The MDM2 309T>G Polymorphism and Ovarian Cancer Risk: A Meta-Analysis of 1534 Cases and 2211 Controls

Background

Recently, there have been a number of studies on the association between MDM2 (Murine Double Minute 2) 309 polymorphism and ovarian cancer risk. However, the results of previous reports remain controversial and ambiguous. Thus, we performed a meta-analysis to explore more precisely the association between MDM2 309 polymorphism and the risk of ovarian cancer.

Methods

A meta-analysis was performed to examine the association between MDM2 309T>G polymorphism and ovarian cancer risk. Odds ratio (OR) and its 95% confidence interval (CI) were used for statistical analysis.

Results

Our publication search identified a total of 6 studies with 1534 cases and 2211 controls. No significant association was found between MDM2 309T>G polymorphism and ovarian cancer risk in total population analysis. In the subgroup meta-analysis by ethnicity, a negative association was shown in Asian subgroup (G vs. T OR = 0.774, 95% CI = 0.628–0.955, P = 0.017, P _het = 0.327; GG vs. TT: OR = 0.601, 95% CI = 0.395–0.914, P = 0.017, P _het = 0.417; dominant model TG+GG vs. TT: OR = 0.661, 95% CI = 0.468–0.934, P = 0.019, P _het = 0.880), and no significant association in any genetic models among Caucasians was observed.

Conclusions

This meta-analysis provides evidence for the association between MDM2 309 polymorphism and ovarian cancer risk, supporting the hypothesis that MDM2 SNP309 G allele acts as an important ovarian cancer protective factor in Asians but not in Caucasians.     

A promoter SNP rs4073T>A in the common allele of the interleukin 8 gene is associated with the development of idiopathic pulmonary fibrosis via the IL-8 protein enhancing mode

Background

Interleukin-8 (IL-8) is a potent chemo-attractant cytokine responsible for neutrophil infiltration in lungs with idiopathic pulmonary fibrosis (IPF). The IL-8 protein and mRNA expression are increased in the lung with IPF. We evaluated the effect of single nucleotide polymorphisms (SNPs) of the IL-8 gene on the risk of IPF.

Methods

One promoter (rs4073T>A) and two intronic SNPs (rs2227307T>G and rs2227306C>T) of the IL-8 genes were genotyped in 237 subjects with IPF and 456 normal controls. Logistic regression analysis was applied to evaluate the association of these SNPs with IPF. IL-8 in BAL fluids was measured using a quantitative sandwich enzyme immunoassay, and promoter activity was assessed using the luciferase reporter assay.

Results

The minor allele frequencies of rs4073T>A and rs2227307T>G were significantly lower in the 162 subjects with surgical biopsy-proven IPF and 75 subjects with clinical IPF compared with normal controls in the recessive model (OR = 0.46 and 0.48, p = 0.006 and 0.007, respectively). The IL-8 protein concentration in BAL fluids significantly increased in 24 subjects with IPF compared with 14 controls (p = 0.009). Nine IPF subjects homozygous for the rs4073 T>A common allele exhibited higher levels of the IL-8 protein compared with six subjects homozygous for the minor allele (p = 0.024). The luciferase activity of the rs4073T>A common allele was significantly higher than that of the rs4073T>A minor allele (p = 0.002).

Conclusion

The common allele of a promoter SNP, rs4073T>A, may increase susceptibility to the development of IPF via up-regulation of IL-8.     

MDM2 SNP309 rs2279744 Polymorphism and Gastric Cancer Risk: A Meta-Analysis

Background

MDM2 is a major negative regulator of p53, and a single nucleotide polymorphism (SNP) in the MDM2 promoter region SNP309 has been demonstrated to be associated with an increased MDM2 expression and a significantly earlier age of onset of several tumors, including gastric cancer. Several studies were published to evaluate the association between SNP309 and gastric cancer risk. However, the results remain conflicting rather than conclusive.

Objective

The aim of this study was to assess the association between the MDM2 SNP309 polymorphism and gastric risk.

Methods

We performed a meta-analysis to investigate this relationship. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association. The pooled ORs were performed for codominant model, dominant model, and recessive model, respectively.

