The relationship between PNP, GSTO-1, AS3MT and ADRB3 gene polymorphisms and urinary arsenic concentration among copper smelter and refinery employers.

INTRODUCTION: The aim of this study was to assess the relationship between polymorphisms of genes encoding enzymes involved in arsenic metabolism and urinary arsenic concentration in people occupationally exposed to arsenic. MATERIALS AND METHODS: The data from 113 employers directly exposed to lead, cadmium, and arsenic in copper smelter in Legnica and Glogow were collected. Urinary arsenic concentration was measured. In addition, blood level of cadmium, lead, and zinc protoporphyrins was assayed. Genetic analyses included polymorphism of PNP (rs 1130650), GSTO-1 (rs 4925), AS3MT (rs 11191439), and ADRB3 (rs4994) genes. RESULTS: Individuals occupationally exposed to arsenic compounds, who have allele T in homozygous constellation in locus rs 1130650 of PNP gene, are predisposed to lower urinary arsenic concentration, while AA homozygosity in locus rs 4925 of GSTO-1 gene may result in statistically significant higher urinary arsenic concentration. Polymorphisms of AS3MT and ADRB3 genes showed no statistically significant correlation with urinary arsenic, however, there was a tendency to higher arsenic concentration in allele A carriers in locus rs4994 of ADRB3 gene and in allele T carriers in rs 11191439 of AS3MT gene. CONCLUSION: This study indicates that arsenic absorption and metabolism depend on polymorphisms of genes encoding PNP and GSTO-1. Individuals with disadvantageous constellation of polymorphisms are more susceptible to harmful effects of arsenic exposure.

The PTPN13 Y2081D (T>G) (rs989902) polymorphism is associated with an increased risk of sporadic colorectal cancer.

AIM: Colorectal cancer (CRC) is one of the most common cancers worldwide and, although the majority of cases are sporadic, its development and progression depends on a range of factors: environmental, genetic and epigenetic. A variety of genetic pathways have been described as being crucial in CRC, including protein tyrosine phosphatases (PTPs). PTPN13 (also called FAP-1) is a non-receptor PTP and interacts with a number of important components of growth and apoptosis pathways. It is also involved in the inhibition of Fas-induced apoptosis. METHOD: The single nucleotide polymorphism genotype at Y2081D (T>G) (rs989902) of PTPN13 exon 39 was determined in DNA extracted from blood samples from 174 sporadic CRC patients and 176 healthy individuals. Also, a meta-analysis was performed based on three articles accessed via the PubMed and ResearchGate databases. RESULTS: The risk of CRC was 2.087 times greater for patients with the GG genotype than for those with the TT genotype (P = 0.0475). In the meta-analysis, a significantly increased risk of cancer associated with the G allele was observed in the squamous cell carcinoma of the head and neck subgroup (TT vs GG+GT, OR 1.23, 95% CI [1.02, 1.47], P = 0.0258), and a significantly decreased risk in the breast cancer subgroup (TT vs GG+GT, OR 0.63, 95% CI [0.41, 0.96], P = 0.0334) and in the CRC subgroup (GT+TT vs GG, OR 0.51, 95% CI [0.41, 0.95], P = 0.0333). CONCLUSION: PTPN13 rs989902 is significantly associated with the risk of CRC in the Polish population. Given that this report provides the first evidence of an association of PTPN13 rs989902 with the risk of CRC in a Caucasian population, further large scale studies are necessary to confirm this finding.

Growth Hormone Treatment Increases Plasma Irisin Concentration in Patients with Turner Syndrome.

