Fractal Analysis of Contrast-Enhanced CT Images to Predict Survival of Patients with Hepatocellular Carcinoma Treated with Sunitinib

Background

Intratumoral heterogeneity is a well-recognized feature of malignancy.

Aims

To assess the heterogeneity of tumor using fractal analysis of contrast-enhanced computed tomography (CE-CT) images for predicting survival of hepatocellular carcinoma (HCC) patients treated with sunitinib.

Methods

The patient cohort comprised 23 patients (19 men, 4 women; mean age 61.5 years) with HCC who underwent CE-CT at baseline and after one cycle of sunitinib. Arterial-phase (AP) and portal-phase (PP) CE-CT images were analyzed using a plugin software for ImageJ (NIH, Bethesda, MD). A differential box-counting method was employed to calculate the fractal dimension (FD) of the tumor. Tumor FD, density, and size were compared with survival.

Results

Median progression-free survival (PFS) was 4.43 months. Patients were grouped into a favorable PFS (PFS >4.43 months; 9 patients) and an unfavorable PFS group (PFS ≤4.43; 13 patients). The baseline FD on both the AP and PP images was lower in the favorable PFS group than in the unfavorable PFS group (both P = 0.03). There was a significant difference in the change of the FD on the AP image between the favorable and unfavorable PFS groups (P = 0.02). Tumor density and size showed no significant correlations with PFS. In the Kaplan–Meier analysis, patients with tumors showing lower FD on the AP image at baseline showed longer PFS (P = 0.002). Patients with tumors showing a greater reduction in the FD on the PP image after one cycle of the therapy showed longer overall survival (P = 0.002).

Conclusion

The FD of the tumor on CE-CT images may be a useful biomarker for HCC patients treated with sunitinib.     

Genetic variants of immune-related genes <Emphasis Type="Italic">IL17F</Emphasis> and <Emphasis Type="Italic">IL10</Emphasis> are associated with functional dyspepsia: A case–control study

Background

Low-grade inflammation may play an important role in pathogenesis of functional dyspepsia (FD). Since cytokines may influence gastric mucosal inflammation, which is associated with FD, we evaluated singe nucleotide polymorphisms (SNPs) of pro-inflammatory IL17F and anti-inflammatory IL10 cytokine genes in patients with FD and healthy subjects (HS).

Methods

Two hundred and thirty-seven consecutive patients with FD (Rome III) and 250 HS were genotyped for IL17F (rs2397084: A/G, rs763780: T/C) and IL10 (rs1800896: G/A, rs1800871: C/T) (PCR-RFLP).

Results

Patients with FD [173 (73%) men, age 38.4±12 years] were comparable with HS [195 (78%) men, age 37.3±12 years] with respect to age and gender. Out of 237 patients, 26 (11%) had epigastric pain, 55 (23.2%) had post-prandial distress syndromes (EPS, PDS), and 156 (65.8%) had EPS–PDS overlap. Among 237 patients with FD, GG (variant) genotype of IL17F (rs2397084) was more common than HS [15 (6.3%) vs. 4 (1.6%), p=0.015, odds ratio (OR)=4.0, 95% confidence interval (CI)=1.3–12.3]. IL17F (rs763780) and IL10 (rs1800896) were comparable among patients and HS (p=0.56, 0.28), respectively. However, TT (variant) genotype of IL10 (rs1800871) was more common among patients than HS [39 (16.5%) vs. 32 (12.8%), p=0.06, OR=1.7, 95% CI=0.98–2.98]. SNPs of IL17F and IL10 (rs2397084, rs763780, rs1800896 and rs1800871) were comparable among patients among sub-types of FD (p=0.80 and 0.44).

Conclusion

SNPs of IL17F (rs2397084) and IL10 (rs1800871) genes are associated with FD.

