Genome-wide association study of serum tumor markers in Southern Chinese Han population.

BACKGROUND: Serum indicators AFP, CA50, CA125, CA153, CA19-9, CEA, f-PSA, SCC-Ag have been confirmed as tumor markers (TMs). We conducted a genome-wide association study on 8 tumor markers of our 427 Han population in southern China, in order to identify genetic loci that are significantly associated with the level of 8 tumor markers. METHODS: We use Gene Titan multi-channel instrument and Axiom Analysis Suite 6.0 software for genotyping. We used IMPUTE2 software for imputation, and 1000 Genomes Project (Phase 3) was used as haplotype reference. After necessary quality control and statistical analysis, genetic loci genome-wide associated with TMs (p < 5E-8) will be identified. Finally, we selected Top SNPs (p < 5E-7) from the GWAS results for replication test. We used SPSS software to draw the distribution box plots of serum TMs under different genotypes of significant loci. RESULTS: The results showed that there were only MUC1 (mucin 1)-rs4072037 significantly genome-wide associated with CA153 (p = 1.28E-18). However, we found that a total of 30 genetic loci have a suggestively significant genome-wide association with the level of 8 serum tumor markers (p < 5E-6). Then 3 Top SNPs (p < 5E-7) were selected for replication verification. The results showed that MUC1-rs4072037 was still significantly associated with CA153 in another population (p = 3.73E-08). Comparing with the TT genotype of rs4072037, the CA153 level was higher under CC or CT genotype of rs4072037. CONCLUSION: MUC1-rs4072037 is significantly genome-wide associated with CA153 level. There are 30 genetic loci suggestively genome-wide associated with level of tumor markers among the Han population from Southern China.

Characterization of a novel allelic variant in HLA-B*40 lineage, HLA-B*40:298:02, by cloning and sequencing.

A novel allelic variant in HLA-B*40 lineage, HLA-B*40:298:02, has been identified in an individual of Han ethnicity afflicted with nasopharyngeal carcinoma in Hunan province, southern China. Following polymerase chain reaction-Sanger sequence-based typing (PCR-SBT), this new variant was further confirmed by two distinct strategies of cloning and sequencing. HLA-B*40:298:02 differs from HLA-B*40:298:01 by a single synonymous cytosine substitution at nucleotide position 26 (T→C) in exon 3, which corresponds to codon 99 of the mature HLA-B mRNA molecule. This new allele has an estimated frequency of 0.0002, in about 2,500 sequence-based typed subjects from the same population.

Evaluation of genetic parameters of 23 autosomal STR loci in a Southern Chinese Han population.

AIM: To evaluate the 23 autosomal short tandem repeat (STR) loci included in GoldenEye™ 25 A kit using forensic human identification and paternity testing. SUBJECTS AND METHODS: In total, 3751 unrelated individuals from the Southern Chinese Han population were genotyped with the 5-dye GoldenEye™ 25 A multiplex amplification system. PCR products were separated using arrayed capillary electrophoresis. Allele frequencies and forensic parameters for the 23 autosomal STR loci were statistically analysed. RESULTS: A total of 344 alleles were observed, with corresponding allelic frequencies ranging from 0.0001-0.5519 for the 23 STR loci. No significant deviation from the Hardy-Weinberg equilibrium and linkage disequilibrium was observed. The combined power of discrimination (CPD) was 1-1.6290 × 10-28 and the combined power of exclusion (CPE) was 0.999 999 999 89 and 0.999 999 286 93 for trio and duo cases, respectively. From 3865 meioses, 87 mutation events were discovered. The mutation rate varied from 0-0.00285 for each locus. One-step mutation accounted for 94.25% of total mutations. The ratio of paternal vs maternal mutation was 3.76:1.13 kinds of n/(n + 1) heterozygote genotypes were observed. CONCLUSIONS: The results show that 23 STR loci of GoldenEye™ 25 A kit are highly polymorphic in the Southern Chinese Han population, indicating the kit is suitable for forensic application.

Characterization of a novel HLA-B*39:01:01-related allele, HLA-B*39:130, by cloning and phasing.

A novel HLA-B*39:01:01-related variant, HLA-B*39:130, has been identified in a normal individual of Han ethnicity in Hunan province, southern China. Following Sanger polymerase chain reaction-sequence-based typing (PCR-SBT), this new allele was further confirmed by cloning, phasing and sequencing. Aligned with HLA-B*39:01:01, HLA-B*39:130 has a nonsynonymous thymine substitution at nucleotide position 94 in exon 4, resulting in amino acid change from threonine to isoleucine at codon 214 (ACA→ATA) of the mature HLA-BmRNA molecule.

Matrix metalloproteinase-1 promoter -1607 bp 1G/2G polymorphism associated with increased risk of spinal tuberculosis in Southern Chinese Han population.

