Recessive Model Of Inheritance Research Articles

Genetic variants of KISS1 gene in association with polycystic ovary syndrome– A meta-analysis

Polycystic ovary syndrome (PCOS) is a widely diagnosed syndrome associated with clinical and metabolic manifestations and even many cases of infertility. Sexual hormone imbalance can be considered as PCOS causal factor. Thus, kisspeptin (KISS1) regulating gonadotropin-releasing hormone (GnRH) levels plays a critical role in this syndrome. This study aimed to investigate the association of KISS1 genetic polymorphisms with PCOS using meta-analysis protocols. In accordance with PRISMA guidelines, systematic search of scientific databases was conducted to find included articles and then meta-analysis was performed using Review Manager 5.4 in dominant, recessive, and allelic models of inheritance. This meta-analysis included 2165 PCOS patients and 2301 healthy reproductive-aged female genotyped for five different polymorphisms of KISS1. In recessive and allelic models, three genetic variations specifically showed significant association with PCOS. This concerns rs12998 (G → A) which was proved as associated with higher risk of PCOS in recessive (p = 0.0002) and allelic models (P = 0.02). In addition, rs372790354 despite the small number of studies was associated with this syndrome in allelic model (P = 0.03). In additive model, rs4889 was shown as associated with higher PCOS risk (P = 0.02). This meta-analysis suggests rs4889, rs12998 and rs372790354 genetic variations in KISS1 as risk factors of PCOS. Results will improve our knowledge about PCOS and form a basis for future trials trying to find new markers for its prognosis and therapy.

CLINICAL COURSE OF OBESITY-ASSOCIATED ASTHMA DEPENDING ON THE GLN27GLU POLYMORPHIC VARIANT OF THE β2-ADRENORECEPTOR GENE, TAKING INTO ACCOUNT THE AGE OF ONSET

Introduction. Studies have shown that bronchial asthma (BA) associated with obesity has a more severe course, lower control, more frequent cases of low efficacy of basic treatment, and exacerbations. Two phenotypes have been distinguished in BA-obesity comorbidity based on age of onset: early atopic and late non-atopic. It is known that genetic factors associated with β2-adrenoceptor (AR) genes are important in the development of both asthma and obesity.
 The purpose of the study aimed to analyze the association of the Gln27Glu polymorphism of the β2-adrenoceptor gene with the severity of the course of bronchial asthma with obesity, taking into account the age of its onset.
 Research material and methods. 195 asthma patients with obesity consented for the study participation were examined. The control group consisted of 95 practically healthy people. Patients were divided into two clinical groups depending on the age of onset of BA: the first group included 100 patients with an early onset, the second group - 95 patients with a late onset.  The diagnosis and treatment of asthma followed the guidelines of the Global Initiative for Asthma (2016) and its updated versions. The study was approved by the Bioethics Commission of the Educational and Scientific Medical Institute of Sumy State University. Determination of the Gln27Glu polymorphism of the β2-AR gene (rs1042714) was performed using the polymerase chain reaction with the subsequent analysis of restriction fragments. Statistical analysis of the obtained results was carried out using the SPSS-17 program. Pearson's chi-squared test was used to compare genotype distributions between experimental groups. To determine the risk of BA and obesity, odds ratios and 95% confidence intervals were calculated for dominant, recessive, superdominant, and additive models of inheritance. Their relevance was assessed using the Akaike information criterion. All tests were two-sided, and values p < 0.05 were considered statistically significant.
 Research results. The frequency of Gln/Gln, Gln/Glu and Glu/Glu genotypes according to the Gln27Glu polymorphism of the β2-AR gene in patients with early-onset obesity-associated asthma was 70.0; 25.0; 5.0% with a mild course and 55.0; 36.2; 8.8% with severe (χ2 = 1.49; p = 0.473); and with a late debut - 50.0; 43.8; 6.2% with mild and 54.0%; 31.7; 14.3%, respectively, with severe (χ2 = 2.10; p = 0.350). Despite the absence of a probable difference in the distribution of genotypes depending on the severity of the course, it was found that the frequency of homozygotes for the minor allele was 1.8 times higher in patients with a severe course of early BA and 2.3 times higher in late BA compared to that in patients with mild BA course.
 The risk of early-onset BA with obesity and a severe course showed no association in all models of inheritance, and in patients with late-onset BA, there was a 1.66-fold increase (95% CI (1.03 – 2.72), p = 0.04) in the additive inheritance model (p = 0.04).
 Conclusions. There are no statistically significant differences in the distribution of genotypes according to the Gln27Glu polymorphism of the β2-AR gene depending on the severity of the course of early and late BA with obesity. The risk of developing a severe course of early BA did not depend on the Gln27Glu polymorphism of the β2-AR gene, and late BA increased by 1.66 times in the additive model of inheritance.

Association between genetic variants of membrane transporters and the risk of high-grade hematologic adverse events in a cohort of Mexican children with B-cell acute lymphoblastic leukemia.

