The –553 T/A polymorphism in the promoter region of the FGF2 gene is associated with increased breast cancer risk in Polish women

Introduction

Fibroblast growth factor-2 (FGF2) is an important signalling molecule contributing to angiogenesis, tumour growth and progression and its expression is implicated in breast cancer (BC) development. We investigated whether –553 T/A FGF2 gene polymorphism is associated with the risk and progression of BC in Polish women.

Material and methods

The –553 T/A polymorphism was genotyped in 230 breast cancer patients and 245 control subjects, using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) approach. Moreover, FastQuant human angiogenesis array was used to measure FGF2 levels in tumour (n = 127) and serum (n = 76) samples.

Results

The T/A genotypes (OR = 2.12, 95% CI: 1.20–3.74) (p = 0.08) and the combined heterozygotes T/A and homozygote A/A (OR = 2.18, 95% CI: 1.24–3.83) (p = 0.006) had an increased risk of BC. The median FGF2 levels in the tumours of A allele carriers were significantly increased compared to T/T patients, whereas in serum FGF2 levels were hardly altered among different genotype carriers. Significantly higher frequency of A allele was found in patients with lymph node metastases (OR = 2.53; 95% CI: 1.23–5.17) (p = 0.009) and human epidermal growth factor receptor 2 positive tumour (OR = 3.22, 95% CI: 1.49–6.99) (p = 0.002). Furthermore, Kaplan-Meier survival analysis showed that the A allele predicted worse disease-free survival (DFS) in BC patients.

Conclusions

Our study shows for the first time that the –553 T/A FGF2 gene polymorphism may be associated with a risk of BC developing and progression in Polish women and may have prognostic value for the assessment of BC high-risk groups.     

The -308 G/A polymorphism in TNF-α gene is associated with asthma risk: an update by meta-analysis

Background  

The −308 G/A polymorphism in TNF-α gene has been extensively investigated for association to asthma; however, results of different studies have been inconsistent. The aim of this study is to comprehensively evaluate the genetic risk of −308 G/A polymorphism in TNF-α gene for asthma.     

IL-10 promoter -1082 polymorphism is associated with elevated IL-10 levels in control subjects but does not explain elevated plasma IL-10 observed in Sjögren's syndrome in a Hungarian cohort

The aim of this study was to investigate the frequency of the −1082 polymorphism of the interleukin-10 (IL-10) gene and the soluble IL-10 levels in Hungarian primary Sjögren's syndrome (SS) patients. Ninety-nine SS patients and 135 healthy volunteers were examined. Samples were analysed by the PCR restriction fragment length polymorphism method, and IL-10 plasma levels were assesed by a commercial enzyme-linked immunosorbent assay. IL-10 plasma levels were higher in the primary SS patients (36.4 ± 57.5 pg/ml, n = 99) compared with the healthy subjects (9.9 ± 20.3 pg/ml, n = 135, P = 10⁻⁶). The elevated IL-10 phenotype of SS patients was not associated with increased G allele frequency as reported earlier, while in the control group, we found higher IL-10 levels among the subjects who were carriers of the GG genotype (17.7 ± 23.2 pg/ml) as compared with the other two genotype carriers (AA 8.98 ± 16.5 and GA 8.5 ± 21.1 pg/ml, P = 0.01). Our data do not support previous observations indicating an association between deregulated IL-10 secretion in SS and higher G allele frequency. However, the results clearly demonstrate that GG homozygosity is associated with elevated IL-10 levels in apparently healthy subjects, but this cannot account for the IL-10-related specific disease features observed in SS. Thus, other genetic factors contribute to the clinical spectrum of this heterogeneous disease at least in the Hungarian population.     

Lifestyle influences on the association between pre-diagnostic hormone replacement therapy and breast cancer prognosis—Results from The Danish ‘Diet,Cancer and Health’ prospective cohort

