Polymorphic Variants Research Articles

Somatic Mutation Accumulations in Micropropagated Cannabis Are Proportional to the Number of Subcultures.

Advancements in micropropagation techniques have made it easier to produce large numbers of cannabis clones, but these methods may also introduce genetic instability over successive generations. This instability often manifests as somaclonal variation, characterized by the progressive accumulation of genetic mutations or epigenetic alterations with each subculture. In this study, we examined how mutations accumulate in cannabis clones subjected to 6-11 subcultures. Using genotyping-by-sequencing, we identified 9405 polymorphic variants across 70 clones. The analysis revealed a correlation between the number of subcultures and the frequency of these mutations, revealing that genetic changes accumulate over successive subcultures despite clones sharing the same chronological age. Furthermore, we evaluated the functional impacts of accumulated mutations, with particular attention to implications on gene function and overall plant health. While rare, 14 high-impact variants were identified in genes that are important for plant development. Notably, six variants were also found in genes related to cannabinoid and terpene synthesis pathways, potentially affecting the plant's biochemical composition. These findings highlight the need for genetic assessments in micropropagation protocols, impacting plant breeding and conservation. Understanding genetic variations in clonally propagated plants optimizes practices for stability. Crucial for cannabis and horticultural plants, it emphasizes techniques to prevent genetic decay and ensure viability.

Association between OX40L polymorphism and type 2 diabetes mellitus in Iranians

IntroductionDiabetes mellitus (DM) is one of the leading causes of morbidity and mortality worldwide. It is a multifactorial disease that genetic and environmental factors contribute to its development. The aim of the study was to investigate the association of OX40L promoter gene polymorphisms with type 2 diabetes mellitus (T2DM) in Iranians.Materials and methodsThree hundred and sixty-eight subjects including 184 healthy subjects and 184 T2DM patients were enrolled in our study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was applied to detect genotype and allele frequencies of rs3850641, rs1234313 and rs10912580. In addition, SNPStats web tool was applied to estimate haplotype frequency and linkage disequilibrium (LD).ResultsThe distribution of tested polymorphisms was statistically different between the T2DM patients and healthy subjects (P < 0.01). rs1234313 AG (OR = 0.375, 95% CI = 0.193–0.727, P = 0.004) and rs10912580 AG (OR = 0.351, 95% CI = 0.162–0.758, P = 0.008) genotypes were associated with the decreased risk of T2DM in Iranians. Moreover, our prediction revealed that AAG (OR = 0.46, 95% CI= (0.28–0.76), P = 0.0028) and GAG (OR = 0.24, 95% CI= (0.13–0.45), P < 0.0001) haplotypes were related to the reduced risk of the disease. However, the tested polymorphisms had no effect on biochemical parameters and body mass index (BMI) in the patient group (P > 0.05).ConclusionOur findings revealed that OX40L promoter gene polymorphisms are associated with T2DM. Moreover, genotype and allelic variations were related to the decreased risk of T2DM in Iranians. Further studies are recommended to show whether these polymorphic variations could affect OX40/OX40L interaction or OX40L phenotype.

CYP21A2 Intron 2 Genetic Variants Might Be Associated with the Clinical Characteristics of Women with PCOS.

Pathogenic variants in the CYP21A2 gene are related to the classic and non-classic forms of congenital adrenal hyperplasia (CAH). However, the role of CAH carrier status in the clinical presentation of polycystic ovarian syndrome (PCOS) is still unclear. Moreover, the possible associations of different CYP21A2 gene polymorphisms with metabolic and reproductive abnormalities in PCOS have not been investigated. Therefore, the present study aims to examine the prevalence of the most common CYP21A2 pathogenic variant IVS2-13A/C>G (c.293-13A/C>G) in Eastern European women with PCOS and to evaluate the associations between common intron 2 genetic polymorphisms and the clinical symptoms of the patients. Sixty consecutively recruited women with PCOS were genotyped for the CYP21A2 intron 2 IVS2-13A/C>G genetic variant. Additionally, CYP21A2 intron 2 polymorphic variants rs6453 (c.293-44G>T), rs6451 (c.293-67C>A/G), rs369651496 (c.293-104del), and rs6474 (c.308G>A/p.R103L) were tested and described. The clinical and hormonal characteristics were compared in women with PCOS and with polymorphic and wild-type genotypes. The heterozygous CYP21A2 pathogenic variant IVS2-13A/C>G was found in one of the investigated PCOS patients (1.67%) with a non-hyperandrogenic type of PCOS. The presence of the rs6453 (c.293-44G>T) T-allele was associated with increased levels of DHEAS (15.18 vs. 9.14 µmol/L, p = 0.003) compared to the wild-type genotype in the investigated group. The rs6451 (c.293-67C>A/G) minor alleles were associated with an earlier age of menarche in the patients (12.0 vs. 13.0 years, p = 0.007). The polymorphic rs369651496 minor 6G allele was related to a better lipid profile in the women with PCOS, while the rs6474 variant modulated the blood pressure of the patients. The presence of CYP21A2 genetic minor alleles of rs6467 (IVS2-13A/C, c.293-13A/C), rs6453 (c.293-44G>T), rs6451 (c.293-67C>A/G), rs369651496 (c.293-104del), and rs6474 (c.308G>A/p.R103L) might modulate the adrenal androgens, age of menarche, and metabolic features in women with PCOS. Further studies on 21-hydroxylase genetic variants (pathogenic and polymorphisms) in different ethnic groups might help reveal the influence of adrenal steroidogenesis on PCOS development, clinical manifestations, and lifelong cardiovascular risks.

