RNT4 3'-UTR insertion/deletion polymorphisms are not associated with atrial septal defect in Chinese Han population: a brief communication

Atrial septal defect (ASD) is a common type of congenital heart disease, which is defined as any communication through atrial septum. Several studies have revealed that genetic factors may influence the susceptibility of ASD. Recent studies have shown that reticulon 4 (RTN4) gene might be involved in some processes relevant to heart development, such as regulation of cell migration and vascular remodeling. This study aimed to evaluate RTN4 gene polymorphisms of CAA and TATC insertion/deletion in relation to the risk of ASD in Chinese Han population. A total of 175 ASD patients and 308 unrelated healthy controls were successfully investigated. The polymorphisms of patients were determined by polymerase chain reaction-polyacrylamide gel electrophoresis. There was no significant difference in the allele frequencies of CAA and TATC insertion/deletion in RNT4 gene between ASD patients and controls. The same results were seen in their genotypes. The present study suggests that CAA and TATC insertion/deletion polymorphisms of RNT4 gene may not be a useful marker to predict the susceptibility of ASD in Chinese Han population.     

Genetic variation in RTN4 3'-UTR and susceptibility to cervical squamous cell carcinoma

Recent studies have suggested that RTN4 is a multifunctional gene, including inhibition of axonal regeneration, vascular remodeling, apoptosis, and tumor suppression. The TATC and CAA insertion/deletion polymorphisms of RTN4 3'-UTR have been linked to schizophrenia, depression, and dilated cardiomyopathy. To test whether these two polymorphisms are associated with cervical squamous cell carcinoma (CSCC), in this research, by using polymerase chain reaction-polyacrylamide gel electrophoresis, we determined the genotypes of the TATC and CAA polymorphisms in 336 CSCC patients and 450 unrelated control subjects. Allele frequencies of TATC and CAA polymorphisms were not significantly different between CSCC patients and control subjects (odds ratio [OR]=1.22, 95% confidence interval [CI]=0.98-1.50 for TATC; OR=0.95, 95% CI=0.76-1.18 for CAA). Decreased CSCC risk was associated with TATC polymorphism in a recessive model (OR=0.49, 95% CI=0.30-0.77), while no significant association was observed between CAA polymorphism and CSCC in different genetic models. Results of stratified analysis revealed that both TATC and CAA polymorphisms were associated with high clinical stage, and CAA polymorphism was also associated with positive parametrial invasion (OR=0.69, 95% CI=0.48-0.98). The present study provides evidence that TATC and CAA insertion/deletion polymorphisms are associated with CSCC, indicating that genetic variation in RTN4 3'-UTR contributes to the susceptibility to CSCC. It is necessary to confirm these findings in ethnically different populations and with a larger sample.     

中国成都汉族与泰国人群Nogo蛋白基因遗传多态性研究

轴索生长抑制因子(Neurite growth inhibitor,Nogo)在中枢神经系统中主要发挥抑制轴突再生的作用,其基因TATA和CAA插入缺失多态性与慢性精神分裂症发病风险有关,在不同种族间RTN4基因型及等位基因频率分布的存在差异.该研究将采用聚合酶链反应和聚丙烯酰胺凝胶电泳方法检测205名中国成都汉族人和101名泰国人RTN4基因多态性,比较两组人群RTN4基因TATC和CAA插入缺失多态性分布情况,并与不同种族人群研究结果进行比较.研究发现在中国成都地区汉族人群中,RTN4基因(TATC)2(TATC)2基因型频率为10.2%,明显低于泰国人群(21.8%),差异具有统计学意义(P=0.006);(TATC)2等位基因在成都汉族人群中占34.9%,明显低于泰国人群(45.0%),差异具有统计学意义(P=0.015).CAA插入缺失基因型和等位基因频率在成都汉族人群和泰国人群中差异均无统计学意义(P>0.05).此外,中国成都地区汉族人群等位基因(TATC)2频率(34.9%)明显低于法国加拿大人(45.0%)和突尼斯人(49.0%),差异具有统计学意义(P<0.05);等位基因(CAA)2频率(66.8%)明显高于法国加拿大人(53.0%)和巴西人(37.8%),差异具有统计学意义(P<0.05);结果表明RTN4基因TATA和CAA插入缺失多态性在不同种族间的分布存在明显差异.     