BACKGROUND: Spinal tuberculosis is the most common form of musculoskeletal tuberculosis. The expression of matrix metalloproteinase-1 (MMP-1) is increased in cells with Mycobacterium tuberculosis infection. MMP-1 plays a curial role in extracellular matrix degradation during the progression of tuberculosis. Although the 1G/2G polymorphism in MMP-1-1607 influences its transcription, its role in spinal tuberculosis remains unknown. METHODS: Healthy controls and patients with spinal tuberculosis of Han ethnicity were recruited between January 2010 and May 2016. The MMP-1-1607 1G/2G polymorphism was genotyped using the Sequenom mass Array polymorphism analysis system. RESULTS: The genotypes of 1G/1G, 1G/2G, and 2G/2G were found in 13.7%, 53.6%, and 32.8% of patients, and 12.2%, 37.4%, and 50.4% of controls, respectively. The 1G/2G genotype were more common in cases than in controls (P=2.05E-04). The 1G allele showed an association with an increased risk for spinal tuberculosis when compared to 2G allele (P=.004). 1G genotypes, having at least one 1G allele, were associated with the risk of developing spinal tuberculosis (1G/1G+1G/2G vs 2G/2G: OR=2.084, 95%CI=1.401-3.100, P=2.65E-04). CONCLUSION: 1G genotypes of the MMP-1-1607 may be associated with susceptibility to spinal tuberculosis in Southern Chinese Han population.

Missense Variant rs28362680 in BTNL2 Reduces Risk of Coronary Heart Disease.

Background: The pathological basis of coronary heart disease (CHD) is atherosclerosis. BTNL2 can inhibit the activation of T cells. We aimed to explore the association between BTNL2 genetic variants and CHD risk in the southern Chinese Han population. Methods: We recruited 1419 participants to perform an association analysis between missense variants in BTNL2 and CHD risk through SNPStats online software. Genotyping of all candidate SNPs were completed by the Agena MassARRAY. In addition, we used false-positive report probability analysis to detect whether the positive findings were noteworthy observations. We also used Haploview 4.2 software and SNPStats online software to conduct the haplotype analysis and analysis of linkage disequilibrium (LD). Finally, the interaction of SNP-SNP in CHD risk was evaluated by multi-factor dimensionality reduction (MDR). Results: The results showed that BTNL2-rs35624343, -rs117896888, -rs41441651, -rs41417449, -rs28362680 and -rs2076523 were significantly associated with the CHD susceptibility. Especially for BTNL2-rs28362680, the allele A (OR = 0.68, p < 0.0001), genotype AA (OR = 0.40, p = 0.001) or GA (OR = 0.68, p < 0.0001) were associated with the reducing CHD risk. And -rs28362680 significantly reduced the CHD risk under all genetic models (dominant: OR = 0.64, p < 0.0001; recessive: OR = 0.47, p = 0.003; overdominant: OR = 0.73, p = 0.004; log-additive: OR = 0.66, p < 0.0001). And -rs28362680 was also closely associated with CHD risk reduction in all stratified analyses (age, gender, smoking, drinking, hypertension and diabetes). In addition, haplotype analysis showed that the "Crs117896888Crs41441651Trs41417449Ars28362680" (OR = 0.65, p < 0.0001) and "Grs117896888Trs41441651Crs41417449Ars28362680" (OR = 0.68, p = 0.013) may reduce CHD risk. Conclusion: Missense variants (rs35624343, rs117896888, rs41441651, rs41417449, rs28362680, rs2076523) may be protective factors for the CHD risk. In particular, there were sufficient evidences that BTNL2-rs28362680 can protective CHD risk.

Association between polymorphisms in ABO gene and stroke patients with small artery occlusion in southern Chinese Han population.

OBJECTIVE: The purpose of this study was to investigate associations between two single nucleotide polymorphisms (SNPs) rs505922 and rs532436 in ABO gene and the risk of small artery occlusion stroke (SAO) in southern Chinese Han population. METHODS: Our case-control study comprising 121 patients with SAO and 136 controls. All participants were Han population of southern China. IS sub-type was defined on the basis of the TOAST criteria. SAO was strictly diagnosed after a systematic physical examination and neuroimaging via MRI. Genotype analysis was conducted by the snapshot technique. RESULTS: The distribution of rs532436 genotype between these two groups showed a statistically significant difference (P = 0.048) while that of rs505922 genotype showed no significant difference (P = 0.572). SNP rs532436 was significantly associated with SAO in overdominant model (GA vs. GG + AA) after adjusting for age, hypertension history, diabetes history and cigarette smoking (adjusted OR = 2.03, 95% CI: 1.14-3.62, P = 0.016). However, under all genetic models, the rs505922 polymorphism failed to show association with SAO. CONCLUSION: The resultsindicate that rs532436 polymorphism in ABO gene may have association with SAO in southern Chinese Han population.