Advances in the understanding of the pathobiology of childhood B-cell acute lymphoblastic leukemia (B-ALL) have led towards risk-oriented treatment regimens and markedly improved survival rates. However, treatment-related toxicities remain a major cause of mortality in developing countries. One of the most common adverse effects of chemotherapy in B-ALL is the hematologic toxicity, which may be related to genetic variants in membrane transporters that are critical for drug absorption, distribution, and elimination. In this study we detected genetic variants present in a selected group genes of the ABC and SLC families that are associated with the risk of high-grade hematologic adverse events due to chemotherapy treatment in a group of Mexican children with B-ALL. Next generation sequencing (NGS) was used to screen six genes of the ABC and seven genes of the SLC transporter families, in a cohort of 96 children with B-ALL. The grade of hematologic toxicity was classified according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, Subsequently, two groups of patients were formed: the null/low-grade (grades 1 and 2) and the high-grade (grades 3 to 5) adverse events groups. To determine whether there is an association between the genetic variants and high-grade hematologic adverse events, logistic regression analyses were performed using co-dominant, dominant, recessive, overdominant and log-additive inheritance models. Odds ratio (OR) and 95% confidence intervals (95% CI) were calculated. We found two types of associations among the genetic variants identified as possible predictor factors of hematologic toxicity. One group of variants associated with high-grade toxicity risk: ABCC1 rs129081; ABCC4 rs227409; ABCC5 rs939338, rs1132776, rs3749442, rs4148575, rs4148579 and rs4148580; and another group of protective variants that includes ABCC1 rs212087 and rs212090; SLC22A6 rs4149170, rs4149171 and rs955434. There are genetic variants in the SLC and ABC transporter families present in Mexican children with B-ALL that can be considered as potential risk markers for hematologic toxicity secondary to chemotherapeutic treatment, as well as other protective variants that may be useful in addition to conventional risk stratification for therapeutic decision making in these highly vulnerable patients.

LEP (G2548A-G19A) and ADIPOQ (T45G-G276T) gene polymorphisms are associated with markers for metabolic syndrome

Background and aimsThere is a link between genetics with metabolic balance and adiposity homeostasis on metabolic syndrome (MetS). Polymorphism in adipokine genes such as leptin and adiponectin may play an important role in its development. This study aimed to determine the association of the individual and general components of MetS with genetic alterations in LEP (rs7799039 and rs2167270) and ADIPOQ (rs1501299 and rs2241766) genes in the Mexican population.Methods and resultsThe polymorphisms of the LEP gene rs7799039 and rs2167270, together with rs1501299 and rs2241766 polymorphisms of the ADIPOQ gene were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) on 328 individuals (n = 131 MetS). The rs7799039 under the recessive inheritance model was found to be associated with increased risk of MetS (OR = 2.16, 95% CI = 1.06–4.37), dyslipidemia (OR = 7.97, 95% CI = 2.17–29.36), low HDL (OR = 7.01, 95% CI = 1.65–29.71) and hypertension (OR = 13.02, 95% CI = 1.76–96.44); the heterozygote demonstrate a protective effect on MetS (OR = 0.48, 95% CI = 0.28–0.88) and diabetes (OR = 0.09, 95% CI = 0.02–0.53) under the over the dominant model. Haplotype analysis showed linkage disequilibrium between the SNPs of ADIPOQ rs1501299/rs2241766, and their association as risk factors for low HDL and hypertension.ConclusionThe association of rs7799039 with the presence of MetS, suggests a risk factor for the development of dyslipidemia, as well as its heterozygous as a protective factor for DM. There is a linkage disequilibrium between the SNPs of ADIPOQ.

GENETIC ASPECTS OF PROOXIDANT-ANTIOXIDANT BALANCE IN PATIENTS WITH DIABETIC NEPHROPATHY

The aim of this work is to study the state of the prooxidative-antioxidant balance in patients with diabetic nephropathy depending on the functional state of the kidneys and taking into account the polymorphism of ACE gene. Participants and methods. This study involved 82 patients with type 2 diabetic and nephropathy. The control group consisted of 20 healthy individuals. The prooxidant-antioxidant balance of blood serum was calculated as the ratio of total hydroperoxide content to total antioxidant activity. The content of total hydroperoxides and total antioxidant activity were determined by the colorimetric method. Results. Oxidative stress plays an important role in the pathogenesis of diabetic nephropathy. Angiotensin I-converting enzyme (ACE) gene polymorphism is associated with the development and progression of acute and chronic kidney diseases. However, the features of antioxidant protection in patients with diabetic nephropathy, who are carriers of different genotypes of this polymorphism, have not been studied. Association analysis using the SNPStats online program has demonstrated that in patients with diabetic nephropathy, the I/I polymorphism is associated with an increase in the concentration of total hydroperoxides in blood serum (difference = 23.62 (6.16-41.08); p = 0.017 — codominant model inheritance; difference = 22.73 (7.70-37.75); p = 0.0042 — recessive model of inheritance). We found a significant increase of total hydroperoxides in diabetic nephropathy patients - carriers of the homozygous I/I genotype of the ACE gene polymorphism, compared to carriers of the D-allele (I/D and D/D genotypes), p=0.03.The highest values of prooxidant-antioxidant balance of blood serum in patients with diabetic nephropathy are noted in carriers of the I/I and I/D genotypes of the ACE gene/ These findings may indicate a negative effect of the I allele on the general state of the prooxidant-antioxidant balance in this category of patients. Conclusions. The analysis of the data we obtained allows us to assume an important influence of the ACE gene polymorphism on the pathogenesis of diabetic kidney disease due to changes in the prooxidant-antioxidant balance in patients with type 2 diabetes.

