Tag Single Nucleotide Polymorphisms Research Articles

Polymorphisms in CLDN1 are associated with age and differentiation of triple-negative breast cancer patients.

Purpose: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease. It is very important to explore novel biomarkers to better clarify the characteristics of TNBC. It has been reported that polymorphisms in claudin 1 (CLDN1) are associated with risk of several cancers. But till now, there is no report about these polymorphisms and TNBC. Patients and methods: Between January 2004 and December 2013, 267 patients with stage I–III primary TNBC were included in our study. We investigated the association between polymorphisms in CLDN1 gene and clinicopathological characteristics or survival of these patients. We used Haploview 4.2 software to identify Tag single nucleotide polymorphisms (SNPs). MassARRAY MALDI-TOF System was used for genotyping. Results: We found that rs10513846 GA genotype was associated with older age [P=0.013, hazard ratios (HR) = 2.231, 95% confidence interval (CI): 1.186–4.195]. Rs10513846 AA genotype carriers were more likely to develop grade 3 tumors (P=0.005, HR = 2.889, 95% CI: 1.389–6.007). And rs9283658 genotypes were also related to grade, more patients with grade 3 tumors were rs9283658 CC genotype carriers (P=0.023, HR = 0.446, 95% CI: 0.222–0.894). There was no association between polymorphisms in CLDN1 and survival of TNBC patients. After multivariate analysis, tumor size (P=0.021, HR = 3.146, 95% CI: 1.185–8.354) and lymph node status (P<0.001, HR = 10.930, 95% CI: 3.276–36.470) were demonstrated to be independent prognostic factors. Conclusion: We first demonstrated that polymorphisms in CLDN1 gene were associated with age and differentiation of TNBC patients.

Identification of susceptibility SNPs in CTLA-4 and PTPN22 for scleritis in Han Chinese.

The aim of this study was to determine the association between 13 single nucleotide polymorphisms (SNPs) in the cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and protein tyrosine phosphatase non-receptor type 22 (PTPN22) genes with scleritis in a Chinese Han population. We recruited 432 scleritis patients and 710 healthy controls. Four tag SNPs of CTLA4 and nine tag SNPs of PTPN22 were selected using Haploview. Genotyping was performed with the Sequenom MassArray® iPLEX GOLD Assay. Genotype and allele frequency differences were analyzed by χ2 test and Bonferroni correction. Haplotype analysis was performed to further evaluate the association of these two genes with scleritis. In this study, CTLA4/rs3087243 G allele frequency and GG genotype frequency were significantly increased in scleritis patients compared to healthy controls [corrected P-value (Pc)=0·02, odds ratio (OR)=1·475, 95% confidence interval (CI)=1·175-1·851; Pc=0·04, OR=1·546, 95% CI=1·190-2·008, respectively]. None of the tested SNPs in the PTPN22 gene showed an association with scleritis. Haplotype analysis revealed a lower frequency of a CTLA4 TCAA haplotype (order of SNPs: rs733618, rs5742909, rs231775, rs3087243) (Pc=4·26×10-3 , OR=0·618, 95% CI=0·540-0·858) and a higher frequency of a PTPN22 TTATACGCG haplotype (order of SNPs: rs3789604, rs150426536, rs1746853, rs1217403, rs1217406, rs3789609, rs1217414, rs3789612, rs2488457) (Pc=2·83×10-4 , OR=1·457, 95% CI=1·210-1·754) in scleritis patients when compared to healthy controls. In conclusion, our findings indicate that CTLA4 and PTPN22 might confer genetic susceptibility to scleritis in a Chinese Han population.