Results

Five published case-control studies, including 1,621 gastric cancer cases and 2,639 controls were identified. We found that the MDM2 SNP309 polymorphism was associated with a significantly increased risk of gastric cancer risk when all studies were pooled into the meta-analysis (GG versus TT, OR = 1.54; 95%CI = 1.04–2.29, and GG versus GT/TT, OR = 1.49, 95%CI = 1.30–1.72). Furthermore, Egger''s test did not show any evidence of publication bias (P = 0.799 for GG versus TT).

Conclusion

Our results suggest that the MDM2 SNP309 polymorphism may be a low-penetrant risk factor for the development of gastric cancer.     

Redox State and Mitochondrial Respiratory Chain Function in Skeletal Muscle of LGMD2A Patients

Background

Calpain-3 deficiency causes oxidative and nitrosative stress-induced damage in skeletal muscle of LGMD2A patients, but mitochondrial respiratory chain function and anti-oxidant levels have not been systematically assessed in this clinical population previously.

Methods

We identified 14 patients with phenotypes consistent with LGMD2A and performed CAPN3 gene sequencing, CAPN3 expression/autolysis measurements, and in silico predictions of pathogenicity. Oxidative damage, anti-oxidant capacity, and mitochondrial enzyme activities were determined in a subset of muscle biopsies.

Results

Twenty-one disease-causing variants were detected along the entire CAPN3 gene, five of which were novel (c.338 T>C, c.500 T>C, c.1525-1 G>T, c.2115+4 T>G, c.2366 T>A). Protein- and mRNA-based tests confirmed in silico predictions and the clinical diagnosis in 75% of patients. Reductions in antioxidant defense mechanisms (SOD-1 and NRF-2, but not SOD-2), coupled with increased lipid peroxidation and protein ubiquitination, were observed in calpain-3 deficient muscle, indicating a redox imbalance primarily affecting non-mitochondrial compartments. Although ATP synthase levels were significantly lower in LGMD2A patients, citrate synthase, cytochrome c oxidase, and complex I+III activities were not different from controls.

Conclusions

Despite significant oxidative damage and redox imbalance in cytosolic/myofibrillar compartments, mitochondrial respiratory chain function is largely maintained in skeletal muscle of LGMD2A patients.     

Association of Mitochondrial DNA Polymerase γ Gene POLG1 Polymorphisms with Parkinsonism in Chinese Populations

Background

Mitochondrial DNA polymerase gamma (POLG1) mutations were associated with levodopa-responsive Parkinsonism. POLG1 gene contains a number of common nonsynonymous SNPs and intronic regulatory SNPs which may have functional consequences. It is of great interest to discover polymorphisms variants associated with Parkinson''s disease (PD), both in isolation and in combination with specific SNPs.

Materials and Methods

We conducted a case-control study and genotyped twenty SNPs and poly-Q polymorphisms of POLG1 gene including in 344 Chinese sporadic PD patients and 154 healthy controls. All the polymorphisms of POLG1 we found in this study were sequenced by PCR products with dye terminator methods using an ABI-3100 sequencer. Hardy-Weinberg equilibrium and linkage disequilibrium (LD) for association between twenty POLG1 SNPs and PD were calculated using the program Haploview.

Principal Results

We provided evidence for strong association of four intronic SNPs of the POLG1 gene (new report: c.2070-12T>A and rs2307439: c.2070-64G>A in intron 11, P = 0.00011, OR = 1.727; rs2302084: c.3105-11T>C and rs2246900: c.3105-36A>G in intron 19, P = 0.00031, OR = 1.648) with PD. However, we did not identify any significant association between ten exonic SNPs of POLG1 and PD. Linkage disequilibrium analysis indicated that c.2070-12T>A and c.2070-64G>A could be parsed into one block as Haplotype 1 as well as c.3105-11T>C and c.3105-36A>G in Haplotype 2. In addition, case and control study on association of POLG1 CAG repeat (poly-Q) alleles with PD showed a significant association (P = 0.03, OR = 2.16) of the non-10/11Q variants with PD. Although intronic SNPs associated with PD didn''t influence POLG1 mRNA alternative splicing, there was a strong association of c.2070-12T>A and c.2070-64G>A with decreased POLG1 mRNA level and protein levels.