РЕГУЛЯЦИЯ СИСТЕМНОГО ВОСПАЛИТЕЛЬНОГО ОТВЕТА У ПАЦИЕНТОВ С МУЛЬТИФОКАЛЬНЫМ АТЕРОСКЛЕРОЗОМ

Introduction. Data on the role of inflammation in the progression and manifestation of multifocal atherosclerosis (MFA) are contradictory. The systemic process of multiple lesions of different vascular beds in patients with an established diagnosis of coronary heart disease (CHD) is due to several parallel pathological mechanisms. In general, in the pathogenesis of both coronary atherosclerosis and atherosclerosis of peripheral arteries, one of the factors is the variability of immune response genes and cytokines, regulators of the inflammatory response. The aim of this work was to determine the role of variability in the genes of cytokines and innate immune response receptors in the structure of mechanisms associated with the development of MFA in patients with coronary artery atherosclerosis. Materials and methods. 260 patients with CAD (mean age 58 years) were examined. Of all those included in the study, at the time of the survey, MFA was found in 180 people (69.23%), while the incidence of MFA in men and women is comparable (70.33 vs. 64.71%, respectively). There is also no significant difference in the incidence of MFA in the two age groups (up to 60 years, 45% have lesions of two or more vascular beds, and in people older than 60 years, MFA was found in 55% of cases). All patients were informed about the course of the study and voluntarily signed an informed consent. Blood was collected from the cubital vein into Vacutainer tubes with K3EDTA. DNA isolation was carried out using the phenol-chloroform extraction method. Genotyping of 47 polymorphic sites with a single nucleotide change (SNV) of 19 genes proven to be associated with the regulation of the systemic inflammatory response (cytokines, innate immunity receptors) was performed in a 96-well format using TaqMan technology (LifeTechnologies, USA) and real-time result detection with using the ViiATM 7 RealTime PCR System (LifeTechnologies, USA) for polymerase chain reaction in accordance with the instructions. Associations were analyzed using Snpstats (https://www.snpstats.net/start.htm). Odds ratio (OR) and 95% CI for OR were calculated for risk assessment. Results. One association has been established that demonstrates a negative impact and increases the risk of developing MFA in young and middle age. Carriage of the G rs11685424 IL1RL1 allele increases the risks of earlier development of peripheral arterial lesions by 2 times (OR 2.11 (95% CI 1.09-4.06), p = 0.024) according to the recessive inheritance model. At the same time, variability in three sites (rs1974675; rs6758936; rs3755276) of the IL18 receptor gene (IL18R1) reduces the risk of MFA detection by three times (p=0.12; p=0.034: p=0.026, respectively) and this pattern is also observed in patients older age group. In the carriers of the A/A rs1974675, T/T rs3755276 and A/A rs6758936 genotypes in persons over 60 years of age, MFA was diagnosed less frequently (p=0.024; p=0.037; p=0.011, respectively). Conclusion. It has been shown that in patients with significant coronary atherosclerosis, the progression of peripheral vascular atherosclerosis is more associated with the variability of the genes responsible for the regulation of the systemic inflammatory response, rather than genes and their variants that determine the severity and strength of the immune response.

Association of C677T and A1298C genetic polymorphisms in MTHFR gene with fetal growth restriction, small for gestational age and low birth weight: A meta-analysis

Impaired fetal growth has a wide range of short-term and long-term effects on physical and mental health. Fetal Growth Restriction (FGR), Small for Gestational Age (SGA) and Low Birth Weight (LBW) are three diagnoses of impaired fetal growth/size, but differences between them are not fully understood. This meta-analysis aimed to investigate the association of two genetic variants C677T and A1298C in methylenetetrahydrofolate reductase (MTHFR) gene with the risk of impaired fetal growth and then confirm this association with specific diagnosis. According to PRISMA protocols, 24 articles were included after searching the following databases: PubMed, Google Scholar, Science Direct, Web of Science, Cochrane Library and Cyber-Lenics. Meta-analysis was conducted in dominant, recessive, and allelic models of inheritance. According to our data, MTHFR C677T is associated with higher risk of impaired fetal growth and especially with FGR susceptibility (OR = 1.93, 95% CI 1.27–2.95, P = 0.002). On the other hand, MTHFR A1298C can be suggested as a risk factor of SGA (OR = 1.61, 95% CI 1.16–2.24, P = 0.005). However, it has no significant association with FGR or LBW. Our findings help to better understand MTHFR impact on fetal growth and distinguish FGR and SGA as separated cases of fetal growth abnormality.

