The MSX1 allele 4 homozygous child exposed to smoking at periconception is most sensitive in developing nonsyndromic orofacial clefts

Abstract

Nonsyndromic orofacial clefts (OFC) are common birth defects caused by certain genes interacting with environmental factors. Mutations and association studies indicate that the homeobox gene MSX1 plays a role in human clefting. In a Dutch case-control triad study (mother, father, and child), we investigated interactions between MSX1 and the parents' periconceptional lifestyle in relation to the risk of OFC in their oVspring. We studied 181 case-and 132 control mothers, 155 case-and 121 control fathers, and 176 case-and 146 control children, in which there were 107 case triads and 66 control triads. Univariable and multivariable logistic regression analyses were applied, and odds ratios (OR), 95% conWdence intervals (CI) were calculated. Allele 4 of the CA marker in the MSX1 gene, consisting of nine CA repeats, was the most common allele found in both the case and control triads. SigniWcant interactions were observed between allele 4 homozygosity of the child with maternal smoking (OR 2.7, 95% CI 1.1-6.6) and with smoking by both parents (OR 4.9, 95% CI 1.4-18.0). Allele 4 homozygosity in the mother and smoking showed a risk estimate of OR 3.2 (95% CI 1.1-9.0). If allele 4 homozygous mothers did not take daily folic acid supplements in the recommended periconceptional period, this also increased the risk of OFC for their oVspring (OR 2.8, 95% CI 1.1-6.7). Our Wndings show that, in the Dutch population, periconceptional smoking by both parents interacts with a speciWc allelic variant of MSX1 to signiWcantly increase OFC risk for their oVspring. Possible underlying mechanisms are discussed.

Genome-wide analysis of parent-of-origin effects in non-syndromic orofacial clefts

“…In this regard, it is interesting to note effects of maternal genotype and maternalspecific environmental modifiers such as smoking, drinking and vitamin intake during pregnancy on oral cleft susceptibility have been previously reported in various studies. 2,[10][11][12][13][14][15][16][17][18][19] However, it should be noted that the parental asymmetry tests we applied here do not specifically test for maternal effects which would be expected to occur via alterations of the in utero environment. Calculation of genomic inflation factors for the MAT and PAT tests showed a small increase for the MAT compared with the PAT in all categories, this increased inflation factor in the MAT does not discern the underlying cause, being consistent with either a true excess of biological associations with the maternally inherited alleles, or alternatively differing population structure between the two parental populations.…”

“…In fact, environmental studies have indicated maternal smoking, and potentially alcohol consumption, during pregnancy greatly increase the risk of clefting in offspring, with some evidence of genetic interactions. 2,10,11 Similarly, according to several studies, multi-vitamin supplements with or without folic acid taken during pregnancy have been shown to decrease the risk of oral clefting, with a stronger effect seen in CL/P as compared with CPO. [12][13][14] If levels of circulating folate are influenced by genetic factors, then it can be hypothesized any maternal genes involved in dictating circulating folate levels could also alter the risk of OFCs in the fetus.…”

Nicotine Exposure During Pregnancy Results in Persistent Midline Epithelial Seam With Improper Palatal Fusion

“…[25][26][27] It was shown that smoking by both parents interacts with a specific allelic variant of MSX1, which significantly increase the OFC risk for their offspring. 28 Moreover, a novel approach was developed by Wehby et al 26 to study the role of maternal smoking and OFC, in which they found out that smoking before and during pregnancy increased the risk of OFC by about 4-5 times at the sample average smoking rate. Furthermore, in a recent genome-wide analysis study (GWAS), biases for maternally inherited genetic factors influencing the risk of OFC was suggested.…”

Clinical and functional data implicate the Arg(151)Ser variant of MSX1 in familial hypodontia

“…[3][4][5][6][7][8][9][10][11][12][13][14] However, MSX1 also clearly affects the common human oral cleft phenotypes, as demonstrated through multiple genetic studies. [15][16][17][18][19][20] Yet, in all but a single case report, 5 MSX1 apparently functions as a complex disease determinant for oral clefting. In this context, there have been multiple reports of MSX1 missense mutations within sporadic clefting cases, 17,18,21,22 but all these reports suffer from a lack of power to discern disease risk.…”

“…Environmental perturbations, such as maternal smoking, can also influence craniofacial phenotypes, for example, maternal smoking in the presence of the CA4 homozygous state increased the risk of clefting. 19,46 Thus, in the interest of future meta-analysis of these questions, we report these data below.…”