ObjectivesThe association between pre-diagnostic hormone replacement therapy (HRT) and breast cancer specific mortality as well as potential influences from other lifestyle factors on the association was investigated.Study designFemale participants from the prospective cohort “Diet, Cancer, and Health” diagnosed with breast cancer (BC) were identified and their pre-diagnostic HRT use evaluated for association with tumour biology and breast cancer outcome in multivariate analysis.Main outcome measureBreast cancer specific mortality.ResultsOf the 1212 patients originally considered 1064 were included. Of these, 105 women died from breast cancer during a median follow-up of 6.3 years (range 0.2–14.3 years). In multivariate analyses women who used HRT at enrolment into the cohort study had 47% lower risk of dying from breast cancer as compared to women who had previously or never used HRT (adjusted HR: 0.53; 95% CI, 0.37–0.85). Pre-diagnostic HRT use was associated with smaller tumour size at the time of diagnosis and a higher frequency of receptor positive breast cancer. Paradoxically, a high pre-diagnostic intake of vitamin D supplements was associated with HRT use but also with a higher BC specific mortality (HR: 1.47; 95% CI, 1.07–2.00)ConclusionsHRT use at enrolment was associated with breast tumours of smaller size at the time of diagnosis and positive receptor status, and with a lower BC mortality. The found association between vitamin D from supplements and higher BC mortality warrants further exploration.     

Gastritis cystica profunda is associated with aberrant p53 and Epstein–Barr virus in gastric cancer: A clinicopathological,immunohistochemical and in situ hybridization study

Gastritis cystica profunda (GCP) is a lesion characterized by cystic gastric glands within the submucosa. Some studies have reported that GCP is a precancerous lesion. Here, we investigated the association between GCP and gastric cancer. Gastric cancer specimens were taken from 1432 patients undergoing surgery or endoscopic submucosal resection and were classified as GCP or non-GCP. The clinicopathological features, immunohistochemistry and in situ hybridization expression of p53, Ki-67, KCNE2, Epstein–Barr virus (EBV) and programmed death ligand 1 (PD-L1) were compared between the two groups, as well as between GCPs and normal pyloric glands. One hundred and eighty patients (12.6%) had GCPs. In the GCP group, no cancerous lesions were found within the GCPs, but 13% were linked to GCPs and 60.2% were located above or near GCPs. Aberrant p53 expression, EBV-positive cancer cells and PD-L1 scores were significantly higher in the GCP group. The p53 score and Ki-67 labelling index were significantly higher and the KCNE2 score was significantly lower in GCPs than in pyloric glands. Although we suggest GCP is paracancerous, GCP has high proliferation activity and gastric cancer with GCP is associated with aberrant p53 and EBV. GCP is associated with aberrant p53 expression and EBV.     

The substantia nigra pars compacta of the Göttingen minipig: an anatomical and stereological study

Parkinson disease (PD) is a neurodegenerative disorder resulting from progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Despite advances in medical and surgical therapies, many PD patients experience progression of their symptoms and medical side effects over time. To explore new treatments, new animal models mimicking the progressive PD nature are needed. The pig is well suited for this purpose with its large gyrated brain, sensitive to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The objective of this study was to provide the anatomical foundation for such a model, describing in detail the SNc in normal Göttingen minipigs and estimating the volume and total number of tyrosine hydroxylase (TH)-positive neurons. The brain stems of 6 Göttingen minipigs were paraffin embedded and serially cut before Nissl staining and immunohistochemical visualization of TH. The volume of the SNc and the total number of TH-positive neurons were estimated by design-based stereology. The substantia nigra was located at the dorsal rim of the crus cerebri extending throughout the mesencephalon. A dorsal pars compacta and a ventral pars reticulata were demonstrated. The SNc merged with the ventral tegmental area medially and the retro-rubral field dorsocaudolaterally. The total number of TH-positive neurons in the SNc unilaterally was estimated to 80,700 [74,100;87,300], and the volume estimate was 26.4 mm³ [25.0;27.8]. We conclude that the anatomy of the SNc in the Göttingen minipig corresponds well with that of higher primates, and is well suited for further studies aimed at optimizing this non-primate large animal model for PD.     

Is BDNF‐Val66Met polymorphism associated with psychotic experiences and psychotic disorder outcome? Evidence from a 6 years prospective population‐based cohort study

