Polymorphisms in genes involved in folate metabolism and orofacial clefts

Background

Orofacial clefts (OFCs) are one of the most common birth defects in humans. Maternal use of folate antagonists including dihydrofolate reductase inhibitors has been associated with a higher risk of OFCs thus suggesting that folate-related metabolism and associated genes may be involved in pathogenesis of OFC. The association between folate intake and risk of OFCs however is inconsistent.

Objective

To review the published evidence that polymorphisms in genes that affect folate metabolism are associated with an increased risk of OFCs.

Methods

We reviewed articles published up until October 2010, on polymorphisms of genes related to folate and homocysteine metabolism and their associations with OFCs. Articles were identified via Medline searches.

Conclusions

No consistent evidence emerged of a strong association between risk of OFCs and any known gene related to folate metabolism. Further, recent genome-wide association studies have not identified associations between OFCs and folate-related genes. Further studies are warranted to determine whether gene–environment interactions, including gene–nutrient interactions and epigenetic modifications of genes affect the risk of OFCs.     

TPM1基因相关多态性与中国北方汉族人群非综合征性唇腭裂的相关研究

目的：分析TPM1基因上游功能区3个单核苷酸多态性（single nucleotide polymorphisms, SNPs）位点与中国北方人群非综合征性唇腭裂（nonsynodromic orofacial clefts, NSOC）的关联。方法：通过对335个NSOC样本及572个健康对照样本外周血DNA的研究对目的位点行聚合酶链反应（polymerase chain reaction, PCR）扩增、DNA测序、基因分型。利用PubMed数据库（https://www.ncbi.nlm.nih.gov/pubmed）采集相关多态性位点基本信息。使用SHEsis在线软件、SPSS 20.0软件对SNPs位点的等位基因频率、基因型及单体型进行分析研究。结果：TPM1相关rs1873147、rs7179658和rs4775599完全连锁,rs1873147在唇腭裂（cleft lip and palate, CLP）组与健康对照组之间的等位基因频率差异有统计学意义（P=0.035）。结论：TPM1相关rs7179658、rs1873147和rs477559与中国北方汉族人群NSOC可...     

Quality of life and family functioning in children with nonsyndromic orofacial clefts at preschool ages

Children with orofacial clefts (OFC) at preschool ages may have to tolerate psychosocial disadvantages due to their altered speech and facial appearance probably affecting their quality of life (QoL) and family functioning. In 147 children with OFC aged between 5 and 6 years and their families, the QoL and family functioning were analyzed using the KINDL questionnaire for measuring health-related QoL in children and impact on family scale. The KINDL scores were lowest in the dimension self-esteem. In all dimensions, the KINDL scores of children were higher than those of the parents suggesting a superior QoL than the caregivers estimated (P<0.001). In affected families, the impact on family scale dimensions personal impact and impact on coping strategies were found highest. Families having children with isolated cleft lip or cleft lip and palate had higher impacts on coping strategies when compared with children having isolated cleft palate (P<0.041). The impact for siblings (P<0.02) was found highest in patients with cleft lip and palate. In all examined dimensions, children with OFC perceived a higher QoL than their caregivers expected. However, self-esteem seems to be problematic in all types of OFC and in both genders. Knowledge of potential impacts related to the type of cleft and the gender of the patient will probably facilitate health care professionals to identify children and families at high risk to experience a reduced QoL and may help to offer specific support and treatment strategies.     

Rs12941170 at SOX9 gene associated with orofacial clefts in Chinese

ObjectiveNon-syndromic orofacial cleftings (NSOCs) are considered as complex trait, which results from genetic and/or environmental modifiers. Current findings could only explain small portion of the NSOCs. SOX9 gene plays an important role during craniofacial development in animal models and the Pierre Robin sequence (PRS). However, its role in non-syndromic clefts remains unknown.DesignIn this study, we selected eight SNPs in and around SOX9 gene to make maximum coverage, and genotyped them by using RFLP-PCR and ligase detection reaction (LDR) methods to test its associations among 151 NSOCs (53 NSCLP, 52 NSCLO and 46 NSCPO) from Western Han Chinese population.ResultsAllelic TDT results showed that G allele at rs12941170 of SOX9 was under-transmitted among NSOCs (p = 0.00014, OR = 0.55 and 95%CI: 0.40–0.75), which could indicate that the G allele is protective against NSOCs; parent-of-origin effect analysis showed that G allele at rs12941170 was maternally under-transmitted (p = 0.002), while there was no statistically difference between the maternal and paternal transmission of it. To test if the adjacent SNPs travel together from parents to the affected individual, we carried out the sliding window haplotype analysis, it is interesting to find that the haplotypes carrying the G allele at rs12941170 also was under-transmitted for NSOCs, NSCL/P, NSCLP and NSCPO (lowest p = 0.00033).ConclusionsThis study suggested that G allele at rs12941170 was protective, which could decrease the risk for NSOCs from Western Han Chinese population, and it will provide new reference for future research and genetic counseling in NSOCs.     