Effect of &lt;i&gt;VEGF&lt;/i&gt; gene polymorphism on the survival of a patient with non-small cell lung cancer

Currently, much attention is paid to studying the vascular endothelial growth factor (VEGF) that stimulates angiogenesis, as a potential target for antiangiogenic therapy. The purpose of this work was to study the effect of polymorphic variants rs2010963 (G-634C), rs699947 (A-2578C), and rs3025039 (C+936T) of the VEGF gene, encoding a vascular endothelial growth factor, on the overall (OS) and adjusted survival (AS) of patients with non-small cell lung cancer (NSCLC) at stages I–III. The effect of VEGF rs699947 polymorphic variants on the extent of tumor spread was shown. A connection between AS and polymorphic variants rs2010963 (G-634C) and rs699947 (A-2578C) was established. The one-year adjusted survival (AS) in the -634G/C genotype carriers was 81.9 ± 3.9 %; in the -634G/G genotype carriers – 92.8 ± 2.5 %; and p = 0.016 was the significance level. Two-year AS was as follows: in the carriers of the -634G/C genotype was 70.4 ± 4.6 %; in the carriers of the -634G/G genotype – 84.3 ± 3.5 %; and p = 0.015. Three-year AS: in the carriers of the -634G/ genotype C was 63.0 ± 4.9 %; in the carriers of the -634G/G genotype – 76.7 ± 4.1 %; and p = 0.029. One-year and two-year AS in the carriers of the -2578A/A genotype was significantly higher than in the carriers of the -2578C/C genotype (p = 0.015 and p = 0.042 respectively). The identified influence of the polymorphic variants rs2010963 and rs699947 on the survival of NSCLC patients during the first three years after the established diagnosis shows a need to use knowledge about the genetic characteristics of a tumor during therapy.

Search for ethnospecific risk markers for the development of paranoid schizophrenia in bashkirs based on the results of a genome-wide association analysis

Schizophrenia is now known to be a multifactorial disease in which both genetic and environmental factors play a role. In recent years, mainly through the use of genome-wide association studies (GWAS), many molecular genetic processes have been identified that increase susceptibility to schizophrenia. The aim of this study was to study genetic risk factors for the development of schizophrenia in a genome-wide association analysis (GWAS) in Bashkirs from the Republic of Bashkortostan. The studied sample consisted of 139 patients with paranoid schizophrenia and 204 healthy individuals. Whole genome genotyping of DNA samples was carried out on the PsychChip biochip, which included 610,000 single nucleotide polymorphic variants (SNPs).

Genetic Markers of Acute Childhood B-Lineage Lymphoblastic Leukemia in the Kazakh Population

Introduction To investigate the genetic contribution of 24 GWAS-associated polymorphic gene variants on the development of children’s B-lineage acute lymphoblastic leukemia (B-ALL) in an ethnically homogeneous population of Kazakhs. Methods A study of 205 children with B-ALL and 204 healthy children was conducted. Genotyping of polymorphic loci was carried out using the TaqMan method. Results Significant associations (p < 0.05) with the risk of childhood B-ALL were found for twelve variants, including rs6457327 of the HLA gene, rs4251961 of the IL1RN gene, and rs1800630 of the TNF gene. Carriage of the minor allele A of the protective rs1801157 polymorphism A of the CXCL12 gene reduces the risk of B-ALL in the Kazakh population by 40%. Discussion The results reveal significant associations of polymorphic genetic variants, which can serve as a basis for the development of effective methods for predicting the risk of B-ALL, early diagnosis, and timely treatment.