SUN-041 Estrogen Pharmacogenetics in Patients with Turner Syndrome

Background: Turner syndrome (TS) is a disorder characterized by complete or partial absence of the second sexual chromosome and the most commonly found abnormalities are short stature and gonadal failure. Most TS patients need estrogen replacement but individual outcomes on uterine volume, breast development and vertebral bone density are highly variable. To our knowledge, the impact of polymorphisms in estrogen receptor 1 (ESR1) over the variability in the development of secondary sexual characteristics and in adult height has not yet been evaluated in TS patients. Objective: To investigate the association among five ESR1 polymorphisms (rs543650, rs1038304, rs2046210, rs2234693 and rs9340799) and breast development, uterine volume, vertebral bone density, FSH and LH levels and adult height in TS patients. Methods: We selected 80 TS patients receiving adult estrogen dose for a minimum period of one year. Patients who had spontaneous complete pubertal development or who have Y chromosome material in karyotype were excluded from analysis. They were submitted to clinical and laboratory evaluation, pelvic ultrasound, bone densitometry and genotyping of the five chosen ESR1 polymorphisms through real time PCR. These polymorphisms were selected through active search in Pubmed and in GWAS catalogs, based on the following criteria: recurrence in studies, being Tag-single nucleotide polymorphisms (Tag-SNPs) or having a minor allele frequency (MAF) which allowed the present study with the available sample. Results: 61% of patients had 45,X karyotype and their mean target height was 158.9cm. 82% of them were treated with rhGH for 5 years on average and they reached a mean adult height of 149cm. Their average age of puberty onset was 14.4 years old and 10% of them had spontaneous thelarche. Their mean uterine volume was 30.1cc but ranged from 5.9 to 83cc. 91% attained adult breast development (Tanner 5) and 93% had normal vertebral bone mass after correction for height (by using the online calculator from University of Washington: courses.washington.edu/bonephys). Only 15% had FSH and/or LH lower than 10 IU/L in two or more measurements. Considering the ESR1 polymorphisms, all of them were in Hardy-Weinberg equilibrium. Statistical analysis with multiple linear regression showed that none of the studied polymorphisms was able to predict any of the above estrogen therapy outcomes in an isolated manner. Conclusion: We could not find a relationship among the studied ESR1 polymorphisms and estrogen therapy outcomes in patients with TS. However, the high variability in estrogen replacement results suggests that genetic variants play an important role. Other efforts to identify polymorphisms associated to estrogen outcomes may allow for individualization of treatment in TS.

Association between AXIN1 Gene Polymorphisms and Bladder Cancer in Chinese Han Population.

Background Previous evidence has indicated that the reduction of axis inhibition protein 1 (AXIN1) expression is related with the poor differentiation of non-small-cell lung cancer (NSCLC). However, the potential association between AXIN1 and bladder cancer (BC) is unknown. We aimed to initially explore the relevance of AXIN1 gene polymorphisms (rs12921862 C/A, rs1805105 T/C, and rs370681 C/T) and BC. Methods Three hundred and sixteen BC patients and 419 healthy controls had been enrolled. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used for genotyping three tag single-nucleotide polymorphisms (SNPs) of AXIN1. The SNPstats online analysis software and SPSS software were used for statistical analysis. Results Our data revealed that three tag SNPs were associated with an increased risk of BC (rs12921862: P < 0.001, OR (95%CI) = 4.61 (3.13-6.81); rs1805105: P = 0.046, OR (95%CI) = 1.35 (1.00-1.82); and rs370681: P = 0.004, OR (95%CI) = 1.56 (1.15-2.10)). For rs12921862, A allele was an independently protective factor which correlated with a better prognosis in non-muscle-invasive bladder cancer (NMIBC) patients (P = 0.03, OR (95%CI) = 0.10 (0.01-0.84)). Stratification analysis demonstrated that rs370681 polymorphism was related with high-grade bladder cancer (P = 0.04, OR (95%CI) = 1.85 (1.04-3.23)). Conclusion The AXIN1 gene polymorphisms might implicate in BC risk, and rs12921862 could be a potential forecasting factor for prognosis of BC patients.

Decision Theory-Based COI-SNP Tagging Approach for 126 Scombriformes Species Tagging.

The mitochondrial gene cytochrome c oxidase I (COI) is commonly used for DNA barcoding in animals. However, most of the COI barcode nucleotides are conserved and sequences longer than about 650 base pairs increase the computational burden for species identification. To solve this problem, we propose a decision theory-based COI SNP tagging (DCST) approach that focuses on the discrimination of species using single nucleotide polymorphisms (SNPs) as the variable nucleotides of the sequences of a group of species. Using the example of 126 teleost mackerel fish species (order: Scombriformes), we identified 281 SNPs by alignment and trimming of their COI sequences. After decision rule making, 49 SNPs in 126 fish species were determined using the scoring system of the DCST approach. These COI-SNP barcodes were finally transformed into one-dimensional barcode images. Our proposed DCST approach simplifies the computational complexity and identifies the most effective and fewest SNPs to resolve or discriminate species for species tagging.

