Łukasz Łaczmański

The vitamin D receptor gene BsmI polymorphism is not associated with anthropometric and biochemical parameters describing metabolic syndrome in postmenopausal women

Aim. Vitamin D could have a direct effect on adipocyte differentiation and metabolism and might be involved in glucose regulation of insulin secretion. In recent years several polymorphisms in the gene encoding the vitamin D receptor (VDR), which are potent to alter the activity of VDR protein, have been described. The present study aimed to investigate the prevalence of the VDR BsmI polymorphism and its association with anthropometric and biochemical features of metabolic syndrome in postmenopausal women. Materials and methods. We studied 351 randomly selected healthy postmenopausal women, with mean age of 55.43 ± 2.75 years and mean body mass index (BMI) of 27.5 ± 4.78 kg/m2, to evaluate the frequency of BsmI polymorphism (by restriction fragment length polymorphism–polymerase chain reaction) in the VDR gene and to find out whether there is an association between this polymorphism and BMI, total fat volume and visceral fat (as determined by total body dual-energy X-ray absorptiometry), blood pressure, lipid profile (total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, triglycerides) glucose and fasting insulin in the whole group, as well as subgroups of obese and non-obese women. Results. The prevalence of BsmI genotypes in the study group was 51.0% Bb, 37.3% bb and 11.7% BB. Genotype distribution did not differ from that expected under Hardy–Weinberg equilibrium conditions (χ2 = 2.95, p = 0.22). Apart from LDL-C levels (F = 3.46, p = 0.032), there were no significant differences in anthropometric or metabolic parameters between genotypes. Conclusions. The BsmI polymorphism in the VDR gene does not seem to predispose to obesity and insulin resistance, but the BB genotype is connected with an unfavorable lipid profile.

Metabolic dysregulation in first-episode schizophrenia patients with respect to genetic variation in one-carbon metabolism.

The aim of this study was to investigate the prevalence of metabolic disturbances in patients with first-episode schizophrenia (FES) and test the hypothesis that genetic variation in one-carbon metabolism may account for metabolic dysregulation in early psychosis. We measured fasting glucose, lipid profile parameters, homocysteine, folate and vitamin B12 in 135 patients with FES and 146 healthy controls (HCs). Polymorphisms in the following genes were determined: MTHFR (C677T and A1298C), MTHFD1 (G1958A), MTRR (A66G) and BHMT (G742A). Serum levels of folate and high-density lipoproteins (HDL) were significantly lower in patients with FES compared to HCs. In turn, serum levels of homocysteine and triglycerides were significantly higher in patients with FES than in HCs. Prevalence of hyperhomocysteinemia, low folate and HDL levels together with dyslipidemia was significantly higher in patients with FES compared to HCs. Higher homocysteine levels, lower vitamin B12 levels and the presence of metabolic syndrome were associated with higher severity of negative symptoms. None of studied polymorphisms was associated with schizophrenia risk. Several associations between studied polymorphisms and cardio-metabolic parameters were found. None of them remained significant after Bonferroni correction. Our results indicate that metabolic dysregulation in patients with FES is not associated with genetic variation in one-carbon metabolism.

Irisin plasma concentration in PCOS and healthy subjects is related to body fat content and android fat distribution

Abstract Irisin (Ir), a recently identified adipo-myokine, cleaved and secreted from the protein FNDC5 in response to physical activity, has been postulated to induce the differentiation of a subset of white adipocytes into brown fat and to mediate the beneficial effects on metabolic homeostasis. Metabolic syndrome (MS), a cluster of factors leading to impaired energy homeostasis, affects a significant proportion of subjects suffering from polycystic ovary syndrome (PCOS). The aim of our study was to investigate the relationship between Ir plasma concentrations and metabolic disturbances. The study group consisted of 179 PCOS patients and a population of 122 healthy controls (both groups aged 25–35 years). A subset of 90 subjects with MS was isolated. A positive association between Ir plasma level and MS in the whole group and in controls was found. In subjects with high adipose body content (>40%), Ir was higher than in lean persons (<30%). Our results showed a significant positive association between Ir concentration and android type of adipose tissue in the whole study group and in the control group. Understanding the role of Ir in increased energy expenditure may lead to the development of new therapeutics for obesity and obesity-related diseases. Chinese abstract 鸢尾素（Ir）,一个新近被发现的脂肪-肌肉细胞因子，由蛋白FNDC5在体力活动时产生应答而裂解和分泌，推测其诱导白色脂肪细胞亚单位分化为棕色脂肪，并介导棕色脂肪对代谢稳态的有益作用。代谢综合征（MS），一系列因素导致能量稳态受损，影响了相当比例的多囊卵巢综合征（PCOS）患者。我们的研究旨在探讨Ir的血浆浓度与代谢紊乱间的关系。实验组包含179名PCOS患者和122名健康对照人群（两组年龄均为25-35岁）。其中90名患有MS的受试者。实验组和对照组均发现Ir血浆浓度和MS呈正相关。在体脂含量较高（＞40%）的受试者中，Ir水平在比较瘦的患者（＜30%）高。我们的结果显示实验组和对照组的Ir浓度和雄性脂肪组织呈显著正相关。了解Ir在增加能量消耗中的作用可能有助于发展肥胖和肥胖相关疾病的新的治疗方法。

