A serum 25-hydroxyvitamin D concentration-associated genetic variant in DHCR7 interacts with type 2 diabetes status to influence subclinical atherosclerosis (measured by carotid intima–media thickness)

Aims/hypothesis

The findings of studies investigating whether or not low serum 25-hydroxyvitamin D [25(OH)D] concentration promotes development of atherosclerosis have been contradictory. The present study employed a Mendelian randomisation approach and carotid artery intima–media thickness (cIMT), a surrogate marker of coronary artery disease, to address this question.

Methods

The multicentre, longitudinal Carotid Intima–Media Thickness and IMT-Progression as Predictors of Vascular Events in a High-Risk European Population (IMPROVE) cohort study, which enrolled individuals with at least three cardiovascular risk factors and no history or symptoms of cardiovascular disease, was used for the present investigation. Participants underwent carotid ultrasound examination at baseline and at months 15 and 30. Six single nucleotide polymorphisms (SNPs) associated with serum 25(OH)D concentration in genome-wide association studies were identified and genotyped in 3,418 individuals, of whom 929 had type 2 diabetes.

Results

SNPs in the genes encoding vitamin D binding protein (GC; rs2282679 and rs7041) and 7-dehydrocholesterol reductase/NAD synthetase-1 (DHCR7; rs12785878 and rs3829251) were negatively associated with 25(OH)D levels. Effect sizes and significance of associations between SNPs and 25(OH)D levels differed between individuals with and without type 2 diabetes, although no significant interactions were observed. A SNP in DHCR7 interacted with type 2 diabetes to significantly influence progression of cIMT measures independent of 25(OH)D levels and established risk factors. Expression analysis demonstrated that this SNP modulates DHCR7 mRNA levels in aortic adventitia.

Conclusions/interpretation

SNPs in GC and DHCR7 were associated with serum levels of 25(OH)D, but only rs3829251 (DHCR7) influenced progression of subclinical atherosclerosis, as measured by cIMT, in a manner dependent on type 2 diabetes status but independent of 25(OH)D levels.     

MGMT −535G>T polymorphism is associated with prognosis for patients with metastatic colorectal cancer treated with oxaliplatin-based chemotherapy

Purpose

The present study analyzed the polymorphisms of DNA repair genes and their impact on the response to chemotherapy and survival of patients with colorectal cancer.

Patients and methods

A total of 94 patients with recurrent or metastatic colorectal cancer treated with oxaliplatin-based combination chemotherapy were enrolled in the present study. The single nucleotide polymorphisms of 16 DNA repair genes were determined using a PCR–RFLP assay.

Results

During the median follow-up duration of 15.9 (2.1–53.0) months, 67 (71.3%) progressions and 29 (30.9%) deaths were observed. Among the 60 patients assessable for response, response to the oxaliplatin-based regimens was found in 27 (45%) patients (9 CR and 18 PR). In a logistic regression analysis adjusted to age, sex, primary site, disease status, and regimen, the POLR2C rs4937 and MSH2 rs3732183 polymorphisms were statistically associated with the response to the oxaliplatin-based chemotherapy. A multivariate survival analysis showed that the TT genotype of the MGMT (rs1625649) ?535G>T polymorphism was found to correlate with a worse progression-free survival (PFS) than the combined GG + GT genotypes (HR = 3.137; 95% CI = 1.423–6.914; P = 0.005), which was also observed among the 60 evaluable patients (HR = 2.653; 95% CI = 1.101–6.392; P = 0.030) For the clinical parameters, curative resection was the most significant prognostic factor in a Cox model for PFS and overall survival (HR = 0.229 and 0.205; P < 0.001 and 0.001, respectively).

Conclusion

The MGMT ?535G>T polymorphism (rs1625649) was found to be correlated with PFS in patients with advanced colorectal cancer treated with oxaliplatin-based chemotherapy.     

Association of a common genetic variant of the IGF-1 gene with event-free survival in patients with HER2-positive breast cancer

Purpose

Insulin-like growth factor 1 (IGF-1) stimulates mitosis and inhibits apoptosis. High circulating IGF-1 levels are linked with an increased risk of colorectal and breast cancer. Recently, IGF-1 single nucleotide polymorphisms (SNPs), especially variant rs2946834, have been associated with poor clinical outcome in patients with colorectal cancer. In the present study, we aimed to investigate the influence of IGF1 polymorphisms associated with IGF-1 plasma levels on event-free survival in patients with HER2-positive breast cancer.