Conclusions

Our findings indicate that POLG1 may play a role in the pathogenesis of PD in Chinese populations.     

Genetic Association Analysis of the Functional c.714T>G Polymorphism and Mucosal Expression of Dectin-1 in Inflammatory Bowel Disease

Background

Dectin-1 is a pattern recognition receptor (PRR) expressed by myeloid cells that specifically recognizes β-1,3 glucan, a polysaccharide and major component of the fungal cell wall. Upon activation, dectin-1 signaling converges, similar to NOD2, on the adaptor molecule CARD9 which is associated with inflammatory bowel disease (IBD). An early stop codon polymorphism (c.714T>G) in DECTIN-1 results in a loss-of-function (p.Y238X) and impaired cytokine responses, including TNF-α, interleukin (IL)-1β and IL-17 upon in vitro stimulation with Candida albicans or β-glucan. The aim of the present study was to test the hypothesis that the DECTIN-1 c.714T>G (p.Y238X) polymorphism is associated with lower disease susceptibility or severity in IBD and to investigate the level of dectin-1 expression in inflamed and non-inflamed colon tissue of IBD patients.

Methodology

Paraffin embedded tissue samples from non-inflamed and inflamed colon of IBD patients and from diverticulitis patients were immunohistochemically stained for dectin-1 and related to CD68 macrophage staining. Genomic DNA of IBD patients (778 patients with Crohn''s disease and 759 patients with ulcerative colitis) and healthy controls (n = 772) was genotyped for the c.714T>G polymorphism and genotype-phenotype interactions were investigated.

Principal Findings

Increased expression of dectin-1 was observed in actively inflamed colon tissue, as compared to non-inflamed tissue of the same patients. Also an increase in dectin-1 expression was apparent in diverticulitis tissue. No statistically significant difference in DECTIN-1 c.714T>G allele frequencies was observed between IBD patients and healthy controls. Furthermore, no differences in clinical characteristics could be observed related to DECTIN-1 genotype, neither alone, nor stratified for NOD2 genotype.

Conclusions

Our data demonstrate that dectin-1 expression is elevated on macrophages, neutrophils, and other immune cells involved in the inflammatory reaction in IBD. The DECTIN-1 c.714T>G polymorphism however, is not a major susceptibility factor for developing IBD.     

The Lewis Histo-Blood Group System: Molecular Analysis of the 59T>G, 508G>A,and 1067T>A Polymorphisms in an Amazonian Population

Background

The Lewis (FUT3) gene is responsible for the expression of the Le^a and Le^b blood group antigens. The individuals, who not synthesize these antigens have the phenotype Lewis negative, due to the presence of some single nucleotide polymorphisms (SNPs), such as 59T>G, 508G>A and 1067T>A, whose distribution is different in various ethnic groups. Our aim was to verify the frequencies of these SNPs in an admixed population of Belém-Pará-Brazil.

Materials and Methods

Polymerase chain reaction/restriction enzyme method were used to detect these SNPs in the FUT3 gene, whereas Lewis phenotypes were defined by the direct hemagglutination and in saliva by Dot-Elisa assay in a random sample of 150 individuals from admixed population of Belém in the northeast Brazilian Amazon region.

Results

The frequency of these SNPs was detected as 47.6% (59T>G), 17.3% (508G>A) and 5.3% (1067T>A).The discrepancies between blood and salivary Lewis phenotypes are related to the relatively high frequencies of 59T>G and the null allele 508G>A. Whereas 38.6% of the individuals were Lewis negative based on blood, only 17.24% also tested negative when their saliva were analyzed.

Conclusion

We have found a marked consistency between the phenotypes and genotypes of the Lewis blood group system. Furthermore, our obtained F_ST values reveal distinct frequencies of the FUT3 SNPs between the present sample and its representative ancestral populations. These observations will help to evaluate the Lewis antigens impact as susceptibility markers, in genetic association studies to certain diseases.     