The relationship between selected VDR, HFE and ALAD gene polymorphisms and several basic toxicological parameters among persons occupationally exposed to lead.

UNLABELLED The aim of this study was to find a relationship between polymorphisms of ALAD rs1805313, rs222808, rs1139488, VDR FokI and HFE C282Y and H63D and basic toxicological parameters (lead and ZnPP blood concentration) in people occupationally exposed to lead. We collected data of 101 workers (age 25-63 years) directly exposed to lead. The toxicological lab tests included blood lead, cadmium and ZnPP concentration measurement and arsenic urine concentration measurement. Workers were genotyped for ALAD (rs1805313, rs222808, rs1139488), HFE (C282Y, H63D) and VDR (FokI). Individuals with the lead exposure and coexisting F allel in the locus Fok-I of VDR gene are suspected of higher zinc protoporphyrins concentrations. Workers exposed to the lead with the Y allel in the locus C282Y of the HFE gene are predisposed to lower ZnPP levels and individuals with coexisting H allel in the locus H63D HFE gene are predisposed to lower Pb-B levels. The T allel in the locus rs1805313 of the ALAD gene determines lower Pb-B and ZnPP levels in lead-exposed individuals. The heterozigosity of the locus rs2228083 of the ALAD gene has a strong predilection to higher Pb-B levels. The carriage of the C allel in the locus rs1139488 of the ALAD gene might determine higher Pb-B levels and the heterozigosity of the locus rs1139488 of the ALAD gene might result in higher ZnPP levels. CONCLUSION The study revealed relationship between VDR, HFE and ALAD genes polymorphism and basic toxicological parameters in occupationally exposed workers.

Classic PCOS phenotype is not associated with deficiency of endogenous vitamin D and VDR gene polymorphisms rs731236 (TaqI), rs7975232 (ApaI), rs1544410 (BsmI), rs10735810 (FokI): a case–control study of lower Silesian women

Abstract Context: The role of endogenous vitamin D and vitamin D receptor (VDR) gene polymorphism in polycystic ovary syndrome (PCOS) is still controversial. Objective: The objective of this study was to investigate for the first time in women with “classic” PCOS phenotype and healthy controls the role of the serum endogenous vitamin D level and VDR gene polymorphisms in PCOS etiology. Design: Ninety-two women with “classic” PCOS phenotype and 85 controls from lower Silesia with comparable body mass index (BMI) were studied. In all women the waist circumference, android/gynoid fat deposit, parameters of lipid and glucose metabolism, testosterone, free androgen index, sex hormone binding globulin (SHBG) and vitamin D were evaluated. Also, VDR gene polymorphisms rs731236, rs7975232, rs1544410 and rs10735810 were assessed. Results: Serum vitamin D levels in both groups were comparable. Also high, comparable frequencies of hypovitaminosis and vitamin D deficiency in both groups were observed. Women with “classic” PCOS phenotype had statistically significantly higher values of all measured parameters, except serum SHBG and high-density lipoprotein (HDL)-cholesterol, which were lower. The frequency of VDR genotype polymorphism was also comparable in both groups. Conclusions: For the first time, we show that endogenous vitamin D deficiency and VDR polymorphisms are not associated with homogeneous “classic” PCOS phenotype.