Genetic Association Between NGFR, ADAM17 Gene Polymorphism, and Parkinson's Disease in the Chinese Han Population.

Parkinson's disease (PD) is a common neurodegenerative disease characterized by neuronal loss in the substantia nigra. The p75 neurotrophin receptor (p75NTR, encoded by NGFR) was found to play an important role in the selective neuronal death of dopamine neurons in the substantia nigra, as well as the pathogenesis and development of PD. To assess the association between NGFR gene polymorphism and the susceptibility of PD, this case-control study consisting of 414 PD patients and 623 age- and sex-matched controls in a Chinese Han cohort was conducted. Twelve tag-single nucleotide polymorphisms (tag-SNPs) were selected from the NGFR gene through the construction of linkage disequilibrium blocks. One tag-SNP from the ADAM17 gene was also selected owing to its function of encoding tumor necrosis factor α-converting enzyme, which is responsible for the shedding of the extracellular domain of p75NTR. A multiplex polymerase chain reaction-ligase detection reaction (PCR-LDR) method was applied for genotyping. The associations between tag-SNPs and the risk of PD with the adjustment for age and sex were analyzed by unconditional logistic regression, and five genetic models including codominant, dominant, recessive, over-dominant, and additive models were applied. The results showed that among the 13 tag-SNPs, rs741073 was associated with a reduced risk of PD in the codominant (OR = 0.71, 95% CI = 0.54-0.93, P = 0.037), dominant (OR = 0.76, 95% CI = 0.58-0.98, P = 0.033), and over-dominant models (OR = 0.71, 95% CI = 0.54-0.92, P = 0.010), and rs1804011 was also associated with a reduced risk of PD in the codominant (OR = 0.69, 95% CI = 0.50-0.95, P = 0.049), dominant (OR = 0.69, 95% CI = 0.50-0.93, P = 0.014), over-dominant (OR = 0.70, 95% CI = 0.51-0.96, P = 0.025), and additive models (OR = 0.72, 95% CI = 0.54-0.94, P = 0.016). However, these associations did not retain after Bonferroni correction. Conclusively, our study failed to reveal the association between the selected tag-SNPs within NGFR, ADAM17, and the susceptibility of PD. The role of p75NTR and its gene polymorphisms in the pathogenesis of PD needs to be further studied.

Association of polymorphisms in MALAT1 with the risk of esophageal squamous cell carcinoma in a Chinese population.

ObjectiveThe main aim of this study was to investigate the association of polymorphisms in long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) with the risk of esophageal squamous cell carcinoma (ESCC) in a Chinese population.MethodsA total of 245 ESCC patients and 490 gender- and age-matched cancer-free controls were genotyped for four tag single nucleotide polymorphisms (SNPs) of MALAT1 (rs3200401 C > T, rs1122709 C > G, rs664589 C > G, and rs619586 A > G). Statistical analyses including chi-squared test and logistic regression were performed to identify the association between the tag SNPs and risk of ESCC, and false discovery rate (FDR) <25% was applied to adjust for multiple comparisons.ResultsWe found that rs3200401 C > T polymorphism of MALAT1 was significantly associated with increased risk of ESCC (CT vs CC: adjusted OR =1.59, 95% CI =1.07–2.35, P=0.021; TT vs CC: adjusted OR =2.27, 95% CI =1.04–4.96, P=0.039; dominant model [CT+TT vs CC]: adjusted OR =1.68, 95% CI =1.16–2.43, P=0.006). In the stratified analysis, rs3200401 TT and CT/TT genotypes were associated with increased risk of ESCC compared with CC genotype in subgroup of never drinking (TT vs CC: adjusted OR =2.34, 95% CI =1.02–5.34, P=0.044; CT/TT vs CC: adjusted OR =1.52, 95% CI =1.02–2.26, P=0.041). However, compared with AA genotype, MALAT1 rs619586 GG was associated with decreased risk of ESCC in ever drinking subgroup (GG vs AA: adjusted OR =0.38, 95% CI =0.15–0.99, P=0.049). The results remained significant after FDR adjustment (FDR value <0.25) except for the comparison between rs619586 GG and AA genotype in ever drinking subgroup.ConclusionTaken together, our findings proposed that polymorphism rs3200401 C > T in MALAT1 gene is associated with increased risk of ESCC. Since the association between rs619586 A > G polymorphism and ESCC risk was not significant after FDR adjustment, there was a minor possibility that rs619586 A > G might be a protective factor for ESCC.