Selected ABCB1, ABCB4 and ABCC2 Polymorphisms Do Not Enhance the Risk of Drug-Induced Hepatotoxicity in a Spanish Cohort

Background and Aims

Flawed ABC transporter functions may contribute to increased risk of drug-induced liver injury (DILI). We aimed to analyse the influence of genetic variations in ABC transporters on the risk of DILI development and clinical presentations in a large Spanish DILI cohort.

Methods

A total of ten polymorphisms in ABCB1 (1236T>C, 2677G>T,A, 3435T>C), ABCB4 (1954A>G) and ABCC2 (−1774G>del, −1549A>G, −24C>T, 1249G>A, 3972C>T and 4544G>A) were genotyped using Taqman 5′ allelic discrimination assays or sequencing in 141 Spanish DILI patients and 161 controls. The influence of specific genotypes, alleles and haplotypes on the risk of DILI development and clinical presentations was analysed.

Results

None of the individual polymorphisms or haplotypes was found to be associated with DILI development. Carriers homozygous for the ABCC2 −1774del allele were however only found in DILI patients. Hence, this genotype could potentially be associated with increased risk, though its low frequency in our Spanish cohort prevented a final conclusion. Furthermore, carriers homozygous for the ABCC2 −1774G/−1549A/−24T/1249G/3972T/4544G haplotype were found to have a higher propensity for total bilirubin elevations when developing DILI.

Conclusions

Our findings do not support a role for the analysed polymorphisms in the ABCB1, ABCB4 and ABCC2 transporter genes in DILI development in Spanish patients. The ABCC2 −1774deldel genotype was however restricted to DILI cases and could potentially contribute to enhanced DILI susceptibility.     

Impact of TP53 Codon 72 and MDM2 SNP 309 Polymorphisms in Pancreatic Ductal Adenocarcinoma

Single-nucleotide polymorphisms (SNPs) of TP53 (codon 72, rs1042522) and MDM2 promoter (SNP 309, rs2279744) have been associated with risk for various human cancers. However, studies analyzing these polymorphisms in pancreatic ductal adenocarcinoma (PDAC) are lacking. We investigated TP53 codon 72 and MDM2 SNP 309 polymorphisms in 32 patients with PDAC, 16 patients with chronic pancreatitis (CP), and 32 normal controls, using formalin-fixed paraffin-embedded tissue. We also examined TP53 and MDM2 protein immunohistochemistry (IHC) to assess the involvement of these differences in malignant transformation and disease progression. TP53 Pro/Pro genotype was significantly more frequent in PDAC patients than in controls (65.6 vs. 15.6%, p < 0.001) and no significant difference was found between CP patients (37.5%) and controls. In MDM2 SNP 309, there were no significant differences among the three groups. Based on the Kaplan-Meier analysis, overall survival was significantly shorter in MDM2 G/G genotypes compared with other genotypes (G/T and T/T) (359 vs. 911 days, p = 0.016) whereas no significant differences in TP53 genotypes were observed (638 vs. 752 days, p = 0.471). Although TP53 IHC was frequent in PDAC patients (53.1%), TP53 and MDM2 protein expression was not correlated with polymorphisms. Our study demonstrated TP53 codon 72 polymorphism is potentially a genetic predisposing factor while MDM2 SNP 309 polymorphism might be useful in predicting survival outcome.     

Variants of the PPARD Gene and Their Clinicopathological Significance in Colorectal Cancer

Background

Peroxisome proliferator-activated receptor delta (PPARD) is nuclear hormone receptor involved in colorectal cancer (CRC) differentiation and progression. The purpose of this study was to determine prevalence and spectrum of variants in the PPARD gene in CRC, and their contribution to clinicopathological endpoints.