A systematic genetic polymorphism analysis of the CYP2C9 gene in four different geographical Han populations in mainland China

While many studies have been focused on CYP2C9*2 and *3 there was a lack of large full gene sequencing on CYP2C9, and this study was designed to fill this gap. We used direct sequencing to systematically screen genetic polymorphisms of the CYP2C9 gene including the 5' -flanking region (2kb), all exons and their adjoining intron regions and the 3' UTR in 400 unrelated healthy Chinese Han volunteers. A total of 27 different CYP2C9 polymorphisms were identified, 3 of which were novel, including one in intron 6, a synonymous variant (1137T>C, Tyr379Tyr), and a deletion mutation in the 3'UTR (1739-1740ATdel), which potentially influences the stability of CYP2C9 mRNA. We identified CYP2C9*1, *2, *3, *8, *11, and *31, of which alleles *8 was identified for the first time in Chinese population while *11 first in Asian. This is the first systematic screening of genetic polymorphisms of CYP2C9 in the Chinese Han population.     

Presenilin-1 polymorphisms are not relevant in susceptibility to ventricular septal defect: a case-control study

Although many studies have demonstrated that presenilin-1 plays a vital role in cardiovascular system development, no data are available concerning association of polymorphisms of presenilin-1 with ventricular septal defect (VSD) in the Chinese population. The aim of this study was to evaluate the association between two single-nucleotide polymorphisms (rs1800844 and rs177415) of presenilin-1 and VSD. A total of 151 isolated VSD patients and 296 controls were included in the study. The genotype of the polymorphisms was determined by polymerase chain reaction-restriction fragment length polymorphism. Our study showed no statistically significant differences in genotype and allele frequencies between VSD and controls with any of the presenilin-1 genetic variants. These data may provide evidence that the presenilin-1 gene is not a genetic marker for VSD susceptibility in the Han Chinese population.     

Forensic characteristic and population structure dissection of Shaanxi Han population in the light of diallelic deletion/insertion polymorphism data

The genetic polymorphisms of diallelic deletion/insertion polymorphic (DIP) loci in the Shaanxi Han population are still not clearly characterized. Herein, allele frequencies and forensic application efficiencies for 30 diallelic DIP loci were investigated in 506 unrelated healthy Han individuals from Chinese Shaanxi province. Based on population data of the same 30 diallelic DIP loci, the genetic differentiations, hierarchical clustering relationships and population architectures among Shaanxi Han and other 50 populations were further dissected through genetic and bioinformatics analyses. Results indicated that most of the 30 diallelic DIP loci were relatively high polymorphisms in the Shaanxi Han population; and there were the genetically intimate relationships between Shaanxi Han and the East Asian populations. In summary, this study provided significant insights into genetic background of Shaanxi Han population, and the multiplex amplification of these 30 diallelic DIP loci was appropriate for forensic individual identification and population genetic research in Shaanxi Han population.     