There is little research on genetic risk for the extended psychosis phenotype ranging from psychotic experiences (PEs) to psychotic disorders (PDs). In this general population‐based prospective cohort study, the longitudinal associations between BDNF‐Val66Met polymorphism and the different levels of the extended psychosis phenotype were investigated. Addresses were contacted in a multistage clustered probability sampling frame covering 11 districts and 302 neighborhoods at baseline (n = 4011). A nested case‐control study (n = 366) recruited individuals with PEs and PDs as well as individuals with no psychotic symptoms. In this subgroup, blood sampling for genetic analysis and assessment of environmental exposures were carried out, followed by clinical re‐appraisal at follow‐up 6 years later (n = 254). The BDNF‐Val66Met polymorphism was significantly associated with the extended psychosis phenotype. The pattern of the association was that the BDNF‐Val66Met polymorphism impacted in a dose‐response but extra‐linear fashion, with stronger impact at the PD end of the extended psychosis phenotype. Associations were still significant after adjusting for sociodemographic factors and environmental exposures including life events, childhood adversity, socioeconomic status, urbanicity, and cannabis use. The BDNF‐Val66Met polymorphism may index susceptibility to expression of psychosis along a spectrum.     

The association of an adenine insertion variant in the 5’UTR of the endothelin-1 gene with hypertension and orthostatic hypotension

Introduction

An adenine insertion polymorphism in the 5’ untranslated region of the endothelin-1 gene is functional and increases the expression of endothelin mRNA and protein in the insertion homozygote. In the present study we hypothesized that this functional polymorphism might be associated with hypertension and/or orthostatic hypotension.

Material and methods

The adenine insertion polymorphism was genotyped in 381 untreated hypertensive patients and 298 normotensive subjects, all of whom underwent an upright posture study for orthostatic blood pressure measurements. Orthostatic hypotension was defined as a drop in blood pressure of 20/10 mm Hg or more within 3 min of assuming the upright posture.

Results

The allele frequency of the adenine insertion was similar in hypertensive and normotensive subjects (15.2% vs. 15.3%, p > 0.05). After adjustment for age, sex and body mass index, blood pressure levels did not differ significantly among the genotypes in both hypertensives and normotensives. No associations were found between the distribution of the adenine insertion genotypes and the risk of orthostatic hypotension in both hypertensive patients and normotensive subjects even after adjustment for demographic parameters and supine systolic or diastolic blood pressure. Neither hypertensive nor normotensive subjects showed significant differences in orthostatic systolic or diastolic blood pressure changes among the genotype groups (all p > 0.05).

Conclusions

We concluded that the functional adenine insertion polymorphism in the endothelin-1 gene is not associated with either hypertension or orthostatic hypotension risk in Chinese.     

The single nucleotide polymorphism −1131T>C in the apolipoprotein A5 (APOA5) gene is associated with elevated triglycerides in patients with hyperlipidemia

The –1131T>C polymorphism in the newly identified apolipoprotein A5 (APOA5) gene has been associated with elevated plasma triglycerides. We determined its incidence in 915 patients attending a lipid outpatient clinic. The frequency of the C allele was significantly higher in patients with triglycerides above the 90th percentile and patients with type III hyperlipidemia compared to those with hypercholesterolemia. The C allele was associated with increased plasma triglycerides and decreased plasma HDL cholesterol, conditions associated with an increased risk of coronary heart disease. The effects on plasma lipids were only observed in overweight (BMI>25) patients and were greater in patients who were also carriers of a least one 4 allele in the APOE gene. Thus additional genetic and/or metabolic factors are required in order for the triglyceride raising and HDL lowering effect of the –1131T>C polymorphism in APOA5 to be expressed.Abbreviations APO Apolipoprotein - BMI Body mass index - DM 2 Diabetes mellitus type 2 - HDL High-density lipoprotein - HLP Hyperlipidemia - LPL Lipoprotein lipase - SNP Single nucleotide polymorphism     

Coping with unfair treatment at work--what is the relationship between coping and hypertension in middle-aged men and Women? An epidemiological study of working men and women in Stockholm (the WOLF study)