     

IL28B polymorphisms predict the virological response to standard therapy in patients with chronic hepatitis C virus genotype 4 infection

Background

Genome-wide association studies have recently revealed that several single-nucleotide polymorphisms (SNPs) in the interleukin (IL) 28B genes can predict the sustained virological response (SVR) to pegylated interferon-α2a/b plus ribavirin in hepatitis C virus (HCV)-genotype 1 patients. However, data for patients infected with HCV genotype 4 (HCV-G4) are limited.

Aim

We analyzed the association of IL28B SNPs (hematological, biochemical, virological, and pathological factors) with SVR in the HCV-G4 monoinfected cohort of patients.

Patients and methods

One hundred twenty-nine treatment-naïve HCV-G4 patients undergoing treatment were recruited from three tertiary care centers in Saudi Arabia. Five IL28B SNPs (rs12979860, rs12980275, rs8105790, rs8099917, and rs72486680) were identified by polymerase chain reaction and DNA sequencing. SVR was statistically correlated with various clinical, histopathological, virological, and genetic parameters.

Results

SVR was significantly associated with the CC and AA alleles of rs12979860 (p = 0.008) and rs12980275 (p = 0.004), respectively. Moreover, albumin levels (p = 0.002) and platelet count (p = 0.039) showed significant differences in the SVR and No SVR groups. On multivariate analysis, the CC allele of rs12979860 (OR, 2.89; 95 % CI 1.6–6.2, p = 0.006) and albumin levels (OR, 1.2; 95 % CI 1.1–1.4, p = 0.001) independently predicted SVR.

Conclusions

IL28B polymorphism (CC allele of rs12979860) predicts the sustained response to antiviral therapy in HCV-G4.     

Association of Genetic Variants in GNβ3 with Functional Dyspepsia: A Meta-Analysis

Background

Functional dyspepsia (FD) is a functional upper gastrointestinal disorder. The etiology and pathogenesis of FD remain unclear, with genetic factors playing an important role. Previous studies investigated the association of C825T in GNβ3 with FD, with conflicting results reported.

Aims

The aim of this meta-analysis is to assess the association of genetic variants in GNβ3 with FD.

Methods

We performed a systematic literature search in PubMed, Cochrane Library, Google Scholar, and Web of Knowledge, and conducted a meta-analysis to assess the association of C825T in GNβ3 with FD. For sensitivity analysis, we analyzed the association between C825T and subtypes of FD. We also performed meta-analyses separately for individual ethnic groups/countries of origin.

Results

A total of eight studies met the eligibility criteria and were included in our analyses. Our meta-analysis finds no association between 825CC and FD (OR 1.19, 95 % CI 0.84–1.67, p = 0.328). However, the association is significant under an additive model (OR 0.59, 95 % CI 0.38–0.92, p = 0.018). Sensitivity analysis indicated a significant association of C825T with FD in participants from Korea but not in those from Japan, Europe, or the United States. We also detected a significant association of this SNP with dysmotility.

Conclusions

The genetic variant C825T in GNβ3 is significantly associated with FD under an additive model and the association is race-specific. Further studies with larger samples sizes are needed to validate our findings and to explore the potential mechanism underlying the association.     

Genetic variation near interleukin 28B and the risk of hepatocellular carcinoma in patients with chronic hepatitis C

Background

We aimed to clarify the association between single nucleotide polymorphism (SNP) located near interleukin 28B and hepatocellular carcinoma (HCC).

Methods

A cohort comprising 792 patients treated with interferon for chronic hepatitis C was investigated. SNPs at rs8099917 and rs12979860 were determined. Cumulative incidence and HCC risk were analyzed by Kaplan–Meier and Cox proportional hazard analyses for a mean follow-up period of 4.9 years. Fibrosis progression rate (FPR) was determined in these patients with a known time of infection (n = 294).

Results

Cumulative HCC incidence was significantly higher in rs8099917 nonTT (minor homozygote or heterozygote) patients than in rs8099917 TT (major homozygote) patients (20.8 vs. 10.5 % over 10 years, logrank test, p = 0.002). This difference was notable in patients infected with genotype 1 and those treated with pegylated interferon and ribavirin. Among nonSVRs, interferon had a limited effect in suppressing alanine aminotransferase (ALT) and/or α-fetoprotein (AFP) levels in nonTT patients. The suppression of these values after interferon therapy was associated with a lower incidence of HCC. FPR were similar in TT and nonTT patients.