Methods

The present study included 161 consecutive white patients with HER2-positive breast cancer. Event-free survival was calculated as the time from cancer diagnosis to either relapse or death from any cause. Genomic DNA was extracted from archived formalin-fixed paraffin-embedded tumor tissue samples; five IGF-1 polymorphisms (rs2946834, rs6220, rs1520220, rs5742694, and rs5742678), all associated with IGF-1 levels, were genotyped by SNaPshot assays.

Results

Kaplan–Meier analysis showed a poorer clinical outcome for carriers of the rare allele of SNP rs2946834 (log-rank test, p = 0.020). Concordantly, in univariate Cox regression analyses, the rare allele of SNP rs2946834 was significantly associated with a decreased event-free survival (HR = 3.06 [1.14–8.22]; p = 0.027). Multivariate analysis adjusted for age and tumor stage confirmed this result (HR = 4.02 [1.36–11.90]; p = 0.012). Other investigated polymorphisms of the IGF1 gene were not significantly associated with event-free survival (all p values >0.05).

Conclusions

This study provides first evidence that IGF1 rs2946834 polymorphism is associated with clinical outcome of HER2-positive breast cancer patients. Further studies are warranted to validate these findings.     

Apoptosis-related Fas and FasL gene polymorphisms’ associations with knee osteoarthritis

To investigate the associations between Fas and FasL gene polymorphisms and susceptibility to knee osteoarthritis. Genomic DNA was obtained from 146 patients with knee osteoarthritis and 102 healthy controls. Genotype distributions and allelic frequencies of four polymorphisms of Fas (-670 G>A rs1800682, -1377 G>A rs2234767) and FasL (IVS2nt-124 A>G rs5030772, -844 T>C rs763110) genes were compared between the groups. Thereafter, this association was investigated between patients and controls of the same sex. There were significant differences between patients with knee osteoarthritis and controls regarding the genotype distributions and allelic frequencies of Fas-1377 G>A polymorphism (P = 0.0001 and P = 0.005, respectively). The Fas-1377 GG genotype and G allele were significantly more frequent in patients with knee osteoarthritis than in controls. Genotype distributions and allelic frequencies of Fas-670 G>A, FasL-844 T>C, and FasL IVS2nt-124 A>G polymorphisms did not differ between the groups (P > 0.05). However, there were no significant differences between patients and controls of the same sex (P > 0.05). These findings suggest that the Fas-1377 G>A polymorphism in the Fas gene related with apoptosis may contribute to susceptibility to knee osteoarthritis in the Turkish population. There is a need for further studies to evaluate the role of apoptosis in large cohorts.     

PPP1R13L variant associated with prognosis for patients with rectal cancer

Background

ERCC1, CD3EAP, and PPP1R13L polymorphisms in the chromosomal region 19q13.2-3 have already been shown to have a synergistic effect on apoptosis and DNA repair pathways. Therefore, the aim of this study was to investigate the association between such genetic variants and the prognosis of colorectal cancer (CRC) following curative surgery.

Methods

DNA was extracted from fresh frozen normal tissue from 349 CRC patients underwent curative surgery and then genotyped for 5 polymorphisms (PPP1R13L rs1970764 and rs1005165; CD3EAP rs967591; ERCC1 rs735482 and rs11615) using PCR-restriction fragment length polymorphism (PCR-RFLP).

Results

Among the 5 polymorphisms, PPP1R13L rs1970764 was significantly associated with relapse-free (RFS) and disease-specific survival (DSS) in a recessive model. In haplotype analysis, three haplotypes (TACC, CGAC, and CGAT) were selected for analysis among 6 haplotypes constructed by the PHASE II program using 4 polymorphisms (rs1005165, rs967591, rs735482, and rs11615) in a moderate to strong linkage disequilibrium (LD) (D′ > 0.4), and a significant difference in RFS was observed among patients with these 3 haplotypes. In the multivariate analysis, the GG genotype of PPP1R13L rs1970764 was identified as an independent prognostic factor for poor RFS and DSS (HR = 1.743 and 1.734; P = 0.003 and 0.010, respectively) when compared with the combine AA/AG genotype adjusted to clinicopathologic variables. In particular, the prognostic impact of PPP1R13L rs1970764 was persistent only in patients with rectal cancer (HR = 3.307 and 3.180; both P < 0.001 for RFS and DSS, respectively).

