Association between 28 single nucleotide polymorphisms and type 2 diabetes mellitus in the Kazakh population: a case-control study.

BACKGROUND: We evaluated the associations between single nucleotide polymorphisms and different clinical parameters related to type 2 diabetes mellitus (T2DM), obesity risk, and metabolic syndrome (MS) in a Kazakh cohort. METHODS: A total of 1336 subjects, including 408 T2DM patients and 928 control subjects, were recruited from an outpatient clinic and genotyped for 32 polymorphisms previously associated with T2DM and obesity-related phenotypes in other ethnic groups. For association studies, the chi-squared test or Fisher's exact test for binomial variables were used. Logistic regression was conducted to explore associations between the studied SNPs and the risk of developing T2DM, obesity, and MS, after adjustments for age and sex. RESULTS: After excluding four SNPs due to Hardy-Weinberg disequilibrium, significant associations in age-matched cohorts were found betweenT2DM and the following SNPs: rs9939609 (FTO), rs13266634 (SLC30A8), rs7961581 (TSPAN8/LGR5), and rs1799883 (FABP2). In addition, examination of general unmatched T2DM and control cohorts revealed significant associations between T2DM and SNPsrs1799883 (FABP2) and rs9939609 (FTO). Furthermore, polymorphisms in the FTO gene were associated with increased obesity risk, whereas polymorphisms in the FTO and FABP2 genes were also associated with the risk of developing MS in general unmatched cohorts. CONCLUSION: We confirmed associations between polymorphisms within the SLC30A8, TSPAN8/LGR5, FABP2, and FTO genes and susceptibility to T2DM in a Kazakh cohort, and revealed significant associations with anthropometric and metabolic traits. In particular, FTO and FABP2 gene polymorphisms were significantly associated with susceptibility to MS and obesity in this cohort.

Polymorphisms in genes involved in the absorption, distribution, metabolism, and excretion of drugs in the Kazakhs of Kazakhstan.

BACKGROUND: Studies of genes involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs are crucial to the development of therapeutics in clinical medicine. Such data provide information that may improve our understanding of individual differences in sensitivity or resistance to certain drugs, thereby helping to avoid adverse drug reactions (ADRs) in patients and improve the quality of therapies. Here, we aimed to analyse single nucleotide polymorphisms (SNPs) involved in the ADME of multiple drugs in Kazakhs from Kazakhstan. RESULTS: A total of 158 SNPs involved in the ADME of various drugs were studied. We analysed 320 Kazakh DNA samples using OpenArray genotyping. Of the 158 SNPs, 75 were not found in heterozygous or homozygous variants. Comparative analysis among Kazakhs and world populations showed a fairly high percentage of population differentiation. CONCLUSION: These results provide further information for pharmacogenetic databases and may contribute to the development of personalized approaches and safer therapies for the Kazakh population. Moreover, these data provide insights into the different racial groups that may have contributed to the Kazakh population.

Association of ADIPOQ Gene Polymorphisms with Type 2 Diabetes and Obesity Risk in the Kazakh Population: A Case-Control and Population-Based Study.

Type 2 diabetes mellitus (T2DM) is a socially significant disease with increasing prevalence worldwide. It is characterized by heterogeneous metabolic disorders and is associated with various risk factors, including BMI, abnormal lipid levels, hypertension, smoking, dietary preferences, physical inactivity, sedentary lifestyle, family history of diabetes, prediabetes or gestational diabetes, inflammation, intrauterine environment, age, sex, ethnicity, and socioeconomic status. Assessing the genetic risk of developing T2DM in specific populations remains relevant. The ADIPOQ gene, encoding adiponectin, is directly related to the risk of developing T2DM, obesity, and cardiovascular diseases. Our study demonstrated significant associations of ADIPOQ gene polymorphisms with the risk of developing T2DM and obesity, as well as with fasting glucose levels and BMI, in the Kazakh population. Specifically, rs266729 was significantly associated with T2DM and obesity in the Kazakh population, while other studied polymorphisms (rs1501299, rs2241766, and rs17846866) did not show a significant association. These findings suggest that ADIPOQ gene polymorphisms may influence T2DM risk factors and highlight the importance of genetic factors in T2DM development. However, further research in larger cohorts is needed to confirm these associations.

Type 2 diabetes mellitus: distribution of genetic markers in Kazakh population.