Conclusions

rs8099917 nonTT is related to higher HCC development in patients with HCV genotype 1 and those treated with pegylated interferon and ribavirin. Higher HCC incidence observed in nonTT patients partly results from the limited suppression of ALT and/or AFP by interferon in these patients.     

Prevalence of irritable bowel syndrome and functional dyspepsia,overlapping symptoms,and associated factors in a general population of Bangladesh

Background

This community-based survey aimed to find out the prevalence of irritable bowel syndrome (IBS), functional dyspepsia (FD), overlapping symptoms, and associated factors for overlap.

Method

By cluster sampling method, 3,000 (1,523 male) randomly selected adult subjects in the Sylhet district of Bangladesh were interviewed by a questionnaire based on ROME III criteria. Multivariate logistic regression analyses were done to find out the factors for overlap with significance level set at ≤0.05.

Results

The mean age of the study population was 33.9?±?16.4 years. Prevalence of IBS and FD and IBS-FD were 12.9 % (n?=?387), 8.3 % (n?=?249), and 3.5 % (n?=?105), respectively. Approximately 27.1 % of IBS patients and 42.1 % of FD patients had overlapping IBS-FD. The odds ratio for IBS-FD overlap was 6.3 (95 % CI, 4.8–8.4). Mean age (p?=?0.011) and epigastric pain (p?=?0.002) were more in overlap patients than FD alone, whereas epigastric pain syndrome subtype (p?<?0.009) was more prevalent in lone FD subjects. In the multivariate logistic analysis, early satiety (OR, 3.0; 95 % CI, 1.2–7.5; p?=?0.018) and epigastric pain (OR, 14.5; 95 % CI, 5.0–42.1; p?=?0.000) in FD patients appeared as independent risk factors for overlap. Bloating (p?=?0.026), <3 stools per week (p?=?0.050), abdominal pain reduced by defecation (p?=?0.002), abdominal pain severity score (p?=?0.004), and overall symptom frequency score (p?=?0.000) were more in overlap patients than IBS-alone patients. In IBS patients, bloating (OR, 3.6; CI, 2.0–6.5; p?=?0.000) was found as potential symptom associated with IBS-FD overlap.

Conclusion

FD was a less prevalent disorder than IBS in our community, and significant overlap existed between the two disorders. Early satiety, epigastric pain, and bloating were important factors associated with overlap.     

Association between genetic variants in the IRGM gene and tuberculosis in a Korean population

Purpose

To investigate immunity-related guanosine triphosphatase family M (IRGM) genetic variants associated with susceptibility to tuberculosis (TB) in a Korean population.

Methods

We conducted a prospective case–control study including 193 patients with active TB in Severance Hospital and 230 age- and sex-matched unrelated controls registered in Yonsei Cardiovascular Genome Center. Based on associations with other chronic inflammatory conditions, we analyzed the allele and genotype frequencies of rs72553867, rs10065172, and rs12654043 among patients with TB and healthy controls.

Results

The T allele of rs10065172 was significantly associated with protection against developing TB based on allele frequency [P = 0.042; odds ratio (OR) 0.75] and genotype distribution in the codominant model (P = 0.036; OR 0.73).

Conclusions

This is the first study to identify a significant association between the IRGM single-nucleotide polymorphism (SNP) rs10065172 and susceptibility to active TB disease in an Asian population. The results suggest that IRGM genetic variants could be associated with susceptibility to active TB disease in the Korean population.     

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.     

Prevalence of Fabry disease in male patients with unexplained left ventricular hypertrophy in primary cardiology practice: prospective Fabry cardiomyopathy screening study (FACSS)

Background

A number of studies have already investigated the prevalence of Fabry disease (FD) in adult patients with unexplained left ventricular hypertrophy (LVH) with rates varying from 0 % up to 12 % reflecting referral and gender bias as well as differences in diagnostic methodology. We aimed to perform a prospective screening study evaluating the prevalence of FD in male patients older than 30 years with strictly defined unexplained LVH followed by general cardiologists.