BACKGROUND: An important hypothesis in psychosomatic medicine is that exposure to psychosocial factors that arouse anger may accelerate the onset of hypertension, particularly if the subject is not allowed to show anger or to deal constructively with the factor that evoked it. For working men and women, being treated in an unfair way at work may be crucial. The present study was designed to answer the question whether the pattern of coping - primarily directed towards the aggressor (open) or directed inwards or towards others (covert) - is associated with hypertension among working men and women. STUDY GROUP: Five thousand seven hundred and twenty working men and women aged 15-64 participated in the study. The participation rate was 76%. METHODS: The coping pattern was studied by means of a Swedish version of a self-administered questionnaire that was originally introduced by Harburg et al. RESULTS: Significant results were confined to the age group 45-54. All analyses were adjusted for age and body mass index. Smoking habits and social class had no effect on the relationships. Low scores (lowest quartile) for open coping tended to be associated with an elevated prevalence ratio (PR) of hypertension both among men (PR 1.3, 95% confidence interval, CI, 0.9-1.7) and women (PR 1.4, 95% CI 1.0-2.0). High scores for covert coping (highest quartile) were associated with an elevated PR of hypertension among men (PR 1.6, 95% CI 1.2-2.2) but not in women. If the analysis was confined to cases without medication, the relationship between a high level of covert coping and high blood pressure was still significant for men. For women, however, no significant findings were made after this operation. Accordingly, the relationship between a low level of open coping and hypertension in women was confined to women with medication. Coping patterns were correlated with psychosocial work environment factors, in particular decision latitude. CONCLUSION: In men, covert coping was associated with prevalence of hypertension. In women, there tended to be a relationship between low scores for open coping and hypertension.     

Obesity is associated with the Arg389Gly ADRB1 but not with the Trp64Arg ADRB3 polymorphism in children from San Luis Potosí and León,México

This research was designed to analyze the possible associations of Arg389Gly ADRB1 and Trp64Arg ADRB3 polymorphisms in children with obesity. A cross-sectional study included 1,046 school-age Mexican participants (6-12 years old) from the cities of San Luis Potosí and León. Children were classified as non-obese or obese according to their body mass index (BMI) percentile; obese children had a BMI≥95th percentile for sex and age. Biochemical data were collected. Polymorphisms were detected using TaqMan qPCR assay. A logistic regression analysis was used to calculate the risk of obesity based on genotypes. Differences were found between groups where obese children had a significant increase in systolic and diastolic blood pressure, fasting plasma glucose, insulin, HOMAIR, LDL-cholesterol, triglycerides, and lower HDL-cholesterol compared with the normal weight group (P < 0.05).The distribution of allele frequency in the population was Arg = 87.4 and Gly = 12.6 (Hardy Weinberg equilibrium c2 = 3.16 , P = 0.07 ); Trp = 81.5 and Arg = 18.5 (Hardy Weinberg equilibrium c2 = 2.2, P = 0.14 ) for ADRB1 and ADRB3, respectively. Even though no different frequencies of Arg389Gly polymorphism between groups were found (P = 0.08), children carriers of one Gly389 ADRB1 allele had a risk for obesity of OR = 1.40 (95%CI, 1.03–1.90, P = 0.03) after adjustment for age and gender. No other association was found for Trp64Arg ADRB3 polymorphism. Only the Arg389Gly ADRB1 polymorphism was associated with risk for obesity in Mexican children.     

The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor γ2 gene is not associated with postprandial responses to glucose or fat tolerance tests in young healthy subjects: the European Atherosclerosis Research Study II

This study investigated whether the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma2 (PPARgamma2) gene is associated with glucose and lipid metabolism in young healthy subjects participating in the European Atherosclerosis Research Study II. Men aged 18-28 years (n=675) were recruited from 14 university student populations in 11 European countries. At their first visit subjects had an oral glucose tolerance test and 1 week later an oral fat tolerance test. Lipid variables and genotype were measured centrally. The Ala allele frequency exhibited a clearcut north-to-south gradient through Europe, decreasing from 0.21 in Baltic countries to 0.07 in Mediterranean countries. There was no significant effect of the Pro12Ala polymorphism on fasting lipid, glucose, or insulin levels, nor on the postprandial changes in these variables after glucose and fat tolerance tests. Neither was the Pro12Ala polymorphism associated with body mass index. This study provides no evidence for a major effect of the Pro12Ala polymorphism on glucose and lipid metabolism in young healthy subjects. Since PPARgamma has a major role in adipogenesis, the differential effect of its polymorphism on weight and related metabolic disorders may become apparent only later in life.     