Association of SOD2 rs2758339, rs5746136 and rs2842980 polymorphisms with increased risk of breast cancer: a haplotype-based case-control study.

A growing body of evidence indicates that oxidative stress, high levels of reactive oxygen species (ROS), is implicated in the pathogenesis of breast cancer (BC). Superoxide dismutase (SOD2), a mitochondria-resident antioxidant enzyme, protects cells from ROS by catalytically converting the superoxide radicals into less reactive species. We aimed to investigate whether SOD2 rs2758339, rs5746136 and rs2842980 polymorphisms are associated with increased risk of BC. A total of 100 patients with BC and 100 healthy controls were enrolled in the study. We used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay for genotyping the SOD2 single-nucleotide polymorphisms (SNPs). Under co-dominant, dominant and recessive inheritance models, the genotypic and allelic associations of SOD2 SNPs with susceptibility to BC were evaluated using logistic regression analysis. The haplotype analysis was performed on the SOD2 SNPs to determine their combined effect on the BC risk. We found that SOD2 rs5746136 was significantly associated with decreased risk of developing BC in co-dominant and dominant inheritance models (P < 0.05). The SOD2 rs5746136 T allele confers an apparent protective effect against breast carcinogenesis (OR: 1.956; 95% CI 1.312-2.916; P < 0.0001). The SOD2 rs5746136/rs2842980 combined genotypes (CT/AA, CT/AT and TT/AA) were significantly more frequent in healthy subjects compared to BC patients (P < 0.05). The CTA and ACA haplotypes (rs2758339, rs5746136, rs2842980) were found to be a protective and a risk factor for BC, respectively. These data strongly suggest that SOD2 rs5746136 was significantly associated with reduced risk of BC, indicating its protective role in BC development.

The correlation between rs2501577 gene polymorphism and biliary atresia: a systematic review and meta-analysis.

Multiple studies indicate a possible correlation between ADD3 rs2501577 and biliary atresia susceptibility; however, a conclusive determination has yet to be made. Investigate the role of ADD3 rs2501577 in biliary atresia susceptibility across diverse populations. The study protocol has been registered on PROSPERO, an international platform for systematic review registration (PROSPERO ID: CRD42023384641). The following databases will be searched until February 1, 2023: PubMed, Embase, Cochrane, CBM, Web of Science, and CNKI. Eight studies were selected from seven papers to assess the data. A total of 7651 participants were included, consisting of 1662 in the BA group and 5989 in the NC group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed while conducting the systematic reviews and meta-analyses. Two authors independently assessed the quality of the included studies using the Newcastle-Ottawa Quality Assessment Scale. The significance of the pooled odds ratio (OR) was evaluated with a Z test, and statistical heterogeneity across studies was assessed using the I2 and Q statistics. Publication bias was assessed using Egger's and Begg's tests. The primary study outcome was the development of biliary atresia. Subgroup analysis was performed based on race, region, and assessment of Hardy-Weinberg equilibrium (HWE). The studies indicate that the ADD3 rs2501577 susceptibility locus increases the risk of developing biliary atresia, regardless of allelic, homozygote, dominant, and recessive gene inheritance models. Furthermore, ADD3 has been found to be associated with apoptosis, cell cycle, and cell damage repair based on functional analysis. The ADD3 rs2501577 polymorphic locus is associated with an increased risk of biliary atresia, particularly in Asian populations. This study recommends further investigation of the ADD3 rs2501577 locus in Asian populations to validate its role in the diagnosis of biliary atresia.

Role of ENPP1 Gene Variants in the Susceptibility to Diabetic Nephropathy in Patients with type 2 Diabetes Mellitus.

Genetic factors are known to play a significant role in the susceptibility of diabetic patients to severe complications such as diabetic nephropathy (DN). This study aimed to evaluate the association between polymorphism of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) variants (rs997509, K121Q, rs1799774, and rs7754561) and DN in patients with type 2 diabetes mellitus (T2DM). A total number of 492 patients with T2DM with and without DN were categorized into case and control groups. The extracted DNA samples were genotyped using TaqMan allelic discrimination assay amplified by polymerase chain reaction (PCR). The haplotype analysis among the case and control groups was performed using an expectation-maximization algorithm by the maximum-likelihood method. The analysis of laboratory findings demonstrated significant differences in fasting blood sugar (FBS) and hemoglobin A1c (HbA1c) between the case and control groups (P < 0.05). The results showed that K121Q was significantly related to DN under a recessive model of inheritance (P = 0.006); however, rs1799774 and rs7754561 both were protective for DN under a dominant model of inheritance (P = 0.034 and P = 0.010, respectively) among four studied variants. Two haplotypes, including C-C-delT-G with a frequency < 0.02 and T-A-delT-G with a frequency < 0.01, were associated with the increased risk of DN (P < 0.05). The present study demonstrated that K121Q was associated with the susceptibility of DN; however, rs1799774 and rs7754561 were protecrtive variants for DN in patients with T2DM.