Replication of the 4p16 Susceptibility Locus in Congenital Heart Disease in Han Chinese Populations

Congenital heart disease (CHD) is the most common form of congenital human birth anomalies and a leading cause of perinatal and infant mortality. Some studies including our published genome-wide association study (GWAS) of CHD have indicated that genetic variants may contribute to the risk of CHD. Recently, Cordell et al. published a GWAS of multiple CHD phenotypes in European Caucasians and identified 3 susceptibility loci (rs870142, rs16835979 and rs6824295) for ostium secundum atrial septal defect (ASD) at chromosome 4p16. However, whether these loci at 4p16 confer the predisposition to CHD in Chinese population is unclear. In the current study, we first analyzed the associations between these 3 single nucleotide polymorphisms (SNPs) at 4p16 and CHD risk by using our existing genome-wide scan data and found all of the 3 SNPs showed significant associations with ASD in the same direction as that observed in Cordell’s study, but not with other subtypes- ventricular septal defect (VSD) and ASD combined VSD. As these 3 SNPs were in high linkage disequilibrium (LD) in Chinese population, we selected one SNP with the lowest P value in our GWAS scan (rs16835979) to perform a replication study with additional 1,709 CHD cases with multiple phenotypes and 1,962 controls. The significant association was also observed only within the ASD subgroup, which was heterogeneous from other disease groups. In combined GWAS and replication samples, the minor allele of rs16835979 remained significant association with the risk of ASD (OR = 1.22, 95% CI = 1.08–1.38, P = 0.001). Our findings suggest that susceptibility loci of ASD identified from Cordell’s European GWAS are generalizable to Chinese population, and such investigation may provide new insights into the roles of genetic variants in the etiology of different CHD phenotypes.     

中国汉族人群CYP4F3基因多态性的研究

目的:研究CYP4F3基因单核苷酸多态性(SNP)在中国汉族人群中的分布,为进一步研究该基因群体遗传学特征及与疾病易感性的相关性提供更为详实的数据。方法:对CYP4F3基因进行重测序,构建连锁不平衡模式,选择标签SNP在192例北京和424例广州汉族个体中进行基因分型。结果:CYP4F3基因重测序共检出30个SNP,连锁不平衡分析显示广州和北京地区人群的连锁不平衡模式不同,但选择的8个标签SNP的等位基因和基因型频率分布在2个人群中的差异无统计学意义。结论:中国北京地区汉族与广州地区汉族人群CYP4F3基因多态性无显著差异,但不同种族间存在差异。     

Genetic polymorphisms of the TYMS gene are not associated with congenital cardiac septal defects in a Han Chinese population

Background

Clinical research indicates that periconceptional administration of folic acid can reduce the occurrence of congenital cardiac septal defects (CCSDs). The vital roles of folate exhibits in three ways: the unique methyl donor for DNA expression regulation, the de novo biosynthesis of purine and pyrimidine for DNA construction, and the serum homocysteine removal. Thymidylate synthase (TYMS) is the solo catalysis enzyme for the de novo synthesis of dTMP, which is the essential precursor of DNA biosynthesis and repair process. To examine the role of TYMS in Congenital Cardiac Septal Defects (CCSDs) risk, we investigated whether genetic polymorphisms in the TYMS gene associated with the CCSDs in a Han Chinese population.

Method

Polymorphisms in the noncoding region of TYMS were identified via direct sequencing in 32 unrelated individuals composed of half CCSDs and half control subjects. Nine SNPs and two insertion/deletion polymorphisms were genotyped from two independent case-control studies involving a total of 529 CCSDs patients and 876 healthy control participants. The associations were examined by both single polymorphism and haplotype tests using logistic regression.

Result

We found that TYMS polymorphisms were not related to the altered CCSDs risk, and even to the changed risk of VSDs subgroup, when tested in both studied groups separately or in combination. In the haplotype analysis, there were no haplotypes significantly associated with risks for CCSDs either.

Conclusion

Our results show no association between common genetic polymorphisms of the regulatory region of the TYMS gene and CCSDs in the Han Chinese population.     

