiers for subtypes of OFCs and further elucidates the genetic mechanisms behind the phenotypic heterogeneity in OFCs.

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BMP2 and BMP4 variations and risk of non-syndromic cleft lip and palate

Cited by 21 publications

References 20 publications

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

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

Association of rs235768 A>T polymorphism of the bone morphogenetic protein 2 gene on non-syndromic orofacial cleft in an Indonesian population

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

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