BACKGROUND: Ethnic differences exist in the frequencies of genetic variations that contribute to the risk of common disease. This study aimed to analyse the distribution of several genes, previously associated with susceptibility to type 2 diabetes and obesity-related phenotypes, in a Kazakh population. METHODS: A total of 966 individuals belonging to the Kazakh ethnicity were recruited from an outpatient clinic. We genotyped 41 common single nucleotide polymorphisms (SNPs) previously associated with type 2 diabetes in other ethnic groups and 31 of these were in Hardy-Weinberg equilibrium. The obtained allele frequencies were further compared to publicly available data from other ethnic populations. Allele frequencies for other (compared) populations were pooled from the haplotype map (HapMap) database. Principal component analysis (PCA), cluster analysis, and multidimensional scaling (MDS) were used for the analysis of genetic relationship between the populations. RESULTS: Comparative analysis of allele frequencies of the studied SNPs showed significant differentiation among the studied populations. The Kazakh population was grouped with Asian populations according to the cluster analysis and with the Caucasian populations according to PCA. According to MDS, results of the current study show that the Kazakh population holds an intermediate position between Caucasian and Asian populations. CONCLUSION: A high percentage of population differentiation was observed between Kazakh and world populations. The Kazakh population was clustered with Caucasian populations, and this result may indicate a significant Caucasian component in the Kazakh gene pool.

PTH Gene Polymorphism and Breast Cancer Risk in Kazakhstan.

INTRODUCTION: Breast cancer is the most common type of cancer among women. In Kazakhstan, breast cancer holds first place among causes of women death caused by cancer in the 45-55 year age group. Many studies have shown that the risk of acquiring breast cancer may be related to the level of calcium in the blood serum. One of the important regulators of calcium metabolism in the body is the parathyroid hormone. Single nucleotide polymorphisms in the gene encoding the parathyroid hormone (PTH) are associated with breast cancer development risk, and may modify the associative interaction between the levels of calcium intake and breast cancer. Experimental studies have shown that PTH gene has a carcinogenic effect. At least three studies showed a weak positive correlation between the risk of acquiring breast cancer and primary hyperparathyroidism, a state with high levels of PTH and often high levels of calcium. The aim of this investigation was to evaluate potential association between PTH gene polymorphism and breast cancer risk among Kazakhstani women. METHODS: Female breast cancer patients (n = 429) and matched control women (n = 373) were recruited into a case - control study,. Genomic DNA was extracted from peripheral venous blood of study participants using Wizard® Genomic DNA Purification Kit (Promega, USA). Detection of PTH gene polymorphism (rs1459015) was done by means of the TaqMan® SNP Genotyping Assay of real-time PCR. Statistical analysis was conducted using SPSS 19.0. RESULTS: PTH gene alleles were in Hardy-Weinberg equilibrium (p > 0.05). Distribution was 59% CC, 35% CT, 6% TT in the group with breast cancer and 50% CC, 43% CT, 6% TT in the control group. Total difference (between the group with breast cancer and the control group) in allele frequencies for PTH polymorphism was not significant (p > 0.05). No association was found between rs1459015 TT and breast cancer risk (OR = 1.039; 95%, CI 0.740 - 1.297; p = 0.893). CONCLUSION: We found no association between PTHrs1459015 polymorphism and breast cancer in our present study. Further studies are required to confirm our results and clarify role of PTH gene genotypes on breast cancer risk.

Short-term effects of a perinatal exposure to a 16 polycyclic aromatic hydrocarbon mixture in rats: assessment of early motor and sensorial development and cerebral cytochrome oxidase activity in pups.

Humans are exposed to polycyclic aromatic hydrocarbons (PAHs), a family of ubiquitous neurotoxic pollutants, mainly through ingestion of contaminated food. Developing organisms can be exposed also to PAHs due to the ability of these compounds to pass through the placental barrier as well as through the breast milk. Previous animal studies have reported that the exposure of rats to a 16 PAH mixture at environmental doses strictly limited to gestation did not induce any long-lasting consequences, whereas gestational and lactational PAH exposure induced long-term behavioral and cerebral metabolic effects. In the present study, short-term effects of exposures to the same PAH mixture during gestation, or during gestation and lactation, were assessed by evaluating motor and sensory development of rat pups, and by measuring cerebral cytochrome oxidase activity (a marker of energetic metabolism) in different brain areas. Brain levels of PAHs and some monohydroxylated metabolites were also evaluated in pups at birth and at 21 days of postnatal life. No significant short-term modifications of behavioral development and of cerebral metabolism were observed following an early PAH exposure whatever the dose and the period of exposure. Surprisingly, the same brain levels of concentration of PAHs and metabolites were observed in control and exposed pups in both studies. These analytical results raise the difficulty in overcoming environmental contamination of control animals and the choice of such controls in experimental studies which focus on neurotoxicity of exposure to low levels of pollutants.