Irisin (Ir) deficiency may be a contributing factor in metabolic disease. This study aimed to investigate the effect of supraphysiological doses of recombinant human growth hormone (rhGH) on Ir plasma concentration in relation to metabolic disorders, including obesity and other components of metabolic syndrome. We studied 36 girls with Turner syndrome (mean age 8.2 years) treated with rhGH (0.05 mg/kg/day). Anthropometric data and fasting blood levels [e. g., Ir, insulin, glucose, glycated hemoglobin (HbA1c), IGF-1, IGFBP-3, cholesterol, insulin resistance (HOMA-IR), and ß-cell function (HOMA-ß)] were analyzed prior to and following rhGH therapy [mean (SD) follow-up of 1.47 (0.89) years]. Insulin sensitivity (Matsuda index) was calculated before and after the glucose load. Following rhGH therapy, an increase in IGF-1 [mean (SD) of 119.40 (62.47) ng/ml to 439.08 (209.91) ng/ml, p=0.000], Ir [2.10 (1.03) µg/ml to 2.48 (0.78) µg/ml, p=0.036], HOMA-IR [median (IQR) of 0.64 (0.45-1.30) to 0.92 (0.67-2.36), p=0.0206], and HOMA-ß values [45.00 (27.69-72.00) to 81.53 (51.43-132.00), p=0.0447] were observed. Multiple regression analysis yielded no associations between Ir and metabolic and hormonal parameters before rhGH treatment; however, on rhGH, the model (R2=0.56, adjusted R2=0.45) showed positive associations between Ir and IGF-1 standard deviation score and HbA1c, and negative associations between Ir and fasting blood glucose, HDL-cholesterol, and triglycerides. Despite manifestation of insulin resistance, rhGH application had a positive effect on Ir regulation, and restored physiological conditions of lipid and glucose metabolism.

Impact of the PPARGC1A Gly482Ser polymorphism on left ventricular structural and functional abnormalities in patients with hypertension.

The Gly482Ser polymorphism in the peroxisome proliferator-activated receptor gamma coactivator-1α (PPARGC1A) has been reported to contribute to the development of left ventricular (LV) hypertrophy. Little is known, however, about its possible impact on cardiac dysfunction. Enhanced myocardial fibrosis accompanying increased LV mass might represent a link with coexisting functional abnormalities. We investigated the association between the PPARGC1A Gly482Ser polymorphism and LV morphology and performance in essential hypertension, with special consideration of fibrosis intensity. A total of 205 hypertensive patients (60±8 years) underwent echocardiography with assessment of cardiac morphology, LV systolic (strain and strain rate) and diastolic function (peak early diastolic mitral flow velocity/peak late diastolic mitral flow velocity (E/A) ratio, peak early diastolic myocardial velocity (Em), and E/e' ratio (where e' is the peak early diastolic mitral annular velocity)), evaluation of serum procollagen type III amino-terminal propeptide (PIIINP) and procollagen type I carboxy-terminal propeptide (PICP)-markers of fibrosis and the PPARGC1A Gly482Ser genotyping. Subjects with the Ser-Ser genotype demonstrated more profound LV hypertrophy and diastolic function impairment, and higher PICP/PIIINP than the Ser-Gly and Gly-Gly groups. In multivariable analysis, the presence of the Ser-Ser allele was an independent correlate of E/e' (ß=0.17, P<0.02), Em (ß=-0.18, P<0.01) and LV mass index (ß=0.28, P<0.001). In conclusion, in hypertensive patients, the PPARGC1A Gly482Ser polymorphism is associated with LV hypertrophy and diastolic dysfunction, with the presence of the Ser-Ser allele promoting these abnormalities. One of the possible mechanisms mediating the adverse effect on diastolic performance might be a relative increase in the anabolism of rigid collagen type I over that of the more elastic collagen type III, as indicated by an increased ratio of PICP to PIIINP.

Normal exon copy number of the GLI2 and GLI3 genes in patients with esophageal atresia.

Esophageal atresia (EA) is a congenital developmental defect of the alimentary tract concerning the interruption of the esophagus with or without connection to the trachea. The incidence of EA is 1 in 3000-3500 of live-born infants, and occurs in both isolated and syndromic (in combination with abnormalities in other organ systems) forms. The molecular mechanisms underlying the development of EA are poorly understood. Knockout studies in mice indicate that genes like Sonic hedgehog, Gli2, and Gli3 play a role in the etiology of EA. These facts led us to hypothesize that Sonic hedgehog-GLI gene rearrangements are associated with EA in humans. To test this hypothesis, we screened patients with isolated and syndromic EA for GLI2 and/or GLI3 microrearrangements using methods to estimate the copy number (Multiplex Ligation-dependent Probe Amplification, real-time polymerase chain reaction). To our best knowledge this is the first study assessing copy number of GLI2 and GLI3 genes in patients with EA.

ADRB3 and PPARγ2 gene polymorphisms and their association with cardiovascular disease risk in postmenopausal women.