Genetic Variability of TCF4 in Schizophrenia of Southern Chinese Han Population: A Case-Control Study.

Objective: Schizophrenia is thought to be a neurodevelopmental disorder. As a key regulator in the development of the central nervous system, transcription factor 4 (TCF4) has been shown to be involved in the pathogenesis of schizophrenia. The aim of our study was to assay the association of TCF4 single nucleotide polymorphisms (SNPs) with schizophrenia and the effect of these SNPs on phenotypic variability in schizophrenia in Southern Chinese Han Population. Methods: Four SNPs (rs9960767, rs2958182, rs4309482, and rs12966547) of TCF4 were genotyped in 1137 schizophrenic patients and 1035 controls in a Southern Chinese Han population using the improved multiplex ligation detection reaction (iMLDR) technique. For patients with schizophrenia, the severity of symptom phenotypes was analyzed by the five-factor model of the Positive and Negative Symptom Scale (PANSS). Cognitive function was assessed using the Brief Assessment of Cognition in Schizophrenia (BACS) scale. Results: The results showed that the genotypes and alleles of the three SNPs (rs2958182, rs4309482, and rs12966547) were not significantly different between the control group and the case group (all P > 0.05). rs9960767 could not be included in the statistics for the extremely low minor allele frequency. However, the genotypes of rs4309482 shown a potential risk in the positive symptoms (P = 0.04) and excitement symptoms (P = 0.04) of the five-factor model of PANSS, but not survived in multiple test correction. The same potential risk was shown in the rs12966547 in positive symptoms of the PANSS (P = 0.03). Conclusion: Our results failed to find the associations of SNPs (rs2958182, rs4309482, and rs12966547) in TCF4 with schizophrenia in Southern Chinese Han Population.

Associations of TF Gene Polymorphisms with the Risk of Ischemic Stroke.

Ischemic stroke (IS) is the main cause of mortality and disability in China; thus, this study aimed to examine the association between six variants and their haplotypes within the transferrin (TF) gene and the risk of IS in the Southern Chinese Han population. Genotyping was performed using the Sequenom MassARRAY platform for 249 IS patients and 249 age- and sex-matched controls. The association between polymorphisms and IS risk was tested by Chi squared test and haplotype and stratification analysis. Odds ratios (ORs) and confidence intervals (CIs) were estimated by unconditional logistic regression analysis. The results of genetic model analyses indicated that the two SNPs (rs1880669 and rs2692695) were associated with decreased IS risk under the co-dominant, dominant, and additive models. Additionally, rs4525863 was also associated with decreased IS risk both under the dominant and additive models in males. Moreover, the CG haplotype of TF (rs1880669 and rs2692695) was significantly associated with a decreased risk of IS in the total population and males. Our findings suggested that polymorphisms (rs4525863, rs1880669, and rs2692695) of the TF gene might be a protective factor for IS in Southern Chinese Han population. Further large prospective studies are required to confirm these findings.

Association of SNPs in the TIMP-2 gene and large artery atherosclerotic stroke in southern Chinese Han population.

Tissue inhibitor of matrix metalloproteinase 2 (TIMP-2) regulates the extracellular matrix degradation, which involved in vascular remodeling and dysfunction, destabilization of atherosclerotic plaque and many other pathological processes. The rupture of atherosclerotic plaque is the trigger of Large artery atherosclerotic (LAA) stroke. We speculate that the Single nucleotide polymorphisms (SNPs) in TIMP-2 may have an association with LAA stroke. To prove this hypothesis, we conducted this case-control study. 250 LAA stroke patients and 250 healthy controls were collected for the analysis of TIMP-2 polymorphisms. Among six SNPs, we detected no deviation from Hardy-Weinberg equilibrium in control group. There was a significant difference in rs4789936 T allele frequency between patient and control groups (OR = 0.68, 95% CI = 0.51-0.91, P = 0.009), which means lower risk of LAA stroke. We observed the rs4789936 had a decreased risk of LAA stroke according to the codominant (OR = 0.64, 95% CI = 0.44-0.92, P = 0.026), dominant (OR = 0.62, 95% CI = 0.43-0.88, P = 0.008), overdominant (OR = 0.68, 95% CI = 0.48-0.98, P = 0.039), log-additive (OR = 0.68, 95% CI = 0.51-0.91, P = 0.009) models analyses. However, these findings could only validate under dominant model (OR = 0.65, 95% CI = 0.42-1.00, P = 0.049) after adjustment of gender and age. The results indicate a potential association between TIMP-2 variants and LAA stroke risk in southern Chinese Han population.