Endocannabinoid type 1 receptor gene (CNR1) polymorphisms (rs806381, rs10485170, rs6454674, rs2023239) and cardiovascular risk factors in postmenopausal women

Introduction. The risk of cardiovascular diseases (CVD) in women increases with menopausal stage. Obesity with metabolic disorders is the most important risk factor for CVD. The incidence of this phenotype of obesity increases in postmenopausal women. The endocannabinoid system plays an important role in regulation of several metabolic pathways. The aim of this work was to investigate whether genetic variations in the cannabinoid receptor gene (CNR1) can affect cardiovascular risk factors (e.g. fat distribution, obesity, fasting glucose, lipid profile, blood pressure, and free androgen and estrogen indexes) in postmenopausal women. Methods. The rs806381, rs10485170, rs6454674, and rs2023239 polymorphisms of the CNR1 gene were genotyped in 384 randomly selected postmenopausal Polish women (aged 50–60) using the minisequencing technique. Results. The rs806381, rs10485170, rs6454674, and rs2023239 polymorphisms were not significantly associated with anthropometric measures (waist circumference, carbohydrate and lipid metabolism, body mass index [BMI], total fat, glucose, insulin, fasting insulin resistance index [FIRI]). However, the rs2023239 polymorphism was associated with the free androgen index (p = 0.03). Discussion. It seems that further genotyping of the endocannabinoid receptor gene cannot be used as a significant marker of predisposition to CVD in postmenopausal women, but it would be interesting to study this interrelation on a larger population of postmenopausal women.

Selected CNR1 polymorphisms and hyperandrogenemia as well as fat mass and fat distribution in women with polycystic ovary syndrome.

Abstract The endocannabinoid system is postulated to play an important role in the etiology of obesity, insulin resistance, fat distribution and metabolic disorders. Insulin resistance associated with abdominal obesity plays a leading role in the etiology of hyperandrogenism and other clinical features of the polycystic ovary syndrome (PCOS). A total of 174 women 16–38 years old, diagnosed with PCOS according to the Rotterdam criteria are recruited. Control group consisted of 125 healthy women 18–45 years old. Medical history, physical examination, anthropometric parameters and metabolic parameters were carried out. Six CNR1 gene polymorphisms were diagnosed. We observed a significantly three times higher risk of GG genotype in the polymorphism rs12720071 in women with PCOS versus the control group (p = 0.0344, OR = 3.01). A similar, significant 8-fold higher risk (p = 0.0176, OR = 8.81) was demonstrated for genotype CC polymorphism rs806368 associated with PCOS. We observed a 3.6-fold increased risk of hyperandrogenemia (free androgen index – FAI > 7) in patients with GG genotype in the rs12720071 polymorphism and AA genotype in the polymorphism rs1049353 (OR = 2.7). Our study may indicate a role of the endocannabinoid system in the occurrence of a specific hyperandrogenemia phenotype of PCOS. Chinese abstract 内源性大麻素系统被假定在肥胖、胰岛素抵抗、脂肪分布和代谢紊乱的病原学方面起重要作用。与腹型肥胖相关的胰岛素抵抗在多囊卵巢综合征（polycystic ovary syndrome，PCOS）雄激素增多症和其他临床特点的病因学上起主要作用。我们招募了174名16-38岁经鹿特丹诊断标准诊断的PCOS患者。对照组为125名18-45岁健康女性。我们对受试者采集病史，进行体格检查，收集人体测量参数和代谢指标。大麻素受体1（cannabinoid receptor 1，CNR1）基因多态性有六种。我们观察到PCOS患者在rs12720071位点多态性的GG基因型风险比对照组高出三倍（p=0.0344, OR=3.01）；类似的，PCOS患者在rs806368位点多态性的CC基因型风险比对照组高8倍（p=0.0176, OR=8.81）。我们也观察到rs12720071位点多态性的GG基因型和rs1049353位点多态性的AA基因型患者的高雄激素血症（free androgen index – FAI>7）风险增加了3.6倍（OR=2.7）。我们的研究可能表明内源性大麻素系统对PCOS一种特定的高雄激素血症表型的发生起作用。

Non-alcoholic fatty liver disease in women with polycystic ovary syndrome — clinical and metabolic aspects and lipoprotein lipase gene polymorphism