Association of PTEN polymorphisms with susceptibility to hepatocellular carcinoma in a Han Chinese population

The phosphate and tension homolog (PTEN) is a tumor suppressor gene that controls a variety of biological processes including cell proliferation, migration, and death. The association of PTEN polymorphisms with risk for many cancers has been reported, but hepatocellular carcinoma (HCC) has not yet been studied. The present study is the first attempt to assess the association of PTEN polymorphisms with HCC susceptibility. We genotyped one insertion/deletion polymorphism (rs34421660) by polymerase chain reaction (PCR) method and three tag single-nucleotide polymorphisms (rs10490920, rs532678, and rs701848) by polymerase chain reaction-restriction fragment length polymorphism in 134 HCC patients and 215 healthy controls. We found that the four polymorphisms were not associated with HCC, at both the allele and genotype levels. However, after reconstructing PTEN haplotypes according to genotyping data and linkage disequilibrium status of four polymorphisms, we found that the T-C-C-del haplotype was associated with decreased HCC risk (odds ratio?=?0.19, 95% confidence interval?=?0.06-0.56) and the T-T-T-ins haplotype was associated with increased HCC risk (odds ratio?=?1.63, 95% confidence interval?=?1.14-2.33). Thus, our results prove that PTEN haplotypes may be associated with HCC susceptibility in a Chinese Han population.     

Analysis of hABC1 gene 5' end: additional peptide sequence, promoter region, and four polymorphisms

Evidence linking mutations in ATP-binding-cassette transporter gene 1 (ABC1) to Tangier disease suggests it functions in the active transport of free cholesterol out of cells. Since its mRNA level is regulated in response to cellular cholesterol stores it is of interest to explore its promoter response elements, and to investigate polymorphisms for their contributions to the prevalence of low levels of HDL in the population that promotes premature coronary heart disease. Investigation of the 5' end of the gene by 5' RACE analysis revealed 455 nucleotides additional to published sequences, and predicts another 60 amino acid N-terminal residues, resulting in a 2261-residue protein. Protein sequence analysis predicts a membrane-spanning region and possible signal peptide. The 5' flanking region was located by a Human Research Project BLAST search. This region contains regulatory elements that potentially control ABC1 gene expression. In addition to numerous SP1 binding sites there are four putative sterol regulatory elements (SREs). Our studies uncovered three single nucleotide substitution polymorphisms, one in the promoter region and two in the 5' untranslated region (5'UTR), plus an insertion/deletion polymorphism.     

Genetic analysis of 30 InDel markers for forensic use in five different Chinese populations

Allele frequencies of 30 insertion/deletion polymorphism (InDel) markers previously selected and validated for forensic purposes were assessed in 419 unrelated individuals originating from five different populations of P.R. China, including Chinese Han, Chinese Hui, Uighur, Mongolians, and Tibetans. Hardy-Weinberg equilibrium tests and linkage disequilibrium analysis were performed; the allele frequency distributions of the 30 InDel markers met the conditions for genetic equilibrium in all five populations and the InDel markers on the same chromosome did not generate any linkage blocking. Analysis of molecular variance indicated that genetic variation among the five populations represents only 4% of the total genetic diversity. We determined the cumulative power of discrimination for each population: 0.99999999999841 in Chinese Han, 0.99999999999690 in Chinese Hui, 0.99999999999709 in Uighur, 0.99999999999772 in Mongolians, and 0.99999999999854 in Tibetans.     

Prevalence of Congenital Heart Disease in Xinjiang Multi-Ethnic Region of China

Background

The prevalence and risk factors of congenital heart disease among Xinjiang, northwestern part of China is currently unknown.

Methods

This multiple-ethnic, community-based, cross-sectional study was conducted to estimate the prevalence and distribution of congenital heart disease (CHD) in Xinjiang, northwestern part of China. Four major ethnics, Uygur, Han, Kazak, and Hui children in this region were investigated during February 2010 and May 2012.