Association of epidermal growth factor receptor (EGFR) gene polymorphisms with endometriosis.

Aims:To investigate the association between polymorphism in the gene encoding the epidermal growth factor receptor (EGFR) and susceptibility to endometriosis among women in southwest China.Methods:A case-control study involving 201 endometriosis patients and 237 control women without endometriosis was carried out at West China Second Hospital of Sichuan University from June 2016 to December 2017. Two tag single-nucleotide polymorphisms (SNPs) of EGFR gene, rs11977660 and rs2072454 were selected, and the distribution of genotypes and alleles was compared between the 2 groups using the chi-squared test with 2-sided contingency tables.Results:Genotype at rs11977660 was significantly associated with endometriosis (P < .05 for genotype and allele). T/T+C/T genotypes were associated with significantly higher risk of developing endometriosis than the C/C genotype (OR 2.129, 95%CI 1.411–3.212). No significant association was found between genotype at rs2072454 and endometriosis.Conclusion:Genotypes with a T nucleotide at rs11977660 may significantly increase risk of endometriosis in Chinese.

Genetic polymorphisms of histone methyltransferase SETD2 predicts prognosis and chemotherapy response in Chinese acute myeloid leukemia patients

BackgroundSETD2, the single mediator of trimethylation of histone 3 at position lysine 36, has been reported associated with initiation progression and chemotherapy resistance in acute myeloid leukemia (AML). Whether polymorphisms of SETD2 affect prognosis and chemotherapy response of AML remains elusive.MethodsThree tag single-nucleotide polymorphisms (tagSNPs) of SETD2 were genotyped in 579 AML patients by using Sequenom Massarray system. Association of the SNPs with complete remission (CR) rate after Ara-C based induction therapy, overall survival (OS) and relapse-free survival (RFS) were analyzed.ResultSurvival analysis indicated that SETD2 rs76208147 TT genotype was significantly associated with poor prognosis of AML (TT vs. CC + CT hazard ratio: HR = 1.838, 95% confidence interval (CI) 1.005–3.360, p = 0.048). After adjusting for the known prognostic factors including risk stratification, age, allo-SCT, WBC count and LDH count, rs76208147 TT genotype was still associated with OS in the multivariate analysis (TT vs. CC + CT HR = 1.923, 95% CI 1.007–3.675, p = 0.048). In addition, after adjusting by other clinical features, patients with rs4082155 allele G carries showed higher rate of complete remission which indicated by CR rate (AG + GG vs. AA odd ratio (OR) = 0.544, 95% CI 0.338–0.876, p = 0.012).ConclusionsSETD2 genetic polymorphism is associated with AML prognosis and chemotherapy outcome, suggesting the possibility for development in AML diagnostics and therapeutics towards SETD2.

Association of genetic variants at 22q11.2 chromosomal region with cognitive performance in Japanese patients with schizophrenia

22q11.2 heterozygous multigene deletions confer an increased risk of schizophrenia with marked impairment of cognition. We explored whether genes on 22q11.2 are associated with cognitive performance in patients with idiopathic schizophrenia. A total of 240 schizophrenia patients and 240 healthy controls underwent the Japanese-language version of the Brief Assessment of Cognition in Schizophrenia (BACS) and were genotyped for 115 tag single-nucleotide polymorphisms (tag SNPs) at the 22q11.2 region using the golden gate assay (Illumina®). Associations between z-scores of the BACS cognitive domains and SNPs and haplotypes were analyzed using linear regression in PLINK 1.07. An additional set of 149 patients with bipolar disorder were included for cognitive assessment and selected SNPs were genotyped using real-time PCR. Patients with schizophrenia and bipolar disorder showed qualitatively comparable profiles of cognitive impairment across BACS subdomains, as revealed by significant correlation between the two groups in the resulting cognitive effect sizes relative to controls. rs4819522 (TBX1) and rs2238769 (UFD1L) were significantly and nominally associated, respectively, with symbol coding in patients with schizophrenia. Haplotype analyses revealed that haplotypes containing the A allele at rs4819522 and G allele at rs2238769 showed significant negative associations with symbol coding in patients with schizophrenia. There was no effect of any haplotypes on cognition in patients with bipolar disorder. Our results have implications for the understanding of the role of haplotypes of UFD1L and TBX1 genes associated with symbol coding in patients with schizophrenia. Further replication studies in a cohort of newly diagnosed patients and other ethnicities are warranted.