An assessment of orofacial clefts in Tanzania

Background  

Clefts of the lip (CL), the palate (CP), or both (CLP) are the most common orofacial congenital malformations found among live births, accounting for 65% of all head and neck anomalies. The frequency and pattern of orofacial clefts in different parts of the world and among different human groups varies widely. Generally, populations of Asian or Native American origin have the highest prevalence, while Caucasian populations show intermediate prevalence and African populations the lowest. To date, little is known regarding the epidemiology and pattern of orofacial clefts in Tanzania.     

An assessment of orofacial clefts in Tanzania

Background

To determine the prevalence of periapical lesions in root canal-treated teeth in a rural, male adult, Turkish population and to investigate the influence of the quality of root canal fillings on prevalence of periapical lesions.

Methods

The sample for this cross-sectional study consisted of 552 adult male patients, 18-32 years of age, presenting consecutively as new patients seeking routine dental care at the Dental Sciences of Gulhane Military Medicine, Ankara. The radiographs of the 1014 root canal-treated teeth were evaluated. The teeth were grouped according to the radiographic quality of the root canal filling and the coronal restoration. The criteria used for the examination were slightly modified from those described by De Moor. Periapical status was assessed by the Periapical Index scores (PAI) proposed by Orstavik.

Results

The overall success rate of root canal treatment was 32.1%. The success rates of adequately root canal treatment were significantly higher than inadequately root canal treatment, regardless of the quality or presence of the coronal restoration (P < .001). In addition, the success rate of inadequate root canal treatment was also significantly affected by the quality of coronal restorations.

Conclusions

Our results revealed a high prevalence of periapical lesions in root canal treatment, which is comparable to that reported in other methodologically compatible studies from diverse geographical locations. In addition, the results from the present study confirm the findings of other studies that found the quality of the root canal treatment to be a key factor for prognosis with or without adequate coronal restoration.     

TGF alpha has low protein expression in nonsyndromic clefts

Genetic studies have demonstrated that nonsyndromic cleft is composed of two separate entities: the cleft palate only and cleft of the lip, alveolus with or without cleft palate; both have a heterogeneous genetic background and environmental factors contribute to the onset of these malformations. The role of transforming growth factor alpha (TGF-A) was considered possible, but conflicting results have been reported. To detect if TGF-A is involved in the onset of cleft diseases, a series of patients with nonsyndromic clefts and control subjects were analyzed with regard to protein expression. Forty-three patients with nonsyndromic clefts and 21 unaffected subjects were enrolled in this study. Paraffin-embedded specimens were matched with TGF-A antibody and then scanned with a computerized image analyzer. TGF-A was scored as absent, moderately (from 10% to 30%), and highly expressed in epithelium, gland, and muscle. Data were statistically analyzed with a Kruskal-Wallis test. Comparison between control subjects and patients with clefts showed that only gland and epithelium reached a significant P value. A subsequent comparison between cleft of the lip, alveolus with or without cleft palate and cleft palate only groups demonstrated a statistically significant difference only for gland. TGF-A was decreasingly expressed in unaffected, cleft of the lip, alveolus with or without cleft palate, and patient with cleft palate only and thus further strength has been given to its role in the onset of the disease.     