INTRODUCTION The aim was to assess associations among PCOS and NAFLD, the lipoprotein lipase polymorphism gene, and metabolic disorders in PCOS. MATERIAL AND METHODS In 184 women with PCOS and 125 healthy, premenopausal volunteers, sex steroids, lipids, glucose, insulin, aminotransferases, free androgen index (FAI), HOMA-IR and E2/T were calculated. Hepatic steatosis was determined by ultrasound. Whole genomic DNA was isolated from blood leucocytes. Lipoprotein lipase polymorphisms rs268 and rs328 were analysed by polymerase chain reaction (PCR) and minisequencing. RESULTS 57.6% of PCOS women had NAFLD, while women without PCOS had NAFLD in 49.6%. PCOS-NAFLD women had higher BMI, WHR and waist circumference compared to women with PCOS without NAFLD and women without PCOS. PCOS-NAFLD women had lower SHBG, E2/T ratio, and higher FAI compared to other groups. ALT levels were higher in PCOS women with NAFLD compared to other groups. PCOS women with and without NAFLD had higher fasting glucose and insulin and HOMA compared to women without PCOS. Women with PCOS had higher triglycerides and lower HDL-C compared to women without PCOS. There was no evidence that evaluated polymorphisms influenced hepatic steatosis in women with and without PCOS. CONCLUSIONS PCOS is not an independent factor influencing NAFLD in women. The influences on NAFLD incidence in women are BMI > 25 kg/m², glucose level > 80 mg/dL, E2/T < 80 and ALT > 19 IU/L as independent factors. Hyperandrogenism in PCOS may increase the risk of NAFLD indirectly by obesity, insulin resistance, and directly by the hepatotoxic effect. Polymorphisms rs328 and rs268 of the lipoprotein lipase gene do not affect the occurrence of NAFLD in women with PCOS or without PCOS.

Uremic Pruritus Is Not Associated with Endocannabinoid Receptor 1 Gene Polymorphisms

Uremic pruritus (UP) is a frequent and bothersome symptom in hemodialysis patients. Its etiology is not fully understood and that is why there is no specific treatment. The endocannabinoid system plays a role in many pathological conditions. There is reliable evidence on the association between cannabinoid system and pruritus. In our study, we aimed to evaluate whether genetic variations in the endocannabinoid receptor 1 (CNR1) gene can affect UP. The rs12720071, rs806368, rs1049353, rs806381, rs10485170, rs6454674, and rs2023239 polymorphisms of the CNR1 gene were genotyped in 159 hemodialysis patients and 150 healthy controls using two multiplex polymerase chain reactions and the minisequencing technique. No statistically significant relationship was found in any of the evaluated genotypes between patients with and without UP, even after excluding patients with diabetes and dyslipidemia. There were no differences between patients with UP and the control group. However, in the group of all HD patients, a significantly higher incidence of GA genotype and lower incidence in GG genotype in the polymorphism rs806381s were revealed versus the control group (p = 0.04). It seems that polymorphisms of the CNR1 gene are not associated with uremic pruritus.

Genetic variation in one-carbon metabolism and changes in metabolic parameters in first-episode schizophrenia patients

Abstract Background: In this study, we aimed to investigate the effects of polymorphisms in genes encoding 1-carbon metabolism enzymes on differential development of metabolic parameters during 12 weeks of treatment with second-generation antipsychotics in first-episode schizophrenia patients. Methods: The following polymorphisms in 1-carbon metabolism genes were genotyped: MTHFR (C677T and A1298C), MTHFD1 (G1958A), MTRR (A66G), and BHMT (G742A). A broad panel of metabolic parameters including body mass index, waist circumference, total cholesterol low and high density lipoproteins, triglycerides, homocysteine, folate, and vitamin B12 was determined. Results: There was a significant effect of the interaction between the MTHFR C677T polymorphism and time on body mass index and waist circumference in the allelic and genotype analyses. Indeed, patients with the MTHFR 677CC genotype had higher increase in body mass index and waist circumference compared with other corresponding genotypes or the MTHFR 677T allele carriers (CT and TT genotypes). In addition, patients with the MTHFR 677TT genotype had higher waist circumference in all time points. Similarly, patients with the MTHFR 677TT genotype had higher body mass index in all time points, but this effect was not significant after correction for multiple testing. Conclusions: Our results indicate that the MTHFR C677T polymorphism may predict antipsychotic-induced weight gain. Effects of the MTHFR C677T polymorphism might be different in initial exposure to antipsychotics compared with long-term perspective.