Conclusions

The present results suggest that the PPP1R13L rs1970764 variant is a possible prognostic marker for patients with rectal cancer.     

TNF superfamily gene polymorphism as prognostic factor in early breast cancer

Purpose

Since apoptosis may play a role in the prognosis of breast cancer, the present study analyzed the polymorphisms of apoptosis-related genes and their impact on the survival of 240 patients with early invasive ductal breast cancer.

Methods

The genomic DNA was extracted from paraffin-embedded tumor-free tissue or blood, and 12 single nucleotide polymorphisms (SNPs) of 11 apoptosis-related genes in the apoptosis pathway determined using a Sequenom MassARRAY system.

Results

During the median follow-up of 53.4 (range 2.9–205.9) months, 37 relapses and 22 deaths occurred. Among the target polymorphisms, the tumor necrosis factor superfamily member 10 gene polymorphism (TNFSF10 rs1131532) in a recessive model of the T allele and prostaglandin-endoperoxide synthase 2 gene polymorphism (PTGS2 rs5275) in a dominant model of the C allele were associated with survival in a log-rank test. The TT genotype of TNFSF10 (rs1131532) was also significantly correlated with a lower disease-free, distant disease-free, and overall survival in a multivariate analysis (HR = 3.304, 4.757, and 6.459; P = 0.002, 0.001, and 0.009, respectively), while PTGS2 rs5275 was only associated with a higher distant disease-free survival (HR = 0.302; P = 0.041). No clinicopathologic difference was observed according to the genotypes of these two polymorphisms.

Conclusion

The TNFSF10 (rs1131532) polymorphism was identified as a possible prognostic factor of survival in patients with operated invasive breast cancer.     

ADAM33 Gene Polymorphisms are Associated with the Risk of Idiopathic Pulmonary Fibrosis

Background

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive dyspnea and worsening lung function due to remodeling of the lung, including epithelial mesenchymal transition. ADAM33 is a disintegrin and metalloprotease domain-containing protein, which may be related to lung fibrosis by exerting angiogenesis and remodeling of the lung. Thus, we evaluated the association of single-nucleotide polymorphisms (SNPs) of ADAM33 with the risk of IPF.

Methods

A total of 237 patients with IPF and 183 healthy subjects participated in the present study. Nine polymorphisms were selected. Genotyping was performed by single-base extension. Polymorphisms and haplotypes were analyzed for associations with the risk of IPF using multiple logistic regression models controlling for age, gender, and smoking status as covariates.

Results

All SNPs were in Hardy-Weinberg equilibrium. The minor allele frequency (MAF) of rs628977G>A in intron 21 was significantly lower in subjects with surgical IPF than in normal controls in the recessive model [33.2 vs. 38.0 %, p = 0.02, OR = 0.40 (0.19–0.84)]. When the subjects with clinical IPF were included, the difference in MAF persisted with a p value of 0.03 [OR = 0.50 (0.27–0.94)].

Conclusions

ADAM33 rs628977G>A was marginally associated with a decreased risk of IPF in a recessive model.     

Angiotensin-Converting Enzyme (ACE) Gene Polymorphisms are Associated with Idiopathic Pulmonary Fibrosis

Background

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive dyspnea and worsening lung function. ACE is increased in the bronchoalveolar lavage fluid from patients with IPF, suggesting the role of ACE in the pathogenesis of IPF. We evaluated the role of single-nucleotide polymorphisms (SNPs) in the development risk of IPF.

Methods

Two-hundred twenty patients with IPF and 456 healthy subjects were included in this study. Eleven polymorphisms were selected among those reported previously. Genotype was performed by single base extension.