Association of lncRNA polymorphisms with triglyceride and total cholesterol levels among myocardial infarction patients in Chinese population

AimThe long noncoding RNAs (lncRNAs) have gradually been reported to be an important class of RNAs with pivotal roles in the development and progression of myocardial infarction (MI). In this study, we hypothesized that genetic variant of cyclin-dependent kinase inhibitor 2B antisense RNA (ANRIL) and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) may affect the prognosis of MI patients. MethodsThe study included 401 Han Chinese MI patients and 409 controls. Four lncRNA tag single nucleotide polymorphisms (SNPs)—ANRIL rs9632884 and rs1537373, MALAT1 rs619586 and rs3200401—were selected. SNP genotyping was performed by an improved multiplex ligation detection reaction assay. Resultsrs9632884 and rs3200401 SNPs were significantly associated with lipid levels in both controls and MI patients (P < 0.003–0.046). Several SNPs interacted with sex and age to modify total cholesterol, low-density lipoprotein cholesterol, and creatinine levels to modify the risk of MI. No association between the lncRNAs SNPs and susceptibility to MI was found (P > 0.05 for all). ConclusionsTaken together, this study provides additional evidence that genetic variation of the ANRIL rs9632884 and MALAT1 rs3200401 can mediate lipid levels in MI patients.

Assessing the Role of 98 Established Loci for BMI in American Indians.

Objective:Meta-analyses of genome-wide association studies (GWAS) in Europeans have identified >98 loci for Body Mass Index (BMI). We analyze transferability of these established associations in Pima Indians.Methods:Among 98 lead SNPs, 82 had minor allele frequency≥0.01 in Pima Indians, and were analyzed for association with the maximum BMI in adulthood (n=3491) and BMI z-score in childhood (n=1958). Common tag SNPs across 98 loci were also analyzed for additional signals.Results:Among the lead SNPs, 13 (TMEM18, TCF7L2, MRPS33P4, PRKD1, ZFP64, FTO, TAL1, CALCR, GNPDA2, CREB1, LMX1B, ADCY9, NLRC3) associated with BMI (p≤0.05) in Pima adults. A multi-allelic genetic risk score (GRS), which summed the risk alleles for 82 lead SNPs, showed a significant trend for a positive relationship between GRS and BMI in adulthood (β=0.48% per risk allele, p=1.6×10−9) and BMI z-score in childhood (β=0.024SD, p=1.7×10−7). GRS significantly associated with BMI across all age groups ≥5 years, except for those ≥50 years. The strongest association was seen in adolescence (age 14–16 years, p=1.84×10−9).Conclusions:In aggregate, European-derived lead SNPs had a notable effect on BMI in Pima Indians. Polygenic obesity in this population manifests strongly in childhood and adolescence, and persists throughout much of adult life.

A PHLDB1 variant associated with the nonfunctional pituitary adenoma.