Results

A total of 14,530 children (0–18 yr) were examined. Of these children, 240 (boys, 43.8%, and girls, 56.3%) were identified with CHD, giving an overall prevalence of 16.5‰ (17.7‰ in Uygur, 6.9‰ in Han, 11.4‰ in Kazak, and 38.1‰ in Hui Chinese, respectively). Ventricular septal defect (VSD, 29.2%), atrial septal defect (ASD, 20.8%), patent ductus arteriosus (PDA, 13.7%), acleistocardia (13.7%), Bicuspid aortic valve (7.9%), pulmonary valve stenosis (5.4%), and tetralogy of fallot (TOF, 4.2%) were common cyanotic and cyanotic defects observed. Compared to non-CHD children, children with CHD had a higher percentage of history of abortion, CHD history of family, consanguinity and premature birth (all P<0.05). In CHD children, 24% of mothers caught a cold, 10% had a febrile illness and 6.7% received antibiotic treatment during the first trimester of pregnancy, that were higher than non-CHD group (all P<0.05).

Conclusion

The overall prevalence of CHD in four ethnic children at ages 0–18 yr in Xinjiang was 16.5‰. VSD, ASD and TOF were the most common acyanotic and cyanotic congenital heart defects, respectively. This study also identified some modifiable risk factors that may contribute to the incidence of CHD among the 4 ethnic groups.     

Characterization of SMAD3 Gene Variants for Possible Roles in Ventricular Septal Defects and Other Congenital Heart Diseases

Background

Nodal/TGF signaling pathway has an important effect at early stages of differentiation of human embryonic stem cells in directing them to develop into different embryonic lineages. SMAD3 is a key intracellular messenger regulating factor in the Nodal/TGF signaling pathway, playing important roles in embryonic and, particularly, cardiovascular system development. The aim of this work was to find evidence on whether SMAD3 variations might be associated with ventricular septal defects (VSD) or other congenital heart diseases (CHD).

Methods

We sequenced the SMAD3 gene for 372 Chinese Han CHD patients including 176 VSD patients and evaluated SNP rs2289263, which is located before the 5’UTR sequence of the gene. The statistical analyses were conducted using Chi-Square Tests as implemented in SPSS (version 13.0). The Hardy-Weinberg equilibrium test of the population was carried out using the online software OEGE.

Results

Three heterozygous variants in SMAD3 gene, rs2289263, rs35874463 and rs17228212, were identified. Statistical analyses showed that the rs2289263 variant located before the 5’UTR sequence of SMAD3 gene was associated with the risk of VSD (P value=0.013 <0.05).

Conclusions

The SNP rs2289263 in the SMAD3 gene is associated with VSD in Chinese Han populations.     

Frequency distribution of single nucleotide polymorphisms in P-selectin gene in Chinese Tibetan and Han populations

Background

Chinese Tibetans have a series of distinctive physiological traits which enable them to tolerate the extreme environment of the Tibetan plateau. P-selectin gene has been proved to be highly polymorphic in Europeans and Americans. Nevertheless, studies on either the frequency distributions of single nucleotide polymorphisms (SNPs) or haplotype diversity and linkage disequilibrium of P-selectin gene in Chinese Tibetan population are still unavailable.

Methods

The frequency distributions of 3 SNPs in P-selectin gene promoter (− 2123C/G, − 1969A/G, − 1817T/C) and 3 SNPs in exon region (Ser290Asn, Val599Leu, Thr715Pro) were investigated by real-time PCR and high-resolution melting method among 314 Chinese Tibetans and 328 age- and sex-matched Han people.

Results

The frequencies of the − 2123G and − 1817T alleles among the Tibetan population had no significant differences from those of the Han population. Among the Tibetan population, the G allele frequency of − 1969A/G and Ser290Asn were both higher than those of the Han population. Val599Leu and Thr715Pro did not show any polymorphism in the two populations. In the Tibetan population, − 2123C/G, − 1969A/G, − 1817T/C and Ser290Asn were in tight linkage disequilibrium with each other.

Conclusions

The frequency distributions of − 1969A/G and Ser290Asn polymorphisms in the Tibetan population were different from those in the Han population.