Exclusive prenatal exposure to a 16 PAH mixture does not impact anxiety-related behaviours and regional brain metabolism in adult male rats: a role for the period of exposure in the modulation of PAH neurotoxicity.

Polycyclic aromatic hydrocarbons (PAHs) are persistent organic pollutants originating from incomplete combustion processes. Humans are mainly exposed through contaminated food ingestion. PAHs are neurotoxic compounds both for human and rodents, and may be found in placenta, umbilical cord blood and breast milk, suggesting that early exposure may impact developing central nervous system. In a previous study we showed that PAH exposure during both gestation and lactation periods in rats increased anxiety-related behaviours and decreased cerebral metabolism in several key structures linked to the limbic system on male pups at the adult stage. The aim of the present study was to assess the effects of an exclusive gestational PAH exposure on the same aspects of brain functionality. Female rats were exposed through diet to a 16 PAH mixture at doses of 2 µg/kg/day or 200 µg/kg/day during gestation. Late neurotoxic effects were evaluated by carrying out behavioural and cognitive tests and histochemical analyses using cytochrome oxidase activity as a cerebral metabolism marker in different brain areas. The results of this study revealed that behaviour and cerebral metabolism on prenatally PAH exposed adult rats was not significantly affected by the exposure to these pollutants. Finally this work highlights that the exposure period to pollutants such as PAHs at very early stages of development play a key role on the neurological impairment induced.

Vitamin D Receptor Gene Polymorphisms and Breast Cancer Risk in Kazakhstan.

INTRODUCTION: The steroid hormone 1,25-dihydroxyvitamin D3 is thought to protect against breast cancer. The activity of 1,25-dihydroxyvitamin D3 is mediated via the vitamin D receptor (VDR), and a number of polymorphisms in the VDR gene have been identified. These result in distinct genotypes, some of which may alter susceptibility to breast cancer. Two common single nucleotide polymorphisms (SNP) in the VDR gene (VDR), rs1544410 (BsmI) and rs2228570 (FokI), have been inconsistently associated with breast cancer risk. Increased risk has been reported for the FokI ff genotype, which encodes a less transcriptionally active isoform of VDR. A reduced risk has been reported for the BsmI BB genotype which may influence VDR mRNA stability. AIM: We have investigated whether specific VDR gene polymorphisms are associated with breast cancer risk in Kazakhstan women. MATERIAL AND METHODS: In a case-control study, female breast cancer patients (315) and a female control group (n=604) were tested for two VDR polymorphisms. Statistical analysis was conducted using SPSS19.0. RESULTS: : The VDR rs2228570 (FokI) polymorphism was associated with an increased occurence of BC [rs2228570 (folk) ff vs. FF genotype: OR=1.71; 95% CI=1.21-2.43]. No association was noted between rs1544410 (BsmI) BB and breast cancer risk [OR=0.68; 95% CI=0.49-0.95]. CONCLUSION: : Although the factors that increase breast cancer susceptibility remain uncertain, future large studies should integrate genetic variation in VDR with biomarkers of vitamin D status. Additional testing on the effect of varying genotypes on the functional mechanisms of the VDR could help to improve future testing and treatment of woman at risk for breast cancer.

Late effects of a perinatal exposure to a 16 PAH mixture: Increase of anxiety-related behaviours and decrease of regional brain metabolism in adult male rats.

Polycyclic Aromatic Hydrocarbons (PAHs) are ubiquitous pollutants originated from incomplete combustion processes. Ingestion of contaminated food is the main route of exposure for humans. These molecules are able to cross the placental barrier and are also found in breast milk. Since PAHs are neurotoxic agents, the potential adverse effects of a perinatal exposure of the developing brain is a key issue for public health especially concerning PAH mixture. In this study, female rats were exposed trough diet to a mixture of 16 PAHs, at doses of 2 µg/kg/day or 200 µg/kg/day during gestation and 1.5 µg/kg/day or 150 µg/kg/day during breast-feeding period. To assess late neurotoxic effects in male offsprings, behavioural and cognitive tests were carried out and histochemical analyses using cytochrome oxidase as a cerebral metabolism marker were performed on adult animals. Results showed that anxiety-related behaviours significantly increased in exposed animals, but there was no significant alteration of motor activity and learning and memory abilities. Several brain areas of the limbic system showed a neuronal hypometabolism in exposed animals. This work highlights that exposure to PAHs at early stages of brain development can cause later troubles on behaviour and that PAHs are able to partly alter the central nervous system metabolism on adulthood.