Previous studies have revealed that PHLDB1 single-nucleotide polymorphisms (SNPs) are associated with glioma risk. Nonetheless, the association between PHLDB1 SNPs and the risk of pituitary adenoma has not been studied. The present study evaluated the association of PHLDB1 SNPs with the risk of pituitary adenomas. We genotyped 27 PHLDB1 tagging and exon SNPs in a case-control study that included 148 patients who got a diagnosis of nonfunctional pituitary adenoma (NFPA) and 375 normal controls within the Korean population. Statistical analyses of the association between PHLDB1 SNPs and the NFPA risk were conducted using logistic regression. We detected an association between a PHLDB1 SNP and the risk of NFPA in the Korean population. Rs67307131 in intron 2 was significantly associated with NFPA (odds ratio [OR] = 2.15, 95% confidence interval [CI] 1.44-3.20; P = 0.0002 in the dominant model). In the referent analysis, a higher OR and stronger association (lower P value) were observed among patients with the "C/T" genotype (OR = 2.39, 95% CI 1.60-3.58; P = 0.00002). In a functional analysis with a SNP annotation tool, this SNP was predicted to be a CpG site and copy number variant; these properties are associated with susceptibility to diseases. Our findings suggest that genetic variation of PHLDB1 may be associated with the risk of NFPA. This is the first report of an association between PHLDB1 variants and NFPA. Further research is needed to confirm the impact of this SNP on NFPA susceptibility.

Identification of Key Long Non-Coding RNAs in the Pathology of Alzheimer's Disease and their Functions Based on Genome-Wide Associations Study, Microarray, and RNA-seq Data.

The pathogenesis of Alzheimer's disease (AD) is identified to be significantly regulated by long non-coding RNA (lncRNA) based on in vivo and clinical experiments. Single nucleotide polymorphisms (SNPs) can strongly impact expression and function of lncRNA in AD, and previous genome-wide associations studies (GWAS) have discovered substantial amount of risk SNPs associated with AD. However, current studies omit the important information about SNPs when identifying potential AD-related lncRNAs. In addition to single discovery approach and small-scale samples in these studies, the number of lncRNAs discovered as keys in AD is limited. Here, multiple computational methods were integrated to discover novel and key lncRNA of the pathology of AD. First, large-scale GWAS data involved in three ethnicities were collected from two authoritative sources, and meta-analyses were conducted to find SNPs significantly associated with AD (tag SNPs). Second, these tag SNPs together with their linkage disequilibrium information were used to discover potential lncRNAs related to AD. Third, after validation by microarray probe re-annotation of 1,282 samples and RNA-seq data analysis of 117 samples, respectively, a total of five key lncRNAs of AD were identified. Finally, possible function of these lncRNAs was predicted by genome mapping, expression quantitative trait loci, differential co-expression, and gene set enrichment analysis. Based on function prediction, four of the five key lncRNAs were identified to affect the risk of AD by regulating corresponding pathogenic genes and pathways, which are involved in regulation of amyloid-β peptide and the immune system. In summary, these findings can facilitate the discovery of potential disease-related lncRNAs and enhance understanding of the pathogenesis of AD.

Clinical relevance of single nucleotide polymorphisms in the CXCL1 and CXCL12 genes in patients with major trauma

Genetic backgrounds have been recognized as significant determinants of susceptibility to sepsis. CXC chemokines play a significant role in innate immunity against infectious diseases. Genetic polymorphisms of CXC chemokine genes have been widely studied in inflammatory and infectious diseases but not in sepsis. Thus, we aimed to investigate the clinical relevance of CXC chemokine gene polymorphisms and susceptibility to sepsis in a traumatically injured population. Thirteen tag single nucleotide polymorphisms were selected from CXC chemokine genes using a multimarker tagging algorithm in the Tagger software. Three independent cohorts of injured patients (n = 1700) were prospectively recruited. Selected single nucleotide polymorphisms were genotyped using an improved multiplex ligation detection reaction method. Cytokine production in lipopolysaccharide-stimulated whole blood was measured using an enzyme-linked immunosorbent assay. Among the 13 tag single nucleotide polymorphisms, four single nucleotide polymorphisms (rs1429638, rs266087, rs2297630, and rs2839693) were significantly associated with the susceptibility to sepsis, and three (rs3117604, rs1429638, and rs4074) were significantly associated with an increased multiple organ dysfunction score in the derivation cohort. However, only the clinical relevance of rs1429638 and rs266087 was confirmed in the validation cohorts. In addition, rs2297630 was significantly associated with interleukin 6 production. The rs1429638 polymorphism in the CXCL1 gene and the rs2297630 polymorphism in the CXCL12 gene were associated with altered susceptibility to sepsis and might be used as important genetic markers to assess the risks of sepsis in trauma patients. Prognostic and epidemiologic study, level II.