Results

Although absolute LD (|D′| = 1 and r ² = 1) was not present, 11 SNPs showed tight LDs. The logistic analysis of the all of 11 SNPs on the ACE genes between patients with IPF and healthy subjects were found to be related with the risk of IPF in recessive type. However, in patients with IPF diagnosed by surgical lung biopsy, only two SNP of ?5538T>C and +21288_insdel SNPs were related with the risk of IPF in co-dominant type, and there were no SNPs related with the risk of IPF in dominant type. In patients with IPF diagnosed by clinical criteria or surgical lung biopsy, four SNPs on promoter (?5538T>C, ?5508A>C, ?3927T>C, ?115T>C), one on intron (+15276A>G), one on exon (+21181G>A), and one in three prime region (+21288_insdel) were related with the risk of IPF.

Conclusions

This study showed a newly discovered SNP of ACE associated with the risk of development of IPF. ACE ?5538T>C and ?5508A>C significantly associated with risk of IPF in Korea.     

Association between survivin -31G>C polymorphism and cancer risk: meta-analysis of 29 studies

Purpose

A growing body of evidence has shown the possible relevance of survivin -31G>C (rs9904341) promoter polymorphism to the genetic susceptibility of cancer. Because of the lack of available conclusive data, we performed a meta-analysis of all relevant available studies to derive a more precise estimation of the relationship.

Methods

A comprehensive literature search of Medline electronic database was conducted to collect relevant studies until August 18, 2013. References of the retrieved articles were also screened. The extracted data were statistically analyzed, and pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated to estimate the association strength using Stata version 11.2 software.

Results

A total of 29 studies with 7,473 cancer cases and 9,086 controls were included in the meta-analysis. Overall, the pooled analysis revealed that suvivin -31G>C polymorphism was significantly associated with increased cancer risk under multiple genetic models (CC vs. GG: OR = 1.37, 95 % CI 1.06–1.76; CC vs. CG: OR = 1.27, 95 % CI = 1.10–1.46; CC vs. CG + GG: OR = 1.31, 95 % CI = 1.10–1.57). In subgroup analysis with different cancer types, the -31G>C polymorphism significantly increased the risk of colorectal, gastric, and urothelial cancers, while this SNP remarkably decreased the susceptibility to hepatocellular carcinoma. Further stratification analysis by ethnicity showed an increasing cancer risk in the Asian population (CC vs. GG: OR = 1.61, 95 % CI 1.17–2.21; CC vs. CG: OR = 1.31, 95 % CI 1.12–1.53; CC vs. CG + GG: OR = 1.43, 95 % CI 1.16–1.77) but not in Europeans.

Conclusions

The survivin -31G>C polymorphism is associated with elevated cancer risk, especially among colorectal, gastric, and urothelial cancers and Asian populations.     

Genetic polymorphisms of SCN10A are associated with functional dyspepsia in Japanese subjects

Background

Visceral sensory impulses are transmitted via C-fibers from the gastrointestinal tract to the central nervous system. The tetrodotoxinresistant (TTX-r) sodium channel, Na(V) 1.8/SNS (sensory-neuron specific), encoded by SCN10A, has been identified on C-fibers. We attempted to clarify the association between functional dyspepsia (FD) and SCN10A non-synonymous polymorphisms (2884 A>G, 3218 C>T and 3275 T>C).

Methods

The study was performed in 642 subjects (345 with no symptoms and 297 with FD). We employed a multiplex polymerase chain reaction single-strand confirmation polymorphism (PCR-SSCP) method to detect the gene polymorphisms.

Results

The 3218 CC homozygotes had a reduced risk for the development of FD [odds ratio (OR) 0.589; 95 % confidence interval (CI) 0.402–0.864; p = 0.0067]. In addition, both 2884 A>G and 3275 T>C, which were in linkage disequilibrium, were also associated with the development of FD (p = 0.039 and 0.028, respectively). Each 2884 G carrier, 3218 CC homozygote, and 3275 C carrier had a reduced risk for the development of both epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS). The subjects with the 2884 G allele, 3275 C allele, and no 3218 T allele had a reduced risk for FD (OR 0.618; 95 % CI 0.448–0.853; p = 0.0034). This haplotype was associated with a reduced risk for both EPS and PDS (p = 0.0011 and 0.0056, respectively). In addition, there was a significant association between FD and this haplotype in Helicobacter pylori-negative subjects (OR 0.463; 95 % CI 0279–0.9768; p = 0.0029).

