The role of genetic and environmental factors in the etiology of or ofacial clefts in the Ethiopian population

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Addis Ababa Universty


Background: Orofacial clefts (OFCs) are the commonest craniofacial birth defects with a worldwide birth prevalence of 1/700 live birth. It varies from 1/2500 to 1/500 births depending on the geographic origin, racial and ethnic backgrounds, and socioeconomic status. The incidence of this anomaly in Ethiopia is not known and the etiology has never been studied. We investigated the contribution of previously reported candidate genes and chromosomal loci to the risk of non-syndromic orofacial clefts (NSOFCs) in the Ethiopian population, which is important for improving the management and prevention. It is also of paramount importance in parental counseling and intervention. We investigated the role of environmental factors in the occurrence of NSOFCs in the Ethiopian population. The quality of life of children affected and their parents was also assessed. Objectives: The main objective of this study was to investigate the role of genetic and environmental factors in the etiology of NSOFCs in the Ethiopian Population Methods: We assessed the epidemiology, etiology and quality of life of those affected and the perception of their parents. The epidemiology of OFCs was assessed using the Ethiopian 2007 sensus retrived from the Federal Ministry of Health (EFMH) and the Smile Train (ST) databases. The data was collected from June 2007 to December 2013. ST is a charity organization, which supports cleft care in Ethiopia. We used data collected from November 2012 to January 2016 on maternal and child demographic data, maternal illness, medication, lifestyle and exposures. Saliva samples collected from the participants (Cases, Case mothers, controls and Control Mothers) for analysis using Oragne saliva collection kits and sponges. The collected saliva samples were sent to University of Iowa, USA for DNA processing. We collaborated with similar projects in Ghana and Nigeria to perform the genetics part of this investigation. We selected &genotyped 48 single-nucleotide polymorphisms (SNPs) on 701 non-syndromic cleft lip and or palate (NSCL/P)&163 non-syndromic cleft palate only (NSCPO) cases, 1070 unaffected relatives &1078 unrelated controls. The association of these SNPs with NSOFCs in Asian and European population was confirmed through Genome-wide xiv association (GWAS)& candidate gene (CG) studies. We conducted association analyses for each population using the cleft-type cohorts described above, and a meta-analysis of the three subpopulations The role of environmental factors in the etiology of NSOFCS was assessed using the data collected on maternal demographic data, maternal illness, maternal medication use, lifestyle and exposure before and during pregnancy. We interviewed 359 mothers of children born with NSOFCs and 401 mothers of children born without any congeneital anomaly. We assessed the oral health related quality of life (OHRQoL) of children born with NSOFCS &the perception of their parents using the child oral health impact profile (COHIP) questionnaire. In this study 41 children born with NSOFCs and treated from December 2008 to December 2016 and equal number of parents participated. Results: We determined the incidence/prevalence of OFCs in Ethiopia using the ST database, which was collected from June 2007-December 2013. During this time 18,073 patients with cleft lip and or palate (CL/P) were operated, out of the total operated patients with OFCs 8,232 are under seven years old. The total number of live births during this period was 18,811,316. This gives an incidence of 44/100,000 live births of orofacial clefts in Ethiopia. The prevalence was estimated using the total number of Cleft patients operated from June 2007 to December 2013 (N=18,073) as a numerator and the total number of population (N= 88,703,914) in 2013 as a denominator. It is estimated to be 20/100,000 populations. We confiremed that SNPS, which were found to be associated withn the occurrence of NSOFCs in European population, were found to be associated with the occurrence of NSOFCs in our study populations. In the Ethiopian subpopulation PAX7 (rs742071, P = 0.005574,OR=1.329 and 95%CI 1.087-1.626), IRF6 (rs642961, P =0.01508;OR= 1.442; 95% CI 1.072-1.94), DYSF (rs2303596, P = 0.00231;OR= 0.6854; 95%CI 0.5371-0.8747), 8q24 (rs987525, P =0.000782; OR= 1.413; 95%CI 1.154-1.73), were found to be Nominally associated with the occurrence of NSCL/P. SNPS in NTN1 (rs8081823, P xv = 0.03251; OR=0.4905, 95% CI 0.216-1.114) were also found to be nominally associated with NSCPO in the Ethiopian population. The role of maternal environmental factors and diseases in the occurrence of NSOFCs was assessed and revealed that mothers who lived outside Addis Ababa during their pregnancy time had a higher risk of delivering a child with NSOFCs and mothers who gave history of threatened abortion and Bronchial Asthma were having a higher risk of delivering a child with NSOFCs. Mothers who had exposure to diagnostic X-Ray were also at higher risk of having a child with NSOFCs No significant differences were found for overall and subscales COHIP scores between the patients and their parents. The maximum overall score parents obtained on the COHIP was 186 and the patients was 190. The mean overall score of the patients and parents was 155. This indicates good OHRQoL of children born with NSOFCs. Conclusion and recommendations: The prevalence 20/100,000 populations found in this study are lower than the previous studies done in many parts of Africa including the study done in Addis Ababa. Loci, which contributed to the occurrence of NSOFCs in European and Asian population, were found to contribute to the occurrence of NSOFCs in sub-Saharan populations (Ethiopia, Ghana and Nigeria). We found out that the affected children who received multidisciplinary cleft care had good OHRQoL and the responses of the affected children and their parents did not differ. We recommend community based prospective study to find out the true incidence of OFCs. We also recommend conducting a prospective case control study to better understand the contribution of environmental factors and the gene environment interaction in the occurrence of birth defects in general and OFCs in particular. Finally, we recommend that the child oral health impact profile (COHIP) questionnaire should be modified to fit the cultural beliefs of various populations and society around the world.



Orofacial clefts, genetic factors, Gene environment interaction