The A/A Genotype of XPO1 rs4430924 Is Associated With Higher Risk of Antituberculosis Drug-Induced Hepatotoxicity in Chinese Patients.

Antituberculosis (anti-TB) drug-induced hepatotoxicity may be related to the excessive reactive oxygen species induced by hepatotoxic metabolites. Antioxidant activity involves the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. The BTB domain and CNC homologue 1 (Bach1) may compete with Nrf2 for binding to transcriptional enhancers. Elimination of Bach1-mediated transcriptional repression depends on nuclear exporter exportin 1 (Xpo1). Thus, Xpo1 may indirectly affect antioxidant activity. The present study aimed to examine the role of tag single-nucleotide polymorphisms in XPO1 in Chinese anti-TB treatment patients. A 1:2 matched case-control study was conducted using 314 anti-TB drug-induced hepatotoxicity cases and 628 controls. After correcting for weight and hepatoprotectant use, conditional logistic regression analysis showed that patients carrying the AA genotype of rs4430924 in XPO1 were at higher risk of anti-TB drug-induced hepatotoxicity than those carrying the GG genotype based on the subgroup of probable cases (adjusted OR, 1.938; 95%CI, 1.035-3.628; P = .039), and marginally significant differences were also found under the recessive model (P = .048) and the additive model (P = .047). Based on this 1:2 matched case-control study, the AA genotype of rs4430924 in XPO1 may be associated with higher risk of anti-TB drug-induced hepatotoxicity in Chinese anti-TB treatment patients. Further studies in larger and more varied populations are required to validate this relationship.

Association Between AXIN1 Gene Polymorphisms and Dilated Cardiomyopathy in a Chinese Han Population.

Dilated cardiomyopathy (DCM) is a common type of cardiomyopathy. The pathogenesis of DCM remains unclear and involves varied genes. AXIN1 is a crucial gene in regulating various functions in cells, it encodes protein Axin1, which regulates the assembly and disassembly of β-catenin destruction complex. In addition, Wnt/β-catenin signaling pathway plays an important role in cardiogenesis. We aimed to detect whether AXIN1 polymorphisms contribute to the susceptibility and prognosis of DCM in a Chinese Han population. A total of 340 DCM patients and 430 controls were enrolled, and patients who had complete contact information were followed up for a median period of 49 months. Polymerase chain reaction-restriction fragment length polymorphism was carried out to genotype the two AXIN1 tag single nucleotide polymorphisms (SNPs) (rs12921862 and rs1805105). All data were analyzed using the statistical software package, SPSS 21.0. The frequencies of allele A in rs12921862 and allele C in rs1805015 were increased in DCM patients compared with healthy controls (p < 0.001). Genotypic frequencies of rs12921862 and rs1805105 were associated with the susceptibility of DCM in codominant, dominant, and overdominant models (p < 0.01). AA/AC and AC genotypes of rs12921862 in the dominant and the overdominant genetic models also presented a correlation with poor prognosis of DCM in both univariate (p < 0.01) and multivariate analyses (p < 0.01) after adjusting for age, gender, left ventricular (LV) end-diastolic diameter, and LV ejection fraction. Our results suggest that AXIN1 polymorphisms are associated with the susceptibility and prognosis of DCM in a Chinese Han population.

PLCE1 Polymorphisms and Risk of Esophageal and Gastric Cancer in a Northwestern Chinese Population.

The reported risk susceptibility between phospholipase C epsilon 1 (PLCE1) polymorphisms and esophageal cancer (EC) and gastric cancer (GC) remained inconsistent and controversial, especially on variants other than rs2274223. The relationship between PLCE1 polymorphisms and gene expression is also unclear. Here we conducted a case-control study from northwest China, genotyped seven tag single nucleotide polymorphisms (SNPs) in PLCE1 with multiplexed SNP MassARRAY assay. Stratified analysis was carried out and PLCE1 expression was evaluated in specified groups with the method of qRT-PCR and immunohistochemistry. Results showed that the minor alleles of rs3765524, rs2274223, and rs10509670 were associated with increased risk of EC and GC. Linkage disequilibrium analysis revealed protective haplotypes of CCAAGTC and CCAA. By stratification, a more significant association was found in subgroups of male, age ≥ 54, tumor stages of I-II and tumor size ≤ 5 cm, EC and cardia cancer (CC) of stomach, and moderate to well differentiated squamous carcinoma. In addition, a significant association for rs3765524 with noncardia cancer (NCC) and adenocarcinoma which is predominant in China was also observed. Further expression analysis identified that PLCE1 was downregulated in NCC tissues comparing to their adjacent noncancerous tissues, and its protein expression was higher in genotype rs3765524 CT/TT than in rs3765524 CC. In summary, our study suggests that PLCE1 polymorphisms may affect its gene expression and are associated with not only EC and CC, but also, to some extent, NCC risk in this study population.