Methods and Findings

Direct sequencing of the PPARD gene was performed in 303 primary tumors, in blood samples from 50 patients with ≥3 affected first-degree relatives, 50 patients with 2 affected first-degree relatives, 50 sporadic patients, 360 healthy controls, and in 6 colon cancer cell lines. Mutation analysis revealed 22 different transversions, 7 of them were novel. Three of all variants were somatic (c.548A>G, p.Y183C, c.425-9C>T, and c.628-16G>A). Two missense mutations (p.Y183C and p.R258Q) were pathogenic using in silico predictive program. Five recurrent variants were detected in/adjacent to the exons 4 (c.1-87T>C, c.1-67G>A, c.130+3G>A, and c.1-101-8C>T) and exon 7 (c.489T>C). Variant c.489C/C detected in tumors was correlated to worse differentiation (P = 0.0397).

Conclusions

We found 7 novel variants among 22 inherited or acquired PPARD variants. Somatic and/or missense variants detected in CRC patients are rare but indicate the clinical importance of the PPARD gene.     

Predictive and prognostic impact of TP53 mutations and MDM2 promoter genotype in primary breast cancer patients treated with epirubicin or paclitaxel

Background

TP53 mutations have been associated with resistance to anthracyclines but not to taxanes in breast cancer patients. The MDM2 promoter single nucleotide polymorphism (SNP) T309G increases MDM2 activity and may reduce wild-type p53 protein activity. Here, we explored the predictive and prognostic value of TP53 and CHEK2 mutation status together with MDM2 SNP309 genotype in stage III breast cancer patients receiving paclitaxel or epirubicin monotherapy.

Experimental Design

Each patient was randomly assigned to treatment with epirubicin 90 mg/m² (n = 109) or paclitaxel 200 mg/m² (n = 114) every 3rd week as monotherapy for 4–6 cycles. Patients obtaining a suboptimal response on first-line treatment requiring further chemotherapy received the opposite regimen. Time from last patient inclusion to follow-up censoring was 69 months. Each patient had snap-frozen tumor tissue specimens collected prior to commencing chemotherapy.

Principal Findings

While TP53 and CHEK2 mutations predicted resistance to epirubicin, MDM2 status did not. Neither TP53/CHEK2 mutations nor MDM2 status was associated with paclitaxel response. Remarkably, TP53 mutations (p = 0.007) but also MDM2 309TG/GG genotype status (p = 0.012) were associated with a poor disease-specific survival among patients having paclitaxel but not patients having epirubicin first-line. The effect of MDM2 status was observed among individuals harbouring wild-type TP53 (p = 0.039) but not among individuals with TP53 mutated tumors (p>0.5).

Conclusion

TP53 and CHEK2 mutations were associated with lack of response to epirubicin monotherapy. In contrast, TP53 mutations and MDM2 309G allele status conferred poor disease-specific survival among patients treated with primary paclitaxel but not epirubicin monotherapy.     

Genes of the RNASE5 pathway contain SNP associated with milk production traits in dairy cattle

Background

Identification of the processes and mutations responsible for the large genetic variation in milk production among dairy cattle has proved challenging. One approach is to identify a biological process potentially involved in milk production and to determine the genetic influence of all the genes included in the process or pathway. Angiogenin encoded by angiogenin, ribonuclease, RNase A family 5 (RNASE5) is relatively abundant in milk, and has been shown to regulate protein synthesis and act as a growth factor in epithelial cells in vitro. However, little is known about the role of angiogenin in the mammary gland or if the polymorphisms present in the bovine RNASE5 gene are associated with lactation and milk production traits in dairy cattle. Given the high economic value of increased protein in milk, we have tested the hypothesis that RNASE5 or genes in the RNASE5 pathway are associated with milk production traits. First, we constructed a “RNASE5 pathway” based on upstream and downstream interacting genes reported in the literature. We then tested SNP in close proximity to the genes of this pathway for association with milk production traits in a large dairy cattle dataset.

Results

The constructed RNASE5 pathway consisted of 11 genes. Association analysis between SNP in 1 Mb regions surrounding these genes and milk production traits revealed that more SNP than expected by chance were associated with milk protein percent (P < 0.05 significance). There was no significant association with other traits such as milk fat content or fertility.

Conclusions

These results support a role for the RNASE5 pathway in milk production, specifically milk protein percent, and indicate that polymorphisms in or near these genes explain a proportion of the variation for this trait. This method provides a novel way of understanding the underlying biology of lactation with implications for milk production and can be applied to any pathway or gene set to test whether they are responsible for the variation of complex traits.     