Methods

A predefined number of 100 men with unexplained LVH, defined as maximal wall thickness ≥ 13 mm, were identified during an echocardiographic examination in primary cardiology practice and screened by assessing α-galactosidase A activity in dried blood spots (DBS) or in plasma.

Results

Four men (52?±?4 years, maximal LV wall thickness 18?±?3 mm) were diagnosed with FD confirmed by enzyme analysis in leukocytes as well as by genetic analysis. Mild extracardiac manifestations of FD were present in two of them.

Conclusions

The prevalence of FD in our cohort of male patients followed in primary cardiology practice with strictly defined otherwise unexplained LVH was 4 %. We recommend systematic screening for FD in all men older than 30 years with LVH of unknown etiology even in the absence of obvious extracardiac manifestations of FD.     

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 Study of Genetic Variants in miRNAs in Patients with Inflammatory Bowel Disease: Preliminary Results

Background

Aberrant expression and structural alteration of miRNAs are considered to participate in inflammation and cancer development. It has been suggested that common single-nucleotide polymorphisms (SNPs) in miRNAs are associated with susceptibility to several human diseases.

Methods

In the present preliminary study we evaluated the associations of two SNPs (rs2910164 and rs11614913 in miR-146a and miR-196a2, respectively) with the risk of inflammatory bowel disease (IBD) in a Greek population.

Results

The rs2910164 and rs11614913 SNPs were genotyped in 242 patients with Crohn’s disease (CD), 210 patients with ulcerative colitis (UC) and 300 healthy individuals. No statistically significant differences were found in the genotype or allele distributions of the rs2910164 SNP among UC and control subjects. However, significant differences were found in the genotype or allele distributions of the rs2910164 polymorphism among CD and control subjects (P < 0.0001 and P < 0.0001, respectively). Concerning the rs11614913, no statistically significant differences were found in the genotype or allele distributions among CD and control patients, whereas TT genotype and T allele seem to have a protective role against UC (P = 0.017 and P = 0.007, respectively). The presence of rs2910164 and rs11614913 SNPs did not influence disease phenotype.

Conclusions

Our results demonstrate that the rs2910164 polymorphism has a major role in genetic susceptibility to CD but not to UC, since the rs11614913 polymorphism had a protective role against UC, at least in the population studied here. Independent studies are needed to validate our findings in larger series and in patients of different ethnic origins.     

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.     

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.     

The impact of patatin-like phospholipase domain-containing protein 3 polymorphism on hepatocellular carcinoma prognosis

Background

The single nucleotide polymorphism (SNP) rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3) is associated with hepatic fat accumulation and disease progression in patients with non-alcoholic fatty liver disease and alcoholic liver disease (ALD). This study was conducted to determine whether PNPLA3 rs738409 SNPs affect development and prognosis of hepatocellular carcinoma (HCC) in patients with various liver diseases.

Methods

We enrolled 638 consecutive Japanese patients newly diagnosed with HCC between 2001 and 2010: 72 patients with hepatitis B virus (HBV), 462 with hepatitis C virus (HCV), and 104 with non-B non-C (NBNC).

Results

NBNC patients exhibited large tumors of advanced TNM stages at HCC diagnosis, and had significantly poorer prognosis than HBV or HCV patients (P < 0.001 and <0.001, respectively; log-rank test). The G/G genotype of PNPLA3 rs738409 SNP had significantly higher distribution in NBNC patients (P < 0.001) and was significantly associated with higher body mass index (BMI) and an increased aspartate aminotransferase to platelet ratio index. No significant differences were observed in survival with differences in PNPLA3 SNP genotypes among the patients, although ALD patients with the G/G genotype of PNPLA3 SNP and low BMI had significantly poorer survival than those with high BMI (P = 0.028).