Genetic Features of Lipid and Carbohydrate Metabolism in Arctic Peoples.

Prolonged adaptation of ancestors of indigenous peoples of the Far North of Asia and America to extreme natural and climatic conditions of the Arctic has resulted in changes in genes controlling various metabolic processes. However, most genetic variability observed in the Eskimo and Paleoasians (the Chukchi and Koryaks) is related to adaptation to the traditional Arctic diet, which is rich in lipids and proteins but extremely poor in plant carbohydrates. The results of population genetic studies have demonstrated that specific polymorphic variants in genes related to lipid metabolism (CPT1A, FADS1, FADS2, and CYB5R2) and carbohydrate metabolism (AMY1, AMY2A, and SI) are prevalent in the Eskimo and Paleoasian peoples. When individuals deviate from their traditional dietary patterns, the aforementioned variants of genetic polymorphism can lead to the development of metabolic disorders. American Eskimo-specific variants in genes related to glucose metabolism (TBC1D and ADCY) significantly increase the risk of developing type2 diabetes. These circumstances indicate the necessity for a large-scale genetic testing of indigenous population of the Far North and the need to study the biochemical and physiological consequences of genetically determined changes in the activity of enzymes of lipid and carbohydrate metabolism.

The Incidence of CD28 Gene Polymorphism (rs3116496) and Gene Expression with Oral Carcinoma in Some Iraqi Samples

Abstract Background: Oral carcinoma is one kind of cancer that develops in the cavity of the oral, lip, tongue, gingiva, and oropharynx. The World Health Organization (WHO) illustrated that oral carcinoma is among the most prevalent cancers in the world, considered the sixteenth most malignant, which is commonly prevalent, and the fifteenth reason that causes mortality in the world. Objective: This study aimed to investigate the association between oral carcinoma with single-nucleotide polymorphism (rs3116496) and CD28 (cluster differentiation 28) gene expression. Materials and Methods: Samples were collected from 61 control and 61 patients with early squamous oral carcinoma from the gum diseases department/Fallujah specialized center. Then we investigated the variation of CD28 polymorphism and gene expression of CD28 using real-time PCR. Results: The results showed that there are significant differences between patients and control in the TT genotype of codominant models with P = 0.003 and OR = 8.89. There were significant differences in the dominant and recessive models with P = 0.03 and 0.008, and OR = 2.4, 7.2, respectively. In addition, the T allele showed significant differences between patients and control with P = 0.002 and OR = 2.61. However, in the CD28 gene expression there were no significant differences between patients and control. Conclusion: The genotype TT and allele T of SNP of the CD28 gene are considered risk factors in oral carcinoma.

Clinical and Genomic Characteristics of Candida auris in Central Ohio: An Insight into Epidemiological Surveillance

Background: Candida auris is an emerging threat to hospitalized patients and invasive disease is associated with high mortality. This study describes clinical and microbiological characteristics of nine patients identified with C. auris at Ohio State Wexner Medical Center discovered through active surveillance or clinical investigation and uses whole genome sequencing (WGS) to compare isolates. Methods: In November 2022, an active C. auris surveillance program was implemented to screen patients admitted to high-risk units (intensive care units and progressive care units). Bilateral axilla and groin swabs were obtained upon unit admission and, if positive, were submitted for C. auris polymerase chain reaction (PCR) with culture and sensitivity testing. Patients with a positive screening or clinical isolate from November 2022 to November 2023 underwent chart review for clinical characteristics, microbiologic data, and index admission information. For each isolate, DNA was extracted and WGS was performed. Core single nucleotide polymorphism (SNP) variation identified from the sequence data was used to infer genetic relationships among the isolates. Results: Nine patients were identified between November 2022 and November 2023. The clinical and microbiologic characteristics are summarized in Table 1. All patients were hospitalized at various acute care facilities across the state at least once in the preceding 12 months. C. auris was determined to be present on admission for 6 patients. For 5 of these patients, it was their first interaction with our healthcare system. Three patients were not in contact isolation for &gt;3 days before C. auris was identified. Unit wide point-prevalence screening was completed in these cases and no evidence of transmission was found. WGS showed eight of the nine isolates were related with 28 or less core SNP differences between isolates (Figure 1). One isolate (8) was genetically distinct with &gt;45000 core SNP differences. Five isolates were highly related with a range of 4-15 SNP differences. No temporal or spatial overlap at our institution was identified among these five patients. Conclusions: The active surveillance program identified several patients colonized with C. auris in addition to those found through clinical testing. Multiple risk factors for C. auris were identified with high patient mortality (67%). Majority of the isolates were closely related without association with a known outbreak or epidemiologic link, suggesting a possible diffuse common reservoir. Next steps with surveillance in acute care and long-term care facilities will be critical for early detection to halt transmission of this organism.