Polymorphism in the Hypoxia-Inducible Factor 1alpha Gene May Confer Susceptibility to LDD in Chinese Cohort

Objective

This study aimed to investigate whether or not hypoxia-inducible factor-1α (HIF-1α) gene variants are associated with the susceptibility and clinical characteristics of lumbar disc degeneration (LDD).

Methods

We examined 320 patients with LDD and 447 gender- and age-matched control subjects. We also determined the HIF-1α gene variants, including C1772T (P582S) and G1790A (A588T) polymorphisms.

Results

Significant differences were observed in allelic and genotypic distributions of 1790 A > G polymorphisms between LDD cases and control subjects. Logistic regression revealed that 1790 AA genotypes indicated a protective effect against the development of LDD. The HIF-1α 1790 A > G polymorphisms also affected the severity of LDD as evaluated based on the modified Japanese Orthopedic Association (mJOA) scores. The 1790 AA genotype carriers exhibited significantly lower mJOA scores than AG and GG carriers. C1772T did not show any association with the risk and severity of LDD.

Conclusion

Our study suggested that HIF-1α 1790 A > G polymorphisms may be used as a molecular marker to determine the susceptibility and severity of LDD.     

miR-485-5p Binding Site SNP rs8752 in HPGD Gene Is Associated with Breast Cancer Risk

Background

Single nucleotide polymorphisms (SNPs) that reside in microRNA target sites may play an important role in breast cancer development and progression. To reveal the association between microRNA target site SNPs and breast cancer risk, we performed a large case-control study in China.

Methods

We performed a two-stage case-control study including 2744 breast cancer cases and 3125 controls. In Stage I, we genotyped 192 SNPs within microRNA binding sites identified from the “Patrocles” database using custom Illumina GoldenGate VeraCode assays on the Illumina BeadXpress platform. In Stage II, genotyping was performed on SNPs potentially associated with breast cancer risk using the TaqMan platform in an independent replication set.

Results

In stage I, 15 SNPs were identified to be significantly associated with breast cancer risk (P<0.05). In stage II, one SNP rs8752 was replicated at P<0.05. This SNP is located in the 3’ untranslated region (UTR) of the 15-hydroxyprostaglandin dehydrogenase (HPGD) gene at 4q34-35, a miR-485-5p binding site. Compared with the GG genotype, the combined GA+AA genotypes has a significantly higher risk of breast cancer (OR = 1.18; 95% CI: 1.06-1.31, P = 0.002). Specifically, this SNP was associated with estrogen receptor (ER) positive breast cancer (P = 0.0007), but not with ER negative breast cancer (P = 0.23), though p for heterogeneity not significant.

Conclusion

Through a systematic case-control study of microRNA binding site SNPs, we identified a new breast cancer risk variant rs8752 in HPGD in Chinese women. Further studies are warranted to investigate the underling mechanism for this association.     

A Functional TNFAIP2 3'-UTR rs8126 Genetic Polymorphism Contributes to Risk of Esophageal Squamous Cell Carcinoma

Background

Accumulated evidences demonstrated that single nucleotide polymorphisms (SNPs) in mRNA 3''-untranslated region (3''-UTR) may impact microRNAs (miRNAs)-mediated expression regulation of oncogenes and tumor suppressors. There is a TNFAIP2 3''-UTR rs8126 T>C genetic variant which has been proved to be associated with head and neck cancer susceptibility. This SNP could disturb binding of miR-184 with TNFAIP2 mRNA and influence TNFAIP2 regulation. However, it is still unclear how this polymorphism is involved in development of esophageal squamous cell carcinoma (ESCC). Therefore, we hypothesized that the functional TNFAIP2 rs8126 SNP may affect TNFAIP2 expression and, thus, ESCC risk.