The single nucleotide polymorphism (SNP) of the estrogen receptor-β gene,rs1256049, is associated with knee osteoarthritis in Korean population

BackgroundEstrogens affect articular cartilage metabolism via estrogen receptors (ER) in chondrocytes and are believed to play an important role in the pathophysiology of osteoarthritis (OA). The aim of this study is to determine whether the single nucleotide polymorphism (SNP) of the estrogen receptor-β (ER-β) is associated with an increased susceptibility to knee OA.MethodsThe possible influence of the SNP of the ER-β was investigated in 286 OA patients and 294 healthy subjects as controls. A polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) assay and a PCR-single strand conformation polymorphism (SSCP) assay were used to identify the Rsa polymorphism genotype among healthy controls and OA patients, respectively.ResultsFor rs1256049 (Rsa), frequencies of genotypes GG, GA, and AA were 49.0% (144/294), 43.5% (128/294), and 7.5% (22/294) in healthy controls, and 35.3% (101/286), 45.5% (130/286), and 19.2% (55/286) in OA patients. Frequencies of alleles G and A among healthy controls were 70.7% (416/588) and 29.3% (172/588); whereas those among OA patients were 58.0% (332/572) and 42.0% (240/572). Statistically significant differences in allele and genotype frequencies of rs1256049 were observed between OA patients and controls (P < 0.0001). In particular, the risk of OA was significantly increased in carriers with the rs1256049A allele and rs1256049 AA homozygotes.ConclusionsThese results suggest a close association of rs1256049 ER-β polymorphisms with susceptibility to OA in the Korean population.Clinical relevanceThe rs1256049 polymorphism of the estrogen receptor-β gene can potentially be used to identify genetically high-risk subgroup of osteoarthritis in advance and to understand pathogenesis of osteoarthritis.     

Cardiac complications associated with trastuzumab in the setting of adjuvant chemotherapy for breast cancer overexpressing human epidermal growth factor receptor type 2 – a prospective study

Introduction

Trastuzumab, a recombinant humanized monoclonal antibody, is targeted against the external domain of the human epidermal growth factor receptor type 2 (HER2). It improves efficacy of HER2-positive breast cancer treatment. The authors present their experience with patients (pts) treated with trastuzumab in the aspects of cardiac complications.

Material and methods

We observed prospectively 253 women with early positive HER2 breast cancer treated with trastuzumab. Assessment of cardiovascular status, ECG and echocardiography was performed initially and every 3 months until 6^th month during follow-up.

Results

Cardiac complications developed in 52 pts (20.55%) and included: asymptomatic left ventricle dysfunction (43), symptomatic heart failure (6), new asymptomatic LBBB (1); new negative T-waves in ECG (2). There was a progressive decline in left ventricular ejection fraction (LVEF) during treatment. It was more enhanced in pts with cardiac complications. Following trastuzumab termination/discontinuation LVEF increased but at month 18 still remained significantly lower than initially in both groups (61.07 ±4.84 vs. 59.97 ±5.23 – no cardiac complications; p < 0.05; 58.14 ±4.08% vs. 53.08 ±5.74% – cardiac complications; p < 0.05). During 6-month follow-up 33 out of 46 pts experienced an improvement in left ventricular status. In 13 pts in whom trastuzumab was discontinued, it was restarted; 6 of them successfully completed total therapy. Univariate analysis revealed no association between any cardiovascular risk factor and the development of cardiotoxicity.

Conclusions

One out of five treated patients discontinues trastuzumab in an adjuvant setting due to cardiac complications. LV dysfunction is the most frequent. Routine cardiac monitoring should be obligatory.     

Sleeping problems as a risk factor for subsequent musculoskeletal pain and the role of job strain: Results from a one-year follow-up of the Malmö shoulder neck study cohort

Background: The role of sleeping problems in the causal pathway between job strain and musculoskeletal pain is not clear.Purpose: To investigate the impact of sleeping problems and job strain on the one-year risk for neck, shoulder, and lumbar pain.Method: A prospective study, using self-administered questionnaires, of a healthy cohort of 4,140 vocationally active persons ages 45–64, residing in the city of Malmö.Results: At follow-up, 11.8% of the men and 14.8% of the women had developed pain. The odds ratios (OR) for pain at follow-up and sleeping problems at baseline were 1.72 (95% CI: 1.13–2.61) in men and 1.91 (1.35–2.70) in women. Regarding exposure to job strain, ORs were 1.39 (0.94–2.05) for men and 1.63 (1.18–2.23) for women. These statistically significant risks remained so when controlled for possible confounding. A modest synergistic effect was noted in women with concurrent sleeping problems and job strain, but not in men.Conclusion: One in 15–20 of all new cases of chronic pain in the population could be attributed to sleeping problems. No evidence was found for a causal chain with job strain leading to musculoskeletal pain by the pathway of sleeping problems.