OBJECTIVES: The contribution of heritability to the development of cardiovascular disease (CVD) is of interest as the identification of genes enhancing the susceptibility of individuals to CVD may help the design of clinical interventions optimized for the individual's genome. METHODS: We studied the associations of polymorphism of ADRB3 and PPARγ2 genes with obesity indices, unfavorable lipid profile parameters and insulin resistance index HOMA in 343 postmenopausal women. RESULTS: No association was found between tested polymorphisms and CVD risk factors such as total cholesterol ≥ 5.0 mmol/l, high density lipoprotein cholesterol < 1.2 mmol/l, low density lipoprotein cholesterol > 3.0 mmol/l and triacylglycerols > 1.7 mmol/l. The presence of arterial hypertension and HOMA value ≥ 1.95 were also not related to these polymorphisms. A significant association between PPARγ2 gene polymorphism and total body fat mass (odds ratio = 1.90 at p = 0.037) as well as android fat deposit mass (odds ratio = 1.82 at p = 0.048) was found. CONCLUSIONS: CVD risk factors in postmenopausal women are not directly associated with the polymorphisms of PPARγ2 and ADRB3 genes. We suggest that some indirect link between PPARγ2 gene polymorphism and susceptibility of postmenopausal women to CVD may exist. This suggestion is based on our finding that high total body fat mass and high android fat deposits are associated with the presence of the Pro12Ala allele of the PPARγ2 gene.

Are endocannabinoid type 1 receptor gene (CNR1) polymorphisms associated with obesity and metabolic syndrome in postmenopausal Polish women?

OBJECTIVE: The aim of this study was to determine whether genetic variation at the cannabinoid receptor-1 (CNR1) locus could have an effect on adiposity, fat distribution and obesity-related metabolic disorders in Polish postmenopausal women. DESIGN AND SUBJECTS: The A3813G (rs12720071), G1422A (rs1049353), A4895G (rs806368) and rs806381, rs10485170, rs6454674 and rs2023239 single-nucleotide polymorphisms of CNR1 were genotyped in 348 randomly selected postmenopausal women aged 50-60 years recruited from the Wroclaw city population. MEASUREMENTS: CNR1 genotypes, anthropometric measures (body mass index (BMI), waist circumference (WC) and body fat distribution by dual energy X-ray absorptiometry) and metabolic parameters (glucose, lipid profile and Fasting Insulin Resistance Index for insulin resistance) were determined. RESULTS: The 3813G allele was not significantly associated with higher body mass, BMI, WC, total fat or fat percentage, but was associated with higher android fat deposit (2971.78±1655.08 vs 2472.64±1300.53, P=0.007) and percentage of android fat (37.59±8.45 vs 35.66±7.63, P=0.062). No associations for the G1422A, A4895G, rs806381, rs10485170, rs6454674 and rs2023239 variants were observed. CONCLUSIONS: There is an association of the variants of CNR1 with obesity-related phenotypes in Polish postmenopausal women. As cannabinoid receptor type 1 is a drug target for obesity, pharmacogenetic receptor gene analysis of obesity treatment by endocannabinoid blockade may be of interest to identify the best responders.

CAG repeat polymorphism in the androgen receptor gene and the level of physical activity (HALS Study).

AIM: Androgens influence human behavior. They affect sport performance, physical activity and emotional responses. CAG repeat polymorphism of androgen receptor (AR) gene is associated with transcriptional activity of AR. Decreased number of CAG repeats leads to increased androgen sensitivity. The purpose of this study was to investigate associations between AR CAG polymorphism and physical activity phenotype. METHODS: Within the framework of the HALS Study we randomly selected 900 adult Caucasian males from one administrative region of Poland (Lower Silesia). Eventually, AR CAG repeat was genotyped by a PCR based assay in 360 male subjects. International Physical Activity Questionnaire (IPAQ) was used to determine the level of physical activity of studied subjects. It was expressed as multiples of resting metabolic rate by minutes of performance during a week (METs-minute/week). RESULTS: No association between AR CAG repeat polymorphism and physical activity (P=0.2, ANOVA) was observed. Men with short CAG presented the lowest level of physical activity reaching 3.44 log (METs-minute/week) (SE 0.053; 95% CI, 3.34-3.54), while in men with medium and long CAG it was respectively 3.58 (SE 0.063; 95% CI, 3.46-3.71) and 3.52 (SE 0.039; 95% CI, 3.44-3.60) log (METs-minute/week). CONCLUSIONS: There is no association between AR CAG repeat polymorphism and the level of physical activity in healthy men.