Methods

We investigated the association between the TNFAIP2 rs8126 variant and ESCC risk as well as the functional relevance on TNFAIP2 expression in vivo. Genotypes were determined in a case-control set consisted of 588 ESCC patients and 600 controls. The allele-specific regulation on TNFAIP2 expression by the rs8126 SNP was examined in normal and cancerous tissue specimens of esophagus.

Results

We found that individuals carrying the rs8126 CC or CT genotype had an OR of 1.89 (95%CI  = 1.23–2.85, P = 0.003) or 1.38 (95%CI  = 1.05–1.73, P = 0.017) for developing ESCC in Chinese compared with individual carrying the TT genotype. Carriers of the rs8126 CC and CT genotypes had significantly lower TNFAIP2 mRNA levels than those with the TT genotypes in normal esophagus tissues (P<0.05).

Conclusions

Our data demonstrate that functional TNFAIP2 rs8126 genetic variant is a ESCC susceptibility SNP. These results support the hypothesis that genetic variants interrupting miRNA-mediated gene regulation might be important genetic modifiers of cancer risk.     

Lymphotoxin Alpha (LTA) Polymorphism Is Associated with Prognosis of Non-Hodgkin’s Lymphoma in a Chinese Population

Background

Non-Hodgkin’s lymphoma (NHL) has been widely reported to be associated with autoimmune and pro-inflammatory response, and genetic polymorphisms of candidate genes involved in autoimmune and pro-inflammatory response may influence the survival and prognosis of NHL patients. To evaluate the role of such genetic variations in prognosis of NHL, we conducted this study in a Chinese population.

Methods

We used the TaqMan assay to genotype six single nucleotide polymorphisms (SNPs) (TNF rs1799964T>C, LTA rs1800683G>A, IL-10 rs1800872T>G, LEP rs2167270G>A, LEPR rs1327118C>G, TNFAIP8 rs1045241C>T) for 215 NHL cases. Kaplan-Meier analysis was performed to compare progression free survival among two common genotypes. Cox proportional hazard models were used to identify independent risk factors.

Results

We observed that LTA rs1800683G>A was significantly associated with risk of progression or relapse in NHL patients (HR = 1.63, 95%CI = 1.06–2.51; P = 0.028), particularly in Diffuse large B cell lymphoma (DLBCL) cases (HR = 1.50, 95%CI = 1.10–2.04, P = 0.01). Both univariate and multivariate Cox regression analysis showed that in DLBCL patients, Ann Arbor stage III/IV, elevated LDH level before treatment and LTA rs1800683 AA genotype carrier were independent risk factors for progression or relapse. While in NK/T cell lymphoma, Ann Arbor stage III/IV and elevated β₂-MG level before treatment indicated poorer prognosis.

Conclusions

The polymorphism of LTA rs1800683G>A contributes to NHL prognosis in a Chinese population. Further large-scale and well-designed studies are needed to confirm these results.     

Role of MDM2 309T>G (rs2279744) and I/D (rs3730485) polymorphisms and haplotypes in risk of papillary thyroid carcinoma,tumor stage,tumor size,and early onset of tumor: A case control study

Murine double minute clone 2 (MDM2) protein plays an important role in the regulation of p53 tumor suppressor. Genetic polymorphisms of the MDM2 gene are the candidate variants in susceptibility to various cancers. In the present study, we aimed to investigate the possible effects of MDM2 309T>G (rs2279744) and I/D (rs3730485) polymorphisms on papillary thyroid carcinoma (PTC) susceptibility and clinical or pathological features of the disease. A case control study was carried out involving in a total of 131 patients with PTC and 144 healthy controls. Both cases and controls were genotyped for MDM2 309T>G and I/D polymorphisms. There was no significant difference regarding MDM2 309T>G and I/D genotypes between patients with PTC and controls in neither dominant nor recessive and allelic models. The frequency of G-D haplotype was higher in patients with PTC and this haplotype was associated with a 1.7-fold increased risk of PTC. The MDM2 309T>G polymorphism was associated with a higher risk of III–IV stages in patients with PTC. The MDM2 ID genotype was significantly higher in patients with PTC less than 40 years and associated with larger tumor size (≥1 cm). In conclusion, the G-D haplotype but not MDM2 309T>G and I/D polymorphisms were associated with higher risk of PTC. MDM2 309T>G polymorphism was associated with a higher incidence of III–IV stages, however, I/D polymorphism was associated with larger tumor size and a lower age of disease occurrence.     

