Single nucleotide polymorphism of CD40 in the 5′-untranslated region is associated with ischemic stroke

Objectives

Ischemic stroke is influenced by both environmental and genetic factors. The CD40/CD40L system is related to proinflammatory and prothrombogenic responses, which are involved in the pathophysiology of ischemic stroke. The aim of this study was to evaluate association between the CD40 -1C/T single nucleotide polymorphism (SNP) and ischemic stroke in a Chinese population.

Methods

We conducted a case–control study including 286 ischemic stroke patients and 336 controls. CD40 -1C/T SNP was genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing methods, and evaluated its relevance to ischemic stroke susceptibility.

Results

Significantly increased ischemic stroke risk was found to be associated with the T allele of CD40 -1C/T (OR = 1.273, 95% CI = 1.016–1.594). The frequencies of CT and TT/CT genotypes of CD40 -1C/T in ischemic stroke patients were significantly higher than those of controls, respectively (for CT: OR = 2.350, 95% CI = 1.601–3.449; for TT/CT: OR = 2.148, 95% CI = 1.479–3.119). And, similar results were obtained after adjusting non-matched variables. We found that the frequency of carried T genotypes (TT and TT/CT) was significantly increased in patients with history of stroke compared with patients without (for TT: OR = 6.538, 95%CI = 1.655–25.833; for TT/CT: OR = 3.469, 95%CI = 1.031–11.670), respectively.

Conclusions

The findings suggested that the CD40 -1C/T polymorphism might contribute to the susceptibility to ischemic stroke in the Chinese population, and might be associated with history of previous stroke.     

Major vault protein (MVP) gene polymorphisms and drug resistance in mesial temporal lobe epilepsy with hippocampal sclerosis

The human major vault protein (MVP) has been implicated in the development of drug resistance in cancer cells. Over expression of MVP has also been reported in brain tissue samples from antiepileptic drug (AED)-resistant human focal epilepsies. To investigate the relationship between single nucleotide polymorphisms (SNPs) involving the MVP gene and AED-resistance, we compared the distribution of three SNPs in the MVP gene, rs4788187, rs3815824 and rs3815823, among 220 patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) (prototype of AED-resistant epilepsy syndrome), 201 patients with juvenile myoclonic epilepsy (JME) (prototype of AED-responsive epilepsy syndrome) and 213 ethnically matched non-epilepsy controls. All the patients and controls were residents of the South Indian state of Kerala for more than three generations. We did not find any significant difference in allele and genotypic frequencies of the studied SNPs between AED-resistant and AED-responsive cohorts, and between AED-resistant and AED-responsive cohorts independently and pooled together when compared with the controls. We conclude that rs4788187, rs3815824, rs3815823 variants of the MVP gene are associated neither with predisposition for epilepsy nor with AED-resistance in the population that we have studied. Our results suggest the need for further research into the link between MVP and AED-resistance.     

Diagnostic utility of HFE variants in Spanish patients: Association with HLA alleles and role in susceptibility to acute lymphoblastic leukemia

Two single nucleotide polymorphisms (SNPs) in the Human Hemochromatosis (HFE) gene, C282Y and H63D, are the major variants associated to altered iron status and it is well known that these mutations are in linkage disequilibrium with certain Human Leukocyte Antigen (HLA)-A alleles. In addition, the C282Y SNP has been previously suggested to confer susceptibility to acute lymphoblastic leukemia (ALL). We have aimed to assess the diagnosis utility of these polymorphisms in a population of Spanish subjects with suspicion of hereditary iron overload and to evaluate the effect of their associations with HLA-A alleles on the susceptibility to ALL. Both the 63DD [OR = 4.31 (1.7–11.2)] and 282YY (p for trend = 0.02) genotypes were more frequently found among subjects with suspicion of iron overload than among controls. 282YY carriers displayed significantly higher transferrin saturation index (TSI) values (p < 0.001) as well as serum iron (p = 0.01) and ferritin (p = 0.01) levels. In addition, transferrin levels were lower in these subjects (p = 0.01). Likewise, patients who were carriers of the compound heterozygous diplotype (282CY/63HD) showed significantly higher TSI and serum iron and ferritin concentrations. The H63D SNP did not significantly affect the analytical parameters measured. All 282YY carriers and 69.2% of compound heterozygotes showed an altered biochemical index. The frequencies of the HFE SNPs in ALL pediatric patients were lower than those found in controls, whereas the HLA-A*24 allele was significantly overrepresented in the patients group [OR = 3.76 (1.9–7.3)]. No HFE-HLA-A associations were found to modulate the ALL risk. These results suggest that it may be useful to test for both HFE H63D and C282Y polymorphisms in patients with iron overload, as opposed to just genotyping for the C282Y SNP, which is customary in some healthcare centers. These HFE variants and their associations with HLA-A alleles were not observed to be relevant for the susceptibility to ALL in our population.     

