The Study Of Genetic And Geography Environmental Factors Invoved In NSCLP

Non-syndromic cleft lip and palate (NSCLP) is a common birth defect diseases. Its etiology was complex, and occurred as multifactorial diseases by the interaction between genetic and environmental factors. About 25%-30% of NSCLP patients have family history, and a variety of environmental and genetic factor interactions can induce to NSCLP.Currently, the candidate genes of NSCLP were more than fifty, about half of them were reported association with the disease, and many of them involved in embryonic development or related pathways. It is reported that CRISPLD2 genes involved in the mandible, palate and nasopharynx development, and the three gene loci rs1546124, rs4783099 and rs16974880 single nucleotide polymorphism (SNP) were associated with the risk of suffering NSCLP. However, subsequent studies in different populations have not agreed conclusions; therefore, the purpose of this study is to assess the population in Northwest China CRISPLD2 gene and NSCLP relevance.Three CRISPLD2 SNPs were genotyped in a case-control study (n=907), including 444 NSCLP patients and 463 healthy individuals, using polymerase chain reaction-denaturing high-performance liquid chromatography (PCR-DHPLC). For cleft lip with or without palate (CL/P) and cleft palate only (CPO) and gender were stratified analysis. Results are as follows:1. CRISPLD2 gene polymorphism was significantly associated with non-syndromic cleft lip and/or palate in patients of northwest China population, especially the loci rs 1546124 has the most significant association with non-syndromic cleft lip and palate.2. In NSCLP group and control group, rs 1546124 locus CC genotype and allele frequencies were significantly different (OR=2.30,95% CI:1.58-3.34, p=1×10-5); rs4783099 locus related with reduce the risk of NSCLP (OR=0.73,95% CI:0.54-1.00, p=0.05); rs16974880 was have nothing to do with the NSCLP the risk.3. The CL/P and CPO two groups were stratificated, rs1546124 not only increased the CL/P risk (OR=2.11,95%CI:1.41-3.15, pcorrect=1.5×10-4), but also had a strong correlation with the risk of CPO (OR= 2.93,95% CI:1.69-5.07, Pcorrect=5.4×10-4); T allele frequency of rs4783099 is relevant with lower risk of CPO; rs16974880 locus was not related with both CL/P and CPO.4. Stratified by gender, we found that all three loci associated with male patients, and has nothing to do with female patients. Rs1546124 CC genotype frequency increased the risk of male NSCLP patients, the prevalence of risk than the normal controls increased to 2.80 (p=1.2×10-4). The rs4783099 and rs16974880 were all decreased risk for men.5. In European Caucasian population, the three loci had a strong association of haplotypes. But in Chinese population, rs1546124 and the other two sites are in different LD region. Rs4783099 and rs16974880 are in the same LD region, and their TT haplotype was associated with increased risk of NSCLP (OR=1.55,95% CI:1.029～2.321, p=0.03, pc=0.12). But the p value did not show strong correlation with NSCLP after Bonferroni multiple corrections.Thus, CRISPLD2 gene seemed have relevance to the the etiology of NSCLP people in northwest China. Rs1546124 single nucleotide polymorphism is closely related with both CL/P and CPO. In addition, three loci associated with the male patients.The analysis of geographical environmental factors was using principal component analysis (PCA) and Canonical correspondence analysis (CCA) method. The study subjects include 444 patients. In the paper, we studied the interaction between three loci (rsl546124, rs4783099 and rs16974880) of CRISPLD2 gene and the geographical location of NSCLP patients (longitude, latitude, altitude, soil type, annual average temperature, annual rainfall and annual sunshine duration). The results showed that, CRISPLD2 gene polymorphism and geographical environment interaction for NSCLP affect the incidence of risk has not statistically significant.In the present work, we collected and analysised pathologically confirmed patients with non-syndromic cleft lip and palate (NSCLP) in Gansu Province from 2004 to 2010. The incidence of NSCLP characteristics of the spatial distribution was analysised and the exploratory spatial data analysis (ESDA) and Kriging from GIS (ArcGIS 9.3) were applicated in disease mapping through the analysis of NSCLP in Gansu province.Visualization of spatial analysis results showed that the NSCLP incidence of Gansu Province have high-incidence and low-incidence areas obviously, the highest incidence rate area about 1.48%o-1.99%o were mainly in Jing Tai County, Xia He County, Li County; the second higher incidence rate about 1.11‰-1.48‰distributed in the Jing Yuan County, Bai Yin City, Yong Deng, Yu Zhong County, Lin Tao, Xi He, Cheng County; the third higher incidence rate about 0.73‰-1.11‰were Yong Chang, Gu Lang, Gao Lan, Lu Qu, Ma Qu, Zhou Qu, Kang County, Jing Ning, QingYang City. The Kriging interpolation projections indicated that three high- incidence regions in Gansu Province are:①The longitude 104.028°, north latitude 36.993°, and radius of 20,000 square kilometers;②longitude 102.845°, north latitude 35.42°, a radius of 0.5 square km;③longitude 105.42°, north latitude 33.75°, a radius of 13,000 square kilometers. The three regions belong to the Bai Yin, Lin Xia, and the south of Gan Nan and Long Nan region of Gansu Province.This is the first time to using GIS spatial analysis to study the relationship between geographical environment and the etiology of NSCLP in Gansu Province. It attempt to assessment a macro exposure and explore the pathogenesis and etiology of NSCLP in Gansu Province. According to the three high-incidence area of geographical features, it was speculated that the main environmental risk factors for NSCLP patients of Gansu three areas may heavy metal pollution and high altitude.In summary, we investigated the pathogenic mechanisms and etiology of NSCLP from both genetic and environmental factors. It will provide new data to fully explore the NSCLP pathogenic mechanism.