Molecular Evaluation of the Impact of Polymorphic Variants in Apoptotic (Bcl-2/Bax) and Proinflammatory Cytokine (TNF-α/IL-8) Genes on the Susceptibility and Progression of Myeloproliferative Neoplasms: A Case-Control Biomarker Study

The regulation of apoptosis (the programmed cell death) is dependent on the crucial involvement of BCL2 and BAX. The Bax-248G>A and Bcl-2-938 C>A polymorphic variations in the promoter sequences of the Bax and Bcl-2 gene have been recently associated with low Bax expression, progression to advanced stages, treatment resistance, and shortened overall survival rate in some hematological malignancies, including chronic myeloid leukemia (CML) and other myeloproliferative neoplasms. Chronic inflammation has been linked to various stages of carcinogenesis wherein pro-inflammatory cytokines play diverse roles in influencing cancer microenvironment leading to cell invasion and cancer progression. Cytokines such as TNF-α and IL-8 have been implicated in cancer growth in both solid and hematological malignancies with studies showing their elevated levels in patients. Genomic approaches have in recent years provided significant knowledge with the regard to the association of certain SNPs (single nucleotide polymerphisms) either in a gene or its promoter that can influence its expression, with the risk and susceptibility to human diseases including cancer. This study has investigated the consequences of promoter SNPs in apoptosis genes Bax-248G>A (rs4645878)/Bcl-2-938C>A (rs2279115) and pro-inflammatory cytokines TNF-α rs1800629 G>A/IL-8 rs4073 T>A on the risk and susceptibility towards hematological cancers. The study design has 235 individuals both male and female enrolled as subjects that had 113 cases of MPDs (myeloproliferative disorders) and 122 healthy individuals as controls. The genotyping studies were conducted through ARMS PCR (amplification-refractory mutation system PCR). The Bcl-2-938 C>A polymorphism showed up in 22% of patients in the study, while it was observed in only 10% of normal controls. This difference in genotype and allele frequency between the two groups was significant (p = 0.025). Similarly, the Bax-248G>A polymorphism was detected in 6.48% of the patients and 4.54% of the normal controls, with a significant difference in genotype and allele frequency between the groups (p = 0.048). The results suggest that the Bcl-2-938 C>A variant is linked to an elevated risk of MPDs in the codominant, dominant, and recessive inheritance models. Moreover, the study indicated allele A as risk allele which can significantly increase the risk of MPDs unlike the C allele. In case of Bax gene covariants, these were associated with an increased risk of MPDs in the codominant inheritance model and dominant inheritance model. It was found that the allele A significantly enhanced the risk of MPDs unlike the G allele. The frequencies of IL-8 rs4073 T>A in patients was found to be TT (16.39%), AT (36.88%) and AA (46.72%), compared to controls who were more likely to have frequencies of TT (39.34%), AT (37.70%) and AA (22.95%) as such, respectively. There was a notable overrepresentation of the AA genotype and GG homozygotes among patients compared to controls in TNF-α polymorphic variants, with 6.55% of patients having the AA genotype and 84% of patients being GG homozygotes, compared to 1.63% and 69%, respectively in controls. The data from the current study provide partial but important evidence that polymorphisms in apoptotic genes Bcl-2-938C>A and Bax-248G>A and pro-inflammatory cytokines IL-8 rs4073 T>A and TNF-α G>A may help predict the clinical outcomes of patients and determine the significance of such polymorphic variations in the risk of myeloproliferative diseases and their role as prognostic markers in disease management using a case-control study approach.

Genetic variants of the vitamin D receptor are related to dynapenia in postmenopausal women

BackgroundDynapenia increases with age and in the case of women is possibly influenced by menopause, yet whether vitamin D affects this increase remains controversial. The influence of genetic variants (single nucleotide polymorphisms) of the vitamin D receptor on dynapenia is an understudied area. AimTo analyze the association between genetic variants of the vitamin D receptor gene and dynapenia in a cohort of community-dwelling postmenopausal women. MethodsWe performed a cross-sectional study of 463 women in a university hospital. Grip strength was used as an indicator of dynapenia. Differences in grip strength among single nucleotide polymorphisms rs11568820 and rs2228570 genotypes of the vitamin D receptor gene were assessed after adjusting for confounding variables, and the percentage of phenotypic variance was estimated by linear regression. ResultsDynapenia (grip strength <20 kg) was diagnosed in 178 of the women (38.45 %). A difference in grip strength, corresponding to variants of the vitamin D receptor gene single nucleotide polymorphism rs11568820, was found when using an additive model of inheritance, with lower grip strength for the TT genotype (ANOVA, p = 0.030, close to the 0.025 significance level determined by Bonferroni correction). Assuming a recessive inheritance model for allele T, the between-group difference in grip strength was significant (TT = 19.79 ± 3.10 kg vs. CC/CT = 21.58 ± 3.49 kg, p = 0.008) after adjusting for age, body mass index, comorbidities, and sociodemographic variables. More women with dynapenia had the TT genotype (60.71 %) than the CC or CT genotype (37.01 %) (p = 0.012). ConclusionThis study demonstrates that the TT genotype of the rs11568820 SNP of the vitamin D receptor gene was associated with decreased grip strength in community-dwelling postmenopausal women.