Conclusion

We conclude that genetic polymorphisms of SCN10A are closely associated with FD (both EPS and PDS), especially in H. pylori-negative subjects, in Japanese.     

Lipiodolized transarterial chemoembolization in hepatocellular carcinoma patients after curative resection

Purpose

To explore the effect of lipiodolized transarterial chemoembolization (lip-TACE) in hepatocellular carcinoma (HCC) patients at different risk of recurrence after curative resection.

Methods

One thousand nine hundred and twenty-four consecutive HCC patients who underwent curative resection were retrospectively analyzed. Patients who underwent resection only were classified into control group, while those received adjuvant lip-TACE were classified into intervention group. Patients were further stratified into 4 groups, that is, tumor ≤5 cm with low or high risk factors, as well as tumor >5 cm with low or high risk factors for recurrence. Tumor number and microscopic tumor thrombus were defined as risk factors for recurrence. The effect of adjuvant lip-TACE on early (<2 year) or late (≥2 year) recurrence was evaluated.

Results

There was no significant difference in recurrence curve between intervention group and control group in each stratum. Adjuvant lip-TACE showed an overall survival benefit in patients with tumor >5 cm and presenting high risk factors, mainly for those with time to recurrence (TTR) <2 years after operation. For them, the median survival was 17 months in the intervention group and 11 months in the control group (P = 0.010). For patients who were confirmed to be recurrence-free at 2 years after operation, it had the negative effect for survival (HR = 1.75, P = 0.004).

Conclusion

Adjuvant lip-TACE had no preventive effect on recurrence, but may be of benefit to detect early recurrence.     

Interferon regulatory factor 5 polymorphisms in sarcoidosis

Objective

Interferon regulatory factor 5 (IRF5) gene polymorphisms are associated with susceptibility to autoimmune diseases. The aim of this study is to determine the roles of IRF5 single-nucleotide polymorphisms (SNPs) in sarcoidosis.

Methods

A total of 175 Japanese patients with biopsy-proven sarcoidosis and 150 sex-matched controls were genotyped for four IRF5 SNPs: rs729302A/C, rs2004640G/T, rs10954213A/G, and rs2280714G/A. The associations of these SNPs with susceptibility to sarcoidosis were examined.

Results

Carriage of rs10954213A and rs2280714A conferred significant risks for sarcoidosis [carriage of rs10954213A: odds ratio (OR) = 1.96, 95 % confidence interval (CI) = 1.15–3.33, P = 0.01, corrected P = 0.04; carriage of rs2280714A: OR = 1.97, 95 % CI = 1.22–3.16, P = 0.005, corrected P = 0.02]. The haplotype carrying rs10954213A and rs2280714A (haplotype 2) was significantly associated with susceptibility to sarcoidosis (OR = 2.00, 95 % CI = 1.24–3.24, P = 0.004, corrected P = 0.01). rs729302 and rs2004640 were not associated with susceptibility to sarcoidosis, whereas carriage of rs2004640G was protective against pulmonary hypertension (OR = 0.017, 95 % CI = 0.002–0.15, P < 0.001, corrected P < 0.001).

Conclusion

A haplotype carrying two functional SNPs of IRF5, rs10954213A and rs2280714A, was associated with the risk of sarcoidosis in the Japanese population.     

Relation of the Fas and FasL gene polymorphisms with susceptibility to and severity of rheumatoid arthritis