Epidemiology underpinning research in the aetiology of orofacial clefts

INTRODUCTION: Epidemiological information gathered through birth defects surveillance is an important adjunct to carrying out clinical and aetiological research. Information on the incidence in the population, causative risk factors and providing baseline data prior to intervention are all important elements. Under the auspices of the World Health Organisation, it was agreed that a global registry and database on craniofacial anomalies should be created and this, the International Database on Craniofacial Anomalies (ICDFA) was designed to gather information on craniofacial abnormalities from existing birth defects registries and databases around the world to become a resource underpinning research. There are currently 62 registries covering 2 million births per year contributing to a database along with information on the size and type of studies used to collect the information, any variation in ascertainment and on the inclusion of syndromes and associated abnormalities. GENERATION OF HYPOTHESES: From the epidemiological data collected it is possible to carry out meta-analysis and to search for trends and consistencies in the data that enable hypothesis to be generated. Issues such as geographical distribution, ethnicity, gender, associated abnormalities and clefts in stillbirths can all be examined in a meta-analytical approach. Collection of information on risk factors such as maternal illnesses, medications, lifestyle factors, nutrition and perhaps occupational exposures enables investigation into environmental contribution to causality and genetic predisposition. A range of techniques are currently being used to identify new candidate genes and ultimately it will be necessary to test genetic and environmental hypothesis in the context of human population studies. CONCLUSIONS: It is only by consistency of association between different populations with different gene pools and maternal exposures, lifestyles, nutrition etc that conclusive evidence regarding causality will be found. It is therefore essential, and a major objective of the WHO that international multicentre collaborative studies are setup to gather the appropriate evidence and improve knowledge and the cause of birth defects in general and orofacial clefts in particular, with the ultimate humanitarian and scientific objective of the WHO being primary prevention. CLINICAL UTILITY AND IMPLICATIONS: This IDCFA project fulfils three basic objectives namely to enable global surveillance of CFA; to create online access to those who wish to contribute to the IDCFA, and to develop an online directory of resources on craniofacial anomalies for the support of research and improving quality of care. The next steps for IPDTOC are to expand the number of participating registries and to actively collect data on other craniofacial birth defects.     

Patterns of tooth agenesis in patients with orofacial clefts

Orofacial clefts are a common oral disorder associated with tooth agenesis. As information on the simultaneous absence of teeth can be an aid in treatment planning, a large sample of orofacial cleft patients was examined. The sample consisted of 910 patients with cleft lip and palate. Tooth agenesis was assessed on the basis of at least two panoramic radiographs and patient records. Third‐molar agenesis was determined in 474 patients. Patterns of tooth agenesis were analysed using Tooth Agenesis Code (TAC) values, according to van Wijk & Tan . Per quadrant, at least 90% of patients could be described according to three different patterns. In the maxilla, 85% of patients with tooth agenesis had a TAC‐value of 2, 16, or 18 on either the left side, right side or bilaterally. In the mandible, 90% of patients with tooth agenesis had a TAC‐value of 16, 1 or 2 on either the left side, right side or bilaterally. In patients with tooth agenesis, patterns were symmetrical in the maxilla in 18.8% and in the mandible in 51%. More extended cleft types were associated with a higher prevalence of tooth agenesis. Third‐molar agenesis (prevalence = 22.4%) was significantly related to the prevalence of other absent teeth. These results show which patterns of tooth agenesis can be expected to occur in most orofacial cleft patients.     

外周血miR-299-5p和miR-127-3p的表达水平与非综合征型唇腭裂相关性研究

目的:研究外周血中miR-299-5p和miR-127-3p的表达水平与非综合征型唇腭裂(NSOC)的相关性.方法:选取于哈尔滨医科大学附属第一医院就诊的唇裂伴或不伴腭裂(CL/P)患儿、单纯腭裂(CPO)患儿和健康儿童各10例,采用实时荧光定量RT-PCR(qRT-PCR)检测各组外周血中miR-299-5p和miR...     

Priorities for future public health research in orofacial clefts.

The National Center on Birth Defects and Developmental Disabilities at the Centers for Disease Control and Prevention conducted a workshop in January 2006, entitled "Prioritizing a Research Agenda for Orofacial Clefts." The goals of the meeting were to review existing research on orofacial clefts (OFCs), identify gaps in knowledge that need additional public health research, and develop a prioritized research agenda that can help guide future public health research. Experts in the field of epidemiology, public health, genetics, psychology, speech pathology, dentistry, and health economics participated to create the research agenda. Research gaps identified by the participants for additional public health research included: the roles of maternal nutrition, obesity, and diabetes in the etiology of OFCs; psychosocial outcomes for children with OFCs; the quality of life for families and children with OFCs; and the health care costs of OFCs. To create the research agenda, the participants prioritized the research gaps by public health importance, feasibility, and outcomes of interest. This report summarizes the workshop.     

Origin of hydrocortisone induced orofacial clefts in the chick embryo

The growth and fusion of facial processes were studied in White Leghorn chicken embryos treated with hydrocortisone. This treatment results in complete bilateral cleft beak in 80-100% of cases. The frontonasal complex of the experimental embryos exhibited marked hypoplasia prior to cleft manifestation. During the critical period for cleft beak formation, the maximum mitotic activity was concentrated in the medial nasal processes, which thus became vulnerable to the mitosis inhibiting effect of corticoids. Primary hypoplasia of the facial processes was documented as a causative factor of corticoid-induced cleft beak which is analogous to mammalian cleft lip/palate.     