Association Study of Myosin Heavy Chain 15 Polymorphisms with Asthma Susceptibility in Chinese Han.

Background The Myosin Heavy Chain 15 gene (MYH15) is expressed in the airway epithelium and variants in the gene have been associated with airway responsiveness. The aim of this study was to perform the first investigation of MYH15 polymorphisms in relation to asthma susceptibility. Methods A total of 410 asthma patients and 418 controls from the Chinese Han population were enrolled in the study. Tag-single nucleotide polymorphisms were genotyped and associations between the polymorphisms and asthma risk were analyzed by logistic regression analysis adjusting for confounding factors. Dual-luciferase reporter gene analysis was performed to detect allele-dependent promoter activity of MYH15 variants in HEK293 cells. Results The A allele of rs9288876 decreased risk of asthma (allelic model: OR=0.808, 95% CI: 0.658-0.993, additive model: OR=0.747, 95% CI: 0.588-0.947, dominant model: OR=0.693, 95% CI: 0.502-0.955). The G alleles of both rs7635009 and rs1454197 were associated with decreased risk of asthma under the additive model (OR=0.779, 95% CI: 0.618-0.981 and OR=0.756, 95% CI: 0.600-0.953, respectively). rs9288876 allele A was associated with higher luciferase activity than allele T (P<0.001). The luciferase activity of rs7635009 allele A was lower than allele G (P=0.001), while rs1454197 allele T had lower luciferase activity than allele G (P<0.001). Conclusion This is the first study to report the association of MYH15 gene polymorphisms with asthma. Polymorphisms of rs9288876, rs7635009, and rs1454197 altered transcriptional regulation of MYH15 and may be functional variants conferring susceptibility to asthma. Further study with larger sample size in different ethnic populations is needed.

The Association between Plasma Omega-6/Omega-3 Ratio and Anthropometric Traits Differs by Racial/Ethnic Groups and NFKB1 Genotypes in Healthy Young Adults.

Evidence for a relationship between omega-6/omega-3 (n-6/n-3) polyunsaturated fatty acid (PUFA) ratio and obesity in humans is inconsistent, perhaps due to differences in dietary intake or metabolism of PUFAs between different subsets of the population. Since chronic inflammation is central to obesity and inflammatory pathways are regulated by PUFAs, the objective of this study was to examine whether variants in the NFKB1 gene, an upstream regulator of the inflammatory response, modify the association between the n-6/n-3 ratio (from diet and plasma) and anthropometric traits in a multiethnic/multiracial population of young adults. Participants’ (n = 898) dietary PUFA intake was assessed using a food frequency questionnaire and plasma PUFA concentrations by gas chromatography. Nine tag single nucleotide polymorphisms (SNP) in NFKB1 were genotyped. Significant interactions were found between racial/ethnic groups and plasma n-6/n-3 ratio for body mass index (BMI) (p = 0.02) and waist circumference (WC) (p = 0.007). Significant interactions were also observed between racial/ethnic groups and three NFKB1 genotypes (rs11722146, rs1609798, and rs230511) for BMI and WC (all p ≤ 0.04). Significant interactions were found between two NFKB1 genotypes and plasma n-6/n-3 ratio for BMI and WC (rs4648090 p = 0.02 and 0.03; rs4648022 p = 0.06 and 0.04, respectively). Our findings suggest that anthropometric traits may be influenced by a unique combination of n-6/n-3 ratio, racial/ethnic background, and NFKB1 genotypes.