To investigate associations of the Fas and FasL genes polymorphisms with rheumatoid arthritis (RA). One hundred patients with RA and age-, sex- and ethnically matched 101 controls were included. Four polymorphisms of Fas (-670 A>G rs1800682, -1377 G>A rs2234767) and FasL (IVS2nt-124 A>G rs5030772, -844 T>C rs763110) genes were typed from genomic DNA. Genotype distributions and allelic frequencies were compared between patients and control subjects. After the history and clinical examination of patients with RA, in terms of pain, fatigue and general health status were evaluated by visual analogue scale. Thereafter, erythrocyte sedimentation rate, C-reactive protein, blood count and rheumatoid factor levels were measured. The Disease Activity Score-28, Health Assessment Questionnaire and modified Sharp score were used to evaluate the disease activity, functional disability and radiological damage, and their relationships with the Fas and FasL gene polymorphisms were investigated. In patients with RA, CT and TT genotypes of FasL-844, polymorphism were twofold and 4.8-fold higher, and AA genotype of FasL IVS2nt-124 polymorphism was 3.4-fold higher than the control group (respectively, p = 0.05, p = 0.002, p = 0.039). T allele of FasL-844 polymorphism was more frequent in patients than controls (respectively, 52.5 vs. 41.4 %, p = 0.027). Any association was not detected between Fas (-670 A>G, -1377 G>A) and FasL (-844 T>C, IVS2nt-124 A>G) gene polymorphisms with the disease activity scores, functional disability and radiological damage. However, the Fas-670 A>G polymorphism was associated with drug therapy (p = 0.049). The distribution of GG genotype was higher compared to GA or AA genotypes in patients using triple disease-modifying antirheumatic drug therapy (71.4, 14.3 and 14.3 %, respectively). These findings suggest that the -844 T>C and IVS2nt-124 A>G polymorphisms in the FasL gene related with apoptosis may increase genetic susceptibility to RA in a Turkish population. In addition, the Fas-670 A>G gene polymorphism may be associated with disease progression. There is a need for further studies to clarify the genetic role of apoptosis in RA.     

Association of a single-nucleotide polymorphism from chromosome 17q12 with the aggressiveness of prostate cancer in a Hispanic population

Purpose

To study the association between the polymorphisms, rs1859962 and rs4430796, from the chromosomes 17q24 and 17q12, respectively, with the risk of prostate cancer (PCa) and its clinical characteristics in a Hispanic (Chilean) population.

Methods

This study included 33 controls and 167 patients diagnosed with PCa. The polymorphisms, rs1859962 and rs4430796, were analyzed on blood specimens using quantitative PCR. The genetic analysis of the qPCR data was performed using the SNPStats program. A comparison between the clinical characteristics of the prostate cancers from the patients and the presence of the different polymorphism genotypes detected in blood specimens obtained from these patients was performed using the IBM SPSS v20.0 software.

Results

We observed no association of the SNPs and the risk of developing PCa (OR 0.84, 95 % CI 0.30–2.38, p = 1.0 to rs1859962 and OR 1.94, 95 % CI 0.57–6.52, p = 0.28 to rs4430796), both sporadic and hereditary. However, patients carrying the genotype G/G from the polymorphism rs4430796 had significantly higher PSA levels than patients carrying the other genotypes (15.05 ng/ml to G/G, 10 and 8.11 ng/ml to genotypes A/G y A/A, respectively, p = 0.01). Furthermore, patients with the genotype G/G of rs4430796 had higher tumor volume than other genotypes (9.45 cc to G/G and 5.22 cc to A/G + A/A, p = 0.04).

Conclusion

The polymorphism rs4430796 of the chromosome 17q12 appears to be a biomarker for cancer aggressiveness, increased PSA and tumor volume of PCa.     

Association of vitamin D serum levels and its common genetic determinants,with severity of liver fibrosis in genotype 1 chronic hepatitis C patients