Replication of two novel susceptibility loci for non‐syndromic orofacial clefts in a Chinese population

Oral Diseases (2011) 17 , 304–308 Objectives: Non‐syndromic orofacial clefts (NSOC) are the most common developmental disorders in human beings. Recently, two genome‐wide association studies in European Caucasians identified three novel NSOC susceptibility loci: rs987525 on 8q24, rs7078160 on 10q25.3, and rs223371 on 17q22. The aim of this study was to determine the association of these polymorphisms with NSOC susceptibility and its subgroups in a Chinese Han population. Material and methods: In this study, 199 NSOC patients and 210 healthy individuals were recruited. SNP rs987525 was not genotyped because of its low frequency in the study subjects. The other two polymorphisms (rs7078160 and rs223371) were respectively genotyped by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) and Taqman‐MGB assay. Results: Overall genotype distributions of rs7078160 and rs223371 polymorphisms were consistent with Hardy–Weinberg equilibrium test. The allele and genotype frequencies of the two polymorphisms were not significantly different between cases and controls. Further analysis indicated that none of the genotypes was associated with increased risk of NSOC. Similar results were also found when all cleft cases were stratified by cleft types. Conclusion: Our findings are consistent with a lack of involvement of the rs7078160 and rs223371 polymorphisms in the development of NSOC in the Chinese Han population.     

The relationship between orofacial clefts and material deprivation in wales.

OBJECTIVE: This study investigated the relationship between material deprivation and the incidence of orofacial clefts (OFC) in South, West, and Central Wales, U.K. DESIGN AND SETTING: The South, West, and Central Wales Orofacial-Cleft Register served as the primary data source for the study. Data on all children born with an orofacial cleft between 1982 and 2003 were geocoded to one of 844 geographic wards. National census data, similarly geocoded, served as the population denominator. Townsend's index of material deprivation was used to assign wards to one of seven levels of deprivation. This permitted investigation of the association of orofacial clefts with material deprivation. RESULTS: Between 1982 and 2003, there were 831 babies born with an orofacial cleft, equating to 109 clefts per 100,000 live births. The incidence of orofacial clefts ranged from 82 per 100,000 (95% confidence interval [C.I.] 64 to 102 per 100,000) in babies born to mothers residing in the least deprived areas to 127 per 100,000 (95% C.I., 112 to 144 per 100,000) in those living in the most deprived areas, a significant linear trend being apparent (p < .001). A statistically significant risk of 1.55 (95% C.I., 1.18 to 2.04) for orofacial clefts was apparent between most and least deprived septiles of deprivation. CONCLUSIONS: This study provides further evidence of an association between material deprivation and orofacial clefts. Further work is required to elicit the degree to which potential risk factors contribute to this association and to determine how deprivation predisposes to orofacial clefts.     

Drug treatment during pregnancy and isolated orofacial clefts in hungary.

OBJECTIVE: To evaluate the possible association between all kinds of drug treatments during pregnancy and isolated cleft lip with or without cleft palate (CL/P) and posterior cleft palate (PCP) in the offspring. SETTING: The dataset of the large population-based Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996, was evaluated. PARTICIPANTS: One thousand three hundred seventy-four cases with isolated CL/P and 601 with PCP, plus 38,151 population controls (without birth defects) and 20,868 malformed controls with other defects. Intervention: In this observation case-control study the data collection was based on prospective medical records particularly prenatal logbook, retrospective maternal data via a self-reported questionnaire, and home visits of nonresponding mothers. MAIN OUTCOME MEASURES: Isolated CL/P and PCP associated with drug treatments during pregnancy. RESULTS: An increased risk for isolated CL/P was found in cases born to mothers treated with amoxicillin, phenytoin, oxprenolol, and thiethylperazine during the second and third month of pregnancy, i.e., the critical period of isolated CL/P. Risk of isolated PCP was increased in mothers with oxytetracycline and carbamazepine treatment during the third and fourth month of pregnancy, i.e., the critical period of PCP. CONCLUSIONS: This study confirmed the orofacial cleft (OFC) inducing effect of phenytoin, carbamazepine, oxytetracycline, and thiethylperazine and suggested a possible association between OFCs and oxprenolol and amoxicillin. However, drugs may have only a limited role in the origin of isolated OFCs.