Association of DROSHA rs6877842, rs642321 and rs10719 polymorphisms with increased susceptibility to breast cancer: A case-control study with genotype and haplotype analysis.

Multiple lines of evidence suggest that single nucleotide polymorphisms (SNPs) in genes encoding components of the microRNA processing machinery may underlie susceptibility to various human diseases, including cancer. The present study aimed to investigate whether rs6877842, rs642321 and rs10719 SNPs of DROSHA, a key component of the miRNA biogenesis pathway, are associated with increased risk of breast cancer. A total of 100 patients diagnosed with breast cancer and 100 healthy women were included. Following extraction of DNA, genotyping was performed by tetra primer- amplification refractory mutation system-PCR (T-ARMS-PCR) technique. Under the co-dominant, dominant and recessive inheritance models, the association between DROSHA SNPs and breast cancer risk was determined by logistic regression analysis. The association of DROSHA SNPs with patients' clinicopathological parameters was assessed. Also, haplotype analysis was performed to evaluate the combined effect of DROSHA SNPs on breast cancer risk. We observed a statistically significant association between DROSHA rs642321 polymorphism and breast cancer susceptibility (P <0.05). Under the dominant inheritance model, DROSHA rs642321 polymorphism was significantly associated with increased risk of breast cancer (OR: 6.091; 95% CI: 3.291-11.26; P =0.0001). Our findings demonstrated that DROSHA rs642321 T allele can contribute to the development of breast cancer (OR: 3.125; 95% CI: 1.984-4.923; P =0.0001). We also found that GTC and GTT haplotypes conferred significant risk for breast cancer (OR: 2.367; 95% CI: 1.453-3.856; P =0.0001 and OR: 7.944; 95% CI: 2.073-30.43; P =0.0001, respectively). These results provide the first evidence that DROSHA rs642321 polymorphism is associated with increased risk of breast cancer. However, further studies are needed to firmly validate these findings.

Association between variants on the vitamin D Receptor gene and chronic kidney disease among a Yoruba population in Ibadan, Nigeria

Chronic kidney disease, characterized by progressive loss of kidney function is a disease of public health importance globally. The burden is on a steep rise in Nigeria and sub-Saharan Africa, thereby contributing to the double epidemic of communicable and non-communicable diseases in this region of the world. Genome-wide association studies have identified several variants on different genes including the Vitamin D receptor (VDR) gene, associated with CKD defining traits. This study evaluated the association between SNPs on the VDR gene rs4334089 (CviAll), rs1544410 (BsmI) and rs7975232 (ApaI) with CKD in a Yoruba population of Nigeria. This case-control study recruited a total of 203 participants. Variants were amplified and genotyped using PCR-RFLP. Genotypes were tested for conformity with the Hardy-Weinberg equilibrium and associations were tested under three inheritance patterns. Results showed the minor allelic frequency of rs1544410 (BsmI) differed significantly from the reference value for the Nigerian population as reported on 1000 Genomes database. We report for the first time the relationship between vitamin D receptor polymorphisms, (rs4334089 (CviAll), rs1544410 (BsmI) and rs7975232 (ApaI) and chronic kidney disease in a Yoruba population from Ibadan southwest Nigeria. We found a significant risk association of CviAII with CKD under the dominant inheritance model (OR = 5.29; p = 7.13e−8), while CviAII was associated with protection to CKD under the recessive inheritance model (OR = 0.04; p = 0.002). This study provides further evidence that vitamin D receptor gene polymorphisms contribute to the risk chronic kidney disease in the Ibadan southwest population.