Lower 25‐hydroxyvitamin D [25(OH)D] serum levels have been associated with the severity of liver fibrosis in genotype 1 chronic hepatitis C patients (G1CHC). In addition, a recent genome‐wide study identified genetic variants (rs12785878, near dehydrocholesterol reductase, DHCR7; rs10741657, near CYP2R1; and rs7041, near vitamin D‐binding protein, GC) affecting 25(OH)D serum levels in healthy populations. We aimed to assess the association between vitamin D serum levels and its genetic determinants, with the severity of liver fibrosis. Two hundred and sixty patients with biopsy‐proven G1CHC were consecutively evaluated. The 25(OH)D serum levels were measured by high‐pressure liquid chromatography. All patients were genotyped for DHCR7 rs12785878, CYP2R1 rs10741657 and GC rs7041 single nucleotide polymorphisms. DHCR7 GG genotype (P = 0.003) and the severity of fibrosis (P = 0.03) were independent factors associated with lower 25(OH)D serum levels in multiple linear regression analysis. Interestingly, 53.8% (7/13) of patients with DHCR7 GG genotype had severe liver fibrosis, compared to 27.1% (67/247) of those with DHCR7 TT/TG genotype (P = 0.03). By multivariate logistic regression analysis, severe fibrosis was independently associated with older age (OR, 1.056; 95% CI, 1.023–1.089, P = 0.001), low cholesterol (OR, 0.984; 95% CI, 0.974–0.994, P = 0.002), high triglycerides (OR, 1.008; 95% CI, 1.002–1.015, P = 0.01), low 25(OH)D (OR, 0.958; 95% CI, 0.919–0.999, P = 0.04), DHCR7 GG genotype (OR, 4.222; 95% CI, 1.106–16.120; P = 0.03), moderate–severe steatosis (OR, 2.588; 95% CI, 1.355–4.943; P = 0.004) and moderate–severe necroinflammatory activity (grading) (OR, 2.437; 95% CI, 1.307–4.763; P = 0.001). No associations were found between liver fibrosis and both CYP2R1 and GC genotypes. In patients with G1CHC, GG homozygosis for DHCR7 gene and lower 25(OH)D levels are independently associated with the severity of liver fibrosis.     

Expression of the calpain system is associated with poor clinical outcome in gastro-oesophageal adenocarcinomas

Background

Surgery is critical in the management of gastro-oesophageal cancer, and the addition of neo-adjuvant chemotherapy has proved to be of benefit. The calpain system has been implicated in tumour progression and response to various anti-cancer therapies, and therefore expression of the system was determined in this tumour type.

Methods

Two cohorts of gastro-oesophageal adenocarcinomas were investigated for calpain-1, calpain-2, calpain-9 and calpastatin expression using conventional immunohistochemistry. 88 patients who received neo-adjuvant chemotherapy and 140 patients who received surgery alone were investigated using a tissue microarray approach.

Results

Calpain-1, calpain-2 and calpastatin expression was associated with adverse cancer-specific survival in the neo-adjuvant cohort (P = 0.004, P = 0.001 and P = 0.012 respectively); which remained significant in multivariate analysis (Hazard ratio (HR) = 0.337; 95 % confidence interval (CI) = 0.140–0.81; P = 0.015, HR = 0.375; 95 % CI = 0.165–0.858; P = 0.020 and HR = 0.481; 95 % CI = 0.257–0.900; P = 0.022 respectively). Calpain-1 and calpastatin expression was also associated with adverse cancer specific survival in the primary surgery cohort (P = 0.001 and P = 0.013 respectively); which remained significant in multivariate analysis (HR = 0.309; 95 % CI = 0.159–0.601; P = 0.001 and HR = 0.418; 95 % CI = 0.205–0.850; P = 0.016 respectively). Calpain-9 expression was not associated with cancer-specific survival in the neo-adjuvant and primary surgery cohorts.

Conclusion

Determining the expression levels of calpain-1, calpain-2 and calpastatin may provide clinically relevant prognostic information for gastro-oesophageal adenocarcinomas; these findings warrant further studies in larger cohorts of patients.     

Superior long-term outcomes after surgery in child-pugh class a patients with single small hepatocellular carcinoma compared to radiofrequency ablation

Background and aims

There are insufficient data comparing long-term prognoses after radiofrequency ablation (RFA) and surgery.

Methods

We compared the baseline characteristics and survival rates of patients (single, ≤3 cm, and Child-Pugh class A) treated surgically (n = 215) and with RFA (n = 255) from January 2000 to December 2007 at our institution.

Results

The surgery group was characterized by younger age, higher prevalence of HBsAg, less cirrhosis, and an increased chance of Child-Pugh score of 5 and CLIP score of 1, compared to the RFA group. During the median follow-up period of 42 months (range 1–109), the 3-, 5- and 7-year overall survival rates in the surgery group were 98, 94, and 94%, respectively, which were significantly higher than those in the RFA group (92, 87, and 76%, respectively, P = 0.002). The 3- and 5-year recurrence-free survival rates were 72 and 66%, respectively, in the surgery group, which were significantly higher than those in the RFA group (34 and 24%, respectively, P < 0.001). The superiority of the survival rates in the surgery group persisted in most patients throughout the subgroup analysis, based on the Child-Pugh score and CLIP score. Multivariate analysis showed that age and surgery as a procedure type were the significant predictive factors for both overall survival [HR = 1.04 (CI 1.001–1.08), P = 0.047 for age; HR = 2.97 (CI 1.19–7.45), P = 0.02 for surgery] and recurrence-free survival [HR = 1.02 (CI 1.01–1.04), P = 0.01 for age; HR = 2.44 (CI 1.76–3.37), P < 0.001 for surgery].