MARVELD2 (DFNB49) Mutations in the Hearing Impaired Central European Roma Population - Prevalence,Clinical Impact and the Common Origin

Background

In the present study we aimed: 1) To establish the prevalence and clinical impact of DFNB49 mutations in deaf Roma from 2 Central European countries (Slovakia and Hungary), and 2) to analyze a possible common origin of the c.1331+2T>C mutation among Roma and Pakistani mutation carriers identified in the present and previous studies.

Methods

We sequenced 6 exons of the MARVELD2 gene in a group of 143 unrelated hearing impaired Slovak Roma patients. Simultaneously, we used RFLP to detect the c.1331+2T>C mutation in 85 Hungarian deaf Roma patients, control groups of 702 normal hearing Romanies from both countries and 375 hearing impaired Slovak Caucasians. We analyzed the haplotype using 21 SNPs spanning a 5.34Mb around the mutation c.1331+2T>C.

Results

One pathogenic mutation (c.1331+2T>C) was identified in 12 homozygous hearing impaired Roma patients. Allele frequency of this mutation was higher in Hungarian (10%) than in Slovak (3.85%) Roma patients. The identified common haplotype in Roma patients was defined by 18 SNP markers (3.89 Mb). Fourteen common SNPs were also shared among Pakistani and Roma homozygotes. Biallelic mutation carriers suffered from prelingual bilateral moderate to profound sensorineural hearing loss.

Conclusions

We demonstrate different frequencies of the c.1331+2T>C mutation in hearing impaired Romanies from 3 Central European countries. In addition, our results provide support for the hypothesis of a possible common ancestor of the Slovak, Hungarian and Czech Roma as well as Pakistani deaf patients. Testing for the c.1331+2T>C mutation may be recommended in GJB2 negative Roma cases with early-onset sensorineural hearing loss.     

Epigenetic regulation of the ELOVL6 gene is associated with a major QTL effect on fatty acid composition in pigs

Background

In previous studies on an Iberian x Landrace cross, we have provided evidence that supported the porcine ELOVL6 gene as the major causative gene of the QTL on pig chromosome 8 for palmitic and palmitoleic acid contents in muscle and backfat. The single nucleotide polymorphism (SNP) ELOVL6:c.-533C > T located in the promoter region of ELOVL6 was found to be highly associated with ELOVL6 expression and, accordingly, with the percentages of palmitic and palmitoleic acids in longissimus dorsi and adipose tissue. The main goal of the current work was to further study the role of ELOVL6 on these traits by analyzing the regulation of the expression of ELOVL6 and the implication of ELOVL6 polymorphisms on meat quality traits in pigs.

Results

High-throughput sequencing of BAC clones that contain the porcine ELOVL6 gene coupled to RNAseq data re-analysis showed that two isoforms of this gene are expressed in liver and adipose tissue and that they differ in number of exons and 3’UTR length. Although several SNPs in the 3’UTR of ELOVL6 were associated with palmitic and palmitoleic acid contents, this association was lower than that previously observed with SNP ELOVL6:c.-533C > T. This SNP is in full linkage disequilibrium with SNP ELOVL6:c.-394G > A that was identified in the binding site for estrogen receptor alpha (ERα). Interestingly, the ELOVL6:c.-394G allele is associated with an increase in methylation levels of the ELOVL6 promoter and with a decrease of ELOVL6 expression. Therefore, ERα is clearly a good candidate to explain the regulation of ELOVL6 expression through dynamic epigenetic changes in the binding site of known regulators of ELOVL6 gene, such as SREBF1 and SP1.

Conclusions

Our results strongly suggest the ELOVL6:c.-394G > A polymorphism as the causal mutation for the QTL on pig chromosome 8 that affects fatty acid composition in pigs.

Electronic supplementary material

The online version of this article (doi:10.1186/s12711-015-0111-y) contains supplementary material, which is available to authorized users.