Conclusions

The G/G genotype of PNPLA3 rs738409 SNP was more frequently distributed, and associated with BMI and fibrosis among NBNC-HCC patients but not among HBV or HCV patients. These genotypes might affect HCC prognosis in ALD patients, but not in HBV, HCV, or NAFLD patients.     

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.     

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.     

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 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.     

Common genetic variants in selected Ca2+ signaling genes and the risk of appropriate ICD interventions in patients with heart failure

Purpose

Defective Ca²⁺ handling in failing cardiomyocites predisposes patients with heart failure (HF) to ventricular arrhythmia. We investigated whether gene variants of Ca²⁺ handling proteins are associated with the occurrence of ventricular tachycardia/fibrillation (VT/VF) in HF patients implanted with a primary prevention implantable cardioverter-defibrillator (ICD).

Methods

One hundred thirty-six patients with HF were followed from ICD implantation to the time of first appropriate ICD intervention for VT?>?170 bpm. The following polymorphisms were genotyped: ATP2A2 rs1860561 and rs56243033; RYR2 rs4142933; CASQ2 rs4074536; SLC8A1 g.-23449C?>?A; PLN rs12198461; FKBP1B rs7568163. Hazard ratios (HR) were derived from Cox proportional-hazards regression analysis.

Results

After a mean follow-up of 879 days (IQ range, 327 to 1,459), 34 patients (25 %) had appropriate ICD intervention. Non-sustained VT (HR, 2.12; 95 %CI, 0.87–5.19; p?=?0.09) and atrial fibrillation (AF) at ICD implantation (HR, 2.33; 95 %CI, 0.89–6.10; p?=?0.08) predicted appropriate ICD interventions with borderline statistical significance. Prevalence of ATP2A2 rs1860561 variant was 17 % in patients without VT/VF and 4 % in those with ventricular arrhythmia (p?=?0.009). After adjustment for AF and NSVT, the rs1860561 A mutant allele independently predicted lower incidence of VT/VF (HR, 0.29; 95 %CI, 0.09–0.98; p?=?0.04).

Conclusions

The observation that ATP2A2 rs1860561 gene variant associated with lower risk of life-threatening arrhythmia in HF patients suggests that selected calcium gene variants may modify the risk of SD even within the complex and polygenic pathological condition of HF. Combining traditional risk factors and genetic profiling could reveal helpful to identify HF patients who will benefit most from ICD implantation.     

Genetic Variants of Peroxisome Proliferator-Activated Receptor δ Are Associated with Gastric Cancer

Background

Peroxisome proliferator-activated receptors (PPAR) are implicated in pathogenesis of insulin resistance and cancers of the digestive system.

Aim

We investigated the associations of single nucleotide polymorphisms (SNPs) of PPAR δ and γ with gastric cancer and explored interactions with risk factors of gastric cancer.

Methods

We conducted our analysis in a case–control study of 196 gastric cancer patients and 397 controls residing in the Taixing region of Jiangsu, China. Six SNPs in the PPARδ (rs2076167, rs3734254) and PPARγ genes (rs10865710, rs1801282, rs3856806, rs13306747) were genotyped. We employed logistic regression to evaluate the association between each genotype and gastric cancer and tested for gene–environment interaction with Helicobacter pylori (H. pylori) infection, smoking status, and meat and salt intake.

Results

We found that the G/G variant rs2076167, in tight linkage disequilibrium with rs3734254 (R ² = 0.97), was associated with increased risk of gastric cancer in a recessive model (OR 2.20, 95 % CI 1.12, 4.32). The association between G/G variant of rs2016167 and gastric cancer was particularly strong among those with higher salt intake (OR 5.11, 95 % CI 1.11, 23.5), but did not vary by H. pylori infection or smoking status.

Conclusion

We found that genetic variants of PPARδ were associated with gastric cancer. If the association is confirmed in larger studies, it may implicate a role for PPARδ activators, such as insulin-sensitizing agents, in prevention of gastric cancer.