Conclusions

The long-term outcome after surgery for Child-Pugh class A and single small HCC is superior to that after RFA.     

The Association of Genetic Variants with Hepatic Steatosis in Patients with Genotype 1 Chronic Hepatitis C Infection

Background

Single-nucleotide polymorphisms (SNPs) in the IL28B and PNPLA3 gene regions have been associated with hepatic steatosis in genotype 1 (G1) chronic HCV infection but their clinical impacts remain to be determined.

Aim

We sought to validate these associations and to explore their impact on treatment response to peginterferon and ribavirin therapy.

Methods

A total of 972 G1 HCV-infected Caucasian patients were genotyped for the SNPs rs12979860 (IL28B) and rs2896019 (PNPLA3). Multivariable analysis tested IL28B and PNPLA3 for association with the presence of any steatosis (>0 %); clinically significant steatosis (>5 %); steatosis severity (grade 0–3/4); and the interacting associations of the SNPs and hepatic steatosis to sustained viral response (SVR).

Results

IL28B and PNPLA3 polymorphisms were associated with the presence of any steatosis (rs12979860, p = 1.87 × 10^?7; rs2896019, p = 7.56 × 10^?4); clinically significant steatosis (rs12979860, p = 1.82 × 10^?3; rs2896019, p = 1.27 × 10^?4); and steatosis severity (rs12979860, p = 2.05 × 10^?8; rs2896019, p = 2.62 × 10^?6). Obesity, hypertriglyceridemia, hyperglycemia, liver fibrosis, and liver inflammation were all independently associated with worse steatosis. Hepatic steatosis was associated with lower SVR, and this effect was attenuated by IL28B. PNPLA3 had no independent association with SVR.

Conclusions

IL28B and PNPLA3 are associated with hepatic steatosis prevalence and severity in Caucasians with G1 HCV, suggesting differing potential genetic risk pathways to steatosis. IL28B attenuates the association between steatosis and SVR. Remediable metabolic risk factors remain important, independently of these polymorphisms, and remain key therapeutic goals to achieve better outcomes for patients with HCV-associated hepatic steatosis.     

Genetic polymorphisms of OCT-1 confer susceptibility to severe progression of primary biliary cirrhosis in Japanese patients

Background

To identify the genetic factors involved in the pathogenesis of primary biliary cirrhosis (PBC), we focused on the organic cation transporter 1 (OCT1/SLC22A1), which is closely associated with phosphatidylcholine synthesis in hepatocytes.

Methods

We selected four (rs683369, rs2282143, rs622342 and rs1443844) OCT-1 single nucleotide polymorphisms (SNPs), and genotyped these SNPs using the TaqMan probe method in 275 Japanese PBC patients and 194 gender-matched, healthy volunteers as controls.

Results

The Chi-square test revealed that the rs683369 variant allele (G) was associated with insusceptibility to PBC development [P = 0.009, odds ratio (OR) 0.60, 95 % confidence interval (CI) 0.40–0.88] in an allele model, and that the rs683369 variant allele (G) was associated with jaundice-type progression in a minor allele dominant genotype model (P = 0.032, OR 3.10, 95 % CI 1.05–9.14). The OCT-1 rs2282143 variant (T) and rs622342 variant (C) were also associated with jaundice-type progression in a minor allele recessive genotype model (P = 0.0002, OR 10.58, 95 % CI 2.36–47.54, and P = 0.006, OR 7.84, 95 % CI 1.39–44.36, respectively). Furthermore, the association of OCT-1 rs683369 and rs622342 with susceptibility to jaundice-type progression was confirmed by a replication study with a distinct set of PBC patients who underwent liver transplantation.

Conclusions

The present study is the first report on the association of OCT-1 genetic polymorphisms with the overall development and jaundice-type progression of PBC.