SNV and haplotype analysis reveals new CSRP1 variants associated with growth and carcass traits

The cysteine and glycine-rich protein 1 and 2 genes (CSRP1 and CSRP2) are an effective growth factor in promoting skeletal muscle growth in vitro and vivo. However, in cattle, the information on the CSRP1 and CSRP2 genes is very limited. The aim of this study was to examine the association of the CSRP1 and CSRP2 variants with growth and carcass traits in cattle breeds. Three single nucleotide variants (SNVs) were identified within the bovine CSRP1 gene, whereas CSRP2 gene has not detected any SNVs, using DNA pooled sequencing, PCR-RFLP, and forced PCR-RFLP methods. These SNVs include g. 801T>C (Intron 2), g. 46T>C (Exon 3) and g. 99C>G (Intron 3). Besides, we also investigated haplotype frequencies and linkage disequilibrium (LD) coefficients for three SNVs in all study populations. LD and haplotype structure of CSRP1 were different between breeds. The result of haplotype analysis demonstrated eight haplotype present in QC (Qinchuan) and one haplotype in CH (Chinese Holstein). Only haplotype 1 (TTC), shared by all two populations, comprised 10.74% and 100.00%, of all haplotypes observed in QC and CH, respectively. Haplotype 5 (CTC) had the highest haplotype frequencies in QC (30.98%) and haplotype 1 had the highest haplotype frequencies in CH (100.00%). The statistical analyses indicated that one single SNV and 19 combined haplotypes were significantly or highly significantly associated with growth and carcass traits in the QC cattle population (P < 0.05 or P < 0.01). Quantitative real-time PCR (qRT-PCR) analyses showed that the bovine CSRP1 and CSRP2 genes were widely expressed in many tissues. The results of this study suggest that the CSRP1 gene possibly is a strong candidate gene that affects growth and carcass traits in the Chinese beef cattle breeding.     

Tagging SNPs in the ERCC4 gene are associated with gastric cancer risk

ERCC4 plays an essential role in the nucleotide excision repair (NER) pathway, which is involved in the removal of a wide variety of DNA lesions. To determine whether the ERCC4 tagging SNPs (tSNPs) are associated with risk of gastric cancer, we conducted a hospital-based case-control study of 350 cases and 468 cancer-free controls. In the logistic regression (LR) analysis, we found a significantly decreased risk of gastric cancer associated with the rs744154 GC/CC genotypes [adjusted odds ratio (OR) = 0.56, 95% confidence interval (CI) = 0.42–0.75, false discovery rate (FDR) P = 0.003] compared with the wild-type GG genotype. Haplotype-based association study revealed that the CGC haplotype that containing the rs744154 C allele can decrease the risk of gastric cancer compared with the most common haplotype GGT (adjusted OR = 0.61, 95% CI = 0.46–0.81). Using the multifactor dimensionality reduction (MDR) analysis, we identified that the SNP rs744154 and smoking status were the best two predictive factors for gastric cancer with a testing accuracy of 55.76% and a perfect cross-validation consistency (CVC) of 10 (P = 0.001). Furthermore, the smokers with the rs744154 GC/CC genotypes showed a decreased risk of gastric cancer (adjusted OR = 0.55, 95% CI = 0.35–0.85) compared with the smokers with the GG genotype using multivariate LR analysis. The above findings consistently suggested that genetic variants in the ERCC4 gene may play a protective role in the etiology of gastric cancer, even in the smokers.     

Association of the variant rs2243421 of human DOC-2/DAB2 interactive protein gene (hDAB2IP) with gastric cancer in the Chinese Han population

Human DOC-2/DAB2 interactive protein (hDAB2IP) gene is a novel member of the Ras GTPase-activating family and has been demonstrated to be a tumor-suppressor gene that inhibits cell survival and proliferation and induces cell apoptosis. It was reported that the expression level of hDAB2IP in gastric cancer tissue was highly correlated with tumor progression, however, whether hDAB2IP genetic variants are associated with the risk of gastric cancer remains yet unknown. In this case–control study, we conducted a genetic analysis for hDAB2IP variants in 311 patients with gastric cancer and 425 controls from the Chinese Han population. We found that the SNP rs2243421 of hDAB2IP gene with the minor allele C significantly revealed strong association with decreased gastric cancer susceptibility (P = 0.007, adjusted odds ratio [OR] = 0.734, 95%CI = 0.586–0.919). Haplotypes rs2243421 and rs10985332 (HaploType: CC, P = 0.012, aOR = 0.760) and haplotypes rs2243421 and rs555996 (HaploType: CG, P = 0.034, aOR = 0.788) represented the decreased risk of gastric cancer, respectively. On the contrary, rs2243421 and rs555996 showed an elevated susceptibility (HaploType: TG, P = 0.010, aOR = 1.320). Our results for the first time provided new insight into susceptibility factors of hDAB2IP gene variants in carcinogenesis of gastric cancer.     