Дослідження зв'язку фенотипу бронхіальна астма-ожиріння з ER22/23EK і TTH111I поліморфізмами гена глюкокортикоїдного рецептора

(GR) gene with the body mass index (BMI) of patients with bronchial asthma (BA), considering the age of BA onset. Materials and methods. 553 patients with BA and 95 practically healthy persons who previously signed an informed consent to participate in the study were examined. Patients were divided into two clinical groups according to the age of BA onset. Group I included 282 patients with late-onset of asthma (late asthma phenotype), and Group II included 271 patients with early onset (early asthma phenotype). The diagnosis of BA and the severity of the course were established according to the recommendations of GINA-2016 and subsequent versions. Diagnosis of obesity was carried out in accordance with the Order of the Ministry of Health of Ukraine dated August 5, 2009, No. 574, and the European Association for the Study of Obesity (EASO, 2016). The study was approved by the Bioethics Committee of the Medical Institute of Sumy State University. Determination of ER22/23EK (rs 6189/6190) and Tth111I (rs10052957) polymorphisms of the GR gene was performed using the polymerase chain reaction followed by the analysis of restriction fragments. Statistical analysis of the obtained results was carried out using the SPSS-17 program. The results. The analysis of anthropometric parameters showed that among the examined patients with BA, there were 152 (27.5 %) patients with normal body weight (NBW), 206 (37.3 %) were overweight, and 195 (35.2 %) with obesity. Visceral type of obesity was verified among all patients. It was established that among overweight and obese BA patients, there was a higher frequency of GG genotype according to the ER22/23EK polymorphism of the GR gene compared to patients with NBW. Heterozygotes were found 5.6 and 3.5 times more often in patients with normal body weight compared to patients with obesity. Analysis of the ratio of G and A alleles depending on BMI shows a higher frequency of the G allele in obese patients compared to patients with NBW. The distribution of alleles and genotypes according to the Tth111I polymorphism in the examined patients with BA depending on the BMI shows a twice higher frequency of homozygotes for the main C allele in overweight and patients with obesity compared to patients with NBW. Carriers of homozygotes for the minor allele were detected 4.7 times and 2.1 times more often in patients with NBW compared to overweight patients and with obesity. A probable difference in the distribution of alleles and genotypes according to the Tth111I polymorphism of the GR gene was established in patients with early and late BA (p = 0.001). Carriers of homozygotes for the main allele of CC were found more often in patients with early and late BA in the presence of obesity. Conclusions. A higher frequency of the GG genotype according to the ER22/23EK polymorphism of the GR gene and homozygotes according to the main CC allele according to the Tth111I polymorphism of the GR gene in overweight BA patients and with obesity compared to patients with NBW was proven. The protective role of the ER22/23EK polymorphism of the GR gene in relation to the occurrence of obesity in the dominant, superdominant and additive models of inheritance and the Tth111I polymorphism of the GR gene in the superdominant model was established. A higher frequency of carriers of homozygotes for the main C allele in patients with early-onset and late-onset BA in the presence of obesity compared to patients with NBW, a protective role of the Tth111I polymorphism of the GR gene on the risk of developing obesity in patients with late-onset BA in superdominant and recessive models of inheritance was established. Key words: bronchial asthma, obesity, onset, course, ER22/23EK, and Tth111I polymorphisms of the glucocorticoid receptor gene.

Methylenetetrahydrofolate Reductase C677T Gene Variant in Relation to Body Mass Index and Folate Concentration in a Polish Population.

Methylenetetrahydrofolate reductase (MTHFR) is an enzyme responsible for producing an active form of folate. The MTHFR T677T genotype may have adverse health effects associated with weight gain and a reduction in folate availability. In this study, we examined the influence of the MTHFR C677T variant on BMI and determined its role as a risk factor for obesity. We also assessed the relationships between the MTHFR C677T genotype and folate and vitamin B12 concentrations in subjects before and after radical weight loss. The study group consisted of 1712 Caucasian adults of Polish nationality with a wide range of body mass indexes (BMIs). DNA was extracted from the blood, and the C677T variant was tested with RFLP-PCR and real-time-PCR. There was no significant influence found for the MTHFR 677 TT genotype on BMI or the obesity risk in codominant, dominant or recessive inheritance models. Individuals with obesity and the TT genotype had significantly lower folate concentrations. After radical weight reduction, the impact of the risk genotype, as well as homeostasis between folate and vitamin B12 in TT homozygotes, seems to be attenuated. Although the MTHFR 677TT genotype is not directly related to a higher BMI in Polish adults, it has a detrimental effect on folate concentrations in individuals with high BMI values.

Single Nucleotide Polymorphisms Of Transforming Growth Factor-Β1 Gene As Potential Asthma Susceptible Variants In Punjabi Population Of Pakistan.

Candidate gene approach based on case-control model is a valuable strategy to determined disease related genetic variants. Two single nucleotide polymorphisms rs1800469 and rs2241715 in TGF β1gene have been reported to affect the asthmatic status in different populations. The main focus of this research was to find any relationship between these SNPs and asthma in Pakistani population. Using case-control model, a total of 108 individuals including 52 asthma patients and 56 healthy controls were screened to find asthma susceptibility of variants rs1800469 and rs2241715. These SNPs were genotyped using SNaPshot minisequencing assay followed by capillary electrophoresis using ABI 3130xl genetic analyzer platform. The statistical analysis of genetic data was performed by using SPSS 21, SHEsis online platform and SNPStats online web software. No association with asthma was seen in allelic model for both SNPs but genotypes analyzed under codominant, dominant, over dominant and recessive models of inheritance revealed that SNP rs2241715 is strongly associated with asthma under genotypic model. rs2241715 was found to be a genetic risk factor for asthma in Pakistani population.