Polymorphic variants of the hOGG1, APEX1, XPD, SOD2, and CAT genes involved in DNA repair processes and antioxidant defense and their association with breast cancer risk.

Breast cancer is one of the leading causes of mortality among women. The most frequently encountered tumors are luminal tumors. Associations of polymorphisms in the hOGG1 (rs1052133), APEX1 (rs1130409), XPD (rs13181), SOD2 (rs4880), and CAT (rs1001179) genes were studied in 313 nonsmoking postmenopausal patients with luminal B subtype breast cancer. The control group consisted of 233 healthy nonsmoking postmenopausal women. Statistically significant associations of the XPD and APEX1 gene polymorphisms with the risk of developing luminal B Her2-negative subtype of breast cancer were observed in a log-additive inheritance model, while the CAT gene polymorphism showed an association in a dominant inheritance model (OR = 1.41; CI 95 %: 1.08-1.85; Padj.= 0.011; OR = 1.39; CI 95 %: 1.07-1.81; Padj = 0.013 и OR = 1.70; CI 95 %: 1.19-2.43; Padj = 0.004, respectively). In the group of elderly women (aged 60-74 years), an association of the CAT gene polymorphism with the risk of developing luminal B subtype of breast cancer was found in a log-additive inheritance model (OR = 1.87; 95 % CI: 1.22-2.85; Padj = 0.0024). Using MDR analysis, the most optimal statistically significant 3-locus model of gene-gene interactions in the development of luminal B Her2-negative subtype breast cancer was found. MDR analysis also showed a close interaction and mutual enhancement of effects between the APEX1 and SOD2 loci and the independence of the effects of these loci from the CAT locus in the formation of luminal B subtype breast cancer.

Exploring immuno-genetic resistance in pigs to the food-borne zoonotic pathogen, Toxoplasma gondii: A serological study in Central Italy

Toxoplasmosis is a re-emerging food-borne zoonosis of warm-blooded animals caused by Toxoplasma gondii, an obligate intracellular parasite with a complex biological cycle. Until now, the genotypic approach for discovering putative resistance immuno-genetic markers has never been adopted for T. gondii infection. Thus, this study aimed, for the first time, to deepen these novel insights. In particular, pigs, reared in different farms in Central Italy, were phenotypically characterized by serological assays performed on diaphragm meat juice. Out of 179 tested animals, 98 resulted seropositive (54.74%), 57 seronegative (31.84%), and 24 doubtful (13.40%), underlining a possible re-emerging diffusion of this protozoan in the investigated areas. Contextually, an RT-PCR assay, followed by Sanger sequencing for IL-18, a pro-inflammatory cytokine with a key role upstream of the infection, was developed. At this stage, for this interleukin, significant polymorphic variations were not detected compared to the reference sequence, except in a seropositive animal. However, the starting outcomes of this novel and preliminary study will be investigated in depth with different approaches also on other target genes, with a crucial activity in the immunity pathway towards T. gondii, to unveil the possible presence of resistance genetic mechanisms and, finally, to make pork derived food safer.

The rs4354668 polymorphism in the SLC1A2 gene for the EAAT2 glutamate transporter is associated with an increased risk of harmful drug use - an exploratory study on a university student population.

Evidence suggests that decreased dopamine secretion in mesocorticolimbic pathways could predispose to increased susceptibility to substance addiction. It has been proposed to define such a phenomenon as the reward deficit syndrome (RDS). Dopaminergic projections of the reward system receive glutaminergic projections from cortex. Research indicates that a reduction in the stimulating glutamatergic transmission on the dopaminergic system could represent an alternative phenotype of RDS. Potential source of this type of abnormality is glutamate reuptake which depends on excitatory amino acid transport proteins (EAAT) function. The most important of them is EAAT2, polymorphisms of which have been linked to several mental disorders. We analyzed the genetic and psychometric data of 125 young adults (n = 125) for the effect of the rs4354668 polymorphism of the SLC1A2 gene for EAAT2 on the risky or harmful drug use (RHDU). After exploratory analysis we used logistic regression models to assess the probability of RHDU in individual groups. In the final model T/T variant of rs4354668 was significantly associated with a lower probability of RHDU occurrence compared to G/G variant (OR: 0.021; 95% CI: 0.001 - 0.275; p = 0.009). Other significant predictors of RHDU were smoking status and risky or harmful drinking of alcohol. The results obtained may indicate a possible relationship of the risk of harmful drug use with variants of the rs4354668 polymorphism of the SLC1A2 gene for EAAT2. Subjects with the T/T variant of this polymorphism appear to be less at risk of developing drug use disorders.