A new method for post Genome-Wide Association Study (GWAS) analysis of colorectal cancer in Taiwan

Recently, single nucleotide polymorphisms (SNPs) located in specific loci or genes have been identified associated with susceptibility to colorectal cancer (CRC) in Genome-Wide Association Studies (GWAS). However, in different ethnicities and regions, the genetic variations and the environmental factors can widely vary. Therefore, here we propose a post-GWAS analysis method to investigate the CRC susceptibility SNPs in Taiwan by conducting a replication analysis and bioinformatics analysis. One hundred and forty-four significant SNPs from published GWAS results were collected by a literature survey, and two hundred and eighteen CRC samples and 385 normal samples were collected for post-GWAS analysis. Finally, twenty-six significant SNPs were identified and reported as associated with susceptibility to colorectal cancer, other cancers, obesity, and celiac disease in a previous GWAS study. Functional analysis results of 26 SNPs indicate that most biological processes identified are involved in regulating immune responses and apoptosis. In addition, an efficient prediction model was constructed by applying Jackknife feature selection and ANOVA testing. As compared to another risk prediction model of CRC for European Caucasians population, which performs 0.616 of AUC by using 54 SNPs, the proposed model shows good performance in predicting CRC risk within the Taiwanese population, i.e., 0.724 AUC by using 16 SNPs. We believe that the proposed risk prediction model is highly promising for predicting CRC risk within the Taiwanese population. In addition, the functional analysis results could be helpful to explore the potential associated regulatory mechanisms that may be involved in CRC development.     

Host genetic risk factors for community-acquired pneumonia

This study was conducted to establish the contribution of genetic host factors in the susceptibility to community acquired pneumonia (CAP) in the Russian population. Patients with CAP (n = 334), volunteers without a previous history of CAP, constantly exposed to infectious agents, control A group (n = 141) and a second control group B consisted of healthy persons (n = 314) were included in the study. All subjects were genotyped for 13 polymorphic variants in the genes of xenobiotics detoxification CYP1A1 (rs2606345, rs4646903, and rs1048943), GSTM1 (Ins/del), GSTT1 (Ins/del), ABCB1 rs1045642); immune and inflammation response IL-6 (rs1800795), TNF-a (rs1800629), MBL2 (rs7096206), CCR5 (rs333), NOS3 (rs1799983), angiotensin-converting enzyme ACE (rs4340), and occlusive vascular disease/hyperhomocysteinemia MTHFR (rs1801133). Seven polymorphic variants in genes CYP1A1, GSTM1, ABCB1, NOS3, IL6, CCR5 and ACE were associated with CAP. For two genes CYP1A1 and GSTM1 associations remained significant after correction for multiple comparisons. Multiple analysis by the number of all risk genotypes showed a highly significant association with CAP (P = 2.4 × 10^− 7, OR = 3.03, 95% CI 1.98–4.64) with the threshold for three risk genotypes. Using the ROC-analysis, the AUC value for multi-locus model was estimated as 68.38.     

PSCA gene variants (rs2294008 and rs2978974) confer increased susceptibility of gallbladder carcinoma in females

Background and aim

PSCA is a tissue specific tumor suppressor or oncogene which has been found to be associated with several human tumors including gallbladder cancer. It is considered to be involved in the cell-proliferation inhibition and/or cell-death induction activity. Therefore, we aimed to investigate the role of PSCA gene polymorphisms in gallbladder cancer risk in North Indian population.

Methodology

A total of 405 gallbladder cancer patients and 247 healthy controls were included in the case–control study for risk prediction. We examined the association of two functional SNPs, rs2294008 and rs2978974 in PSCA gene by genotyping using Taqman allelic discrimination assays. Statistical analysis was done using SPSS software, version 17. Linkage disequilibrium and haplotype analysis was done with the help of SNPstats software. FDR test was used to correct for multiple comparisons.

Results

No significant associations of rs2294008 and rs2978974 genetic variants of the PSCA gene were found with GBC risk at allele, genotype or haplotype levels. Stratifying the subjects on the basis of gallstone also did not show any significant result. However, on gender stratification, we found a significant association of T_rs2294008-G_rs2978974 haplotype with higher risk of GBC in females (FDR Pcorr = 0.021, OR = 1.6). In contrary, T_rs2294008-A _rs2978974 haplotype conferred significant lower risk in males (FDR Pcorr = 0.013; OR = 0.25).

Conclusions

These findings suggest that PSCA genetic variants may have a significant effect on GBC susceptibility in a gender specific manner.