Increased Carotid Intima-Media Thickness in Asymptomatic Individuals Is Associated with the PCSK9 (rs2149041) Gene Polymorphism in the Mexican Mestizo Population: Results of the GEA Cohort.

The increase in carotid intima-media thickness (CIMT) and coronary artery calcification (CAC) are features of subclinical atherosclerosis that might be determined by the genetic background of patients. Among the multiple risk factors, the proprotein convertase subtilisin kexin type 9 (PCSK9) has a great impact on atheroma development. Then, we focused on the potential association of the PCSK9 gene polymorphism (rs2149041) with the risk of an increased CIMT. We included 881 unrelated, asymptomatic individuals (732 normal CIMT and 149 increased CIMT) who lacked coronary calcification (CAC score = 0). Under the recessive inheritance model and adjusted by several cardiovascular risk factors, the rs2149041 polymorphism, determined by TaqMan genotyping assay, was associated with a high risk of increased CIMT (OR = 2.10, 95% IC = 1.26–3.47, P recessive = 0.004). Our results suggest that the rs2149041 polymorphism could be a risk marker for increased CIMT in asymptomatic individuals without coronary artery disease determined by the absence of a CAC score.

A Gly684Ala substitution in the androgen receptor is the cause for azoospermia in a Chinese family with mild androgen insensitivity syndrome and normal hormone levels.

Androgen receptor gene (AR) is essential for male growth and fertility. Its mutations are responsible for androgen insensitivity syndrome (AIS) that usually shows the phenotype of azoospermia resulting in male infertility. This study reported the first case of mild AIS with complete normal serum hormones in a Chinese family. The proband referred for infertility because of azoospermia. His uncle and two cousins are both infertile and have azoospermia. Whole-exome sequencing in the genetic analyses showed that the proband carries a novel hemizygous AR missense mutation, NM_000044.6: c.2051G>C (p.Gly684Ala), in exon four within the ligand-binding domain. His mother and maternal aunt are heterozygous carriers, while his father and brother are wildtype, indicating that the mutation in the proband was inherited from his mother. This pattern is consistent with the genetic model of the X-linked recessive inheritance of AR in AIS pathogenesis. HOPE predicts that p.Gly684Ala increases the hydrophobicity of AR but does not change the AR conformation. PolyPhen-2 predicts that p.Gly684Ala is harmful. This study provides the new knowledge to understand the AR gene mutations in MAIS.

Relationship of -31G/C (rs9904341) polymorphism in the survivin gene &lt;i&gt;BIRC5&lt;/i&gt; and the risk of bladder cancer

Purpose: To study the relationship between the -31G/C (rs9904341) polymorphism in the promoter region of the survivin protein gene and the predisposition to bladder cancer (BC) in patients of the Krasnoyarsk region. Material and methods. The allelic composition of the studied gene was determined in a group of 158 BC patients, consisting of 30 women and 128 men (mean age 65.6 ± 10.7, median: 66.5; C25–C75: 59–72). The control group included 117 healthy donors and consisted of 27 women and 90 men with an average age of 60.2 ± 5.1 (median: 60; C25–C75: 57–63.25). The allelic composition was determined using the bioluminescent method. A sample with the GC genotype confirmed by sanger sequencing (center for collective use “genomika”, Novosibirsk, Russia) was used as a control. The Mann–Whitney U test was used to compare quantitative data. the studied sample was in Hardy–Weinberg equilibrium (p&gt;0.5). The pearson χ2 test was used to compare the frequencies of gene variants among BC cases and control samples. The association between variants rs9904341 and BC was assessed in terms of odds ratio (OR) with a 95 % confidence interval (CI); p values&lt;0.05 were considered significant. Results. The allelic composition was determined for the genes of patients and control group participants: GG – 62 (39.2%) vs 43 (36.8%); GC – 82 (51.9%) vs 54 (46.2%); CC – 14 (8.9%) vs 20 (17.15%). The relationship between the presence of the C allele and BC was assessed using the recessive inheritance model, combining all carriers – heterozygotes and homozygotes. The frequency of occurrence of genotypes for patients and the control group was established: GG + GC – 144 (91.1%) vs 97 (82.9%); CC – 14 (8.9%) vs 20 (17.1%). Thus, carriers of the CС genotype were significantly less in patients: OR (95% CI) 0.47 (0.23–0.98), p=0.04. The relationship with tumor invasion was not significant (p=0.08). Conclusion. Based on the results of detecting the rs9904341 (G/C) polymorphism among BC patients of the Krasnoyarsk region, a protective effect of the carriage of the CC genotype was found. In order to study the allelic composition with the threat of recurrence of the disease, additional research is needed.