Neuropathologically-directed profiling of PRNP somatic and germline variants in sporadic human prion disease.

Creutzfeldt-Jakob Disease (CJD), the most common human prion disease, is associated with pathologic misfolding of the prion protein (PrP), encoded by the PRNP gene. Of human prion disease cases, ~1% were transmitted by misfolded PrP, ~15% are inherited, and ~85% are sporadic (sCJD). While familial cases are inherited through germline mutations in PRNP, the cause of sCJD is unknown. Somatic mutations have been hypothesized as a cause of sCJD, and recent studies have revealed that somatic mutations accumulate in neurons during aging. To investigate the hypothesis that somatic mutations in PRNP may underlie sCJD, we performed deep DNA sequencing of PRNP in 205 sCJD cases and 170 age-matched non-disease controls. We included 5 cases of Heidenhain variant sporadic CJD (H-sCJD), where visual symptomatology and neuropathology implicate focal initiation of prion formation, and examined multiple regions across the brain including in the affected occipital cortex. We employed Multiple Independent Primer PCR Sequencing (MIPP-Seq) with a median depth of >5,000X across the PRNP coding region and analyzed for variants using MosaicHunter. An allele mixing experiment showed positive detection of variants in bulk DNA at a variant allele fraction (VAF) as low as 0.2%. We observed multiple polymorphic germline variants among individuals in our cohort. However, we did not identify bona fide somatic variants in sCJD, including across multiple affected regions in H-sCJD, nor in control individuals. Beyond our stringent variant-identification pipeline, we also analyzed VAFs from raw sequencing data, and observed no evidence of prion disease enrichment for the known germline pathogenic variants P102L, D178N, and E200K. The lack of PRNP pathogenic somatic mutations in H-sCJD or the broader cohort of sCJD suggests that clonal somatic mutations may not play a major role in sporadic prion disease. With H-sCJD representing a focal presentation of neurodegeneration, this serves as a test of the potential role of clonal somatic mutations in genes known to cause familial neurodegeneration.

Search for molecular markers of joint hypermobility

Background: Joint hypermobility (JH) is a condition that can be either benign or accompanied by pain and early development of osteoarthritis. For early verification of the risk of complications, it is necessary to study the molecular pathogenesis of various JH variants. The aim of the study: The aim of this study was to search for candidate genes involved in connective tissue metabolism and causing joint hypermobility in a form isolated or combined with connective tissue dysplasia (CTD). Materials and methods: The study involved young (21,86±0,22 y.o.) people (n=181). A clinical study was conducted for the presence of signs of JH (Beighton scale) and CTD (tables Kadurina T.I.). Further, a molecular genetic study was carried out and the search for associations of polymorphic variants of genes (vitamin D receptor (VDR), lumican (LUM), tenascin (TNXB), growth/differentiation factor 5 (GDF5), magnesium ion channel TRPM6), bone morphogenetic protein type 5 (BMP5)) and JH, CTD in isolated and combined forms. Statistical data processing was carried out by comparing qualitative features using the χ2 test, Fisher's exact test, and the χ2 test with Yates' correction for contingency tables 2x2. The strength of associations was assessed in terms of the odds ratio (Odds Ratio, OR, at p&lt;0.05), the correction for multiple comparisons was carried out using the FDR method (Benjamin- Hochberg). Quantitative data were evaluated in pairs using the Student's t-test, the normality of distribution according to the Kolmogorov-Smirnov test. Results: Associations of the G allele and the GG genotype of the rs3734444 locus of the BMP5 gene with the presence of JH (OR=3.70 and OR=5.10), the A allele of the rs1470527 locus of the BMP5 gene and the presence of JH+CTD- (OR=8.00), the T allele and the TT genotype of the rs11144134 locus of the TRPM6 gene with JH in isolated (OR=3.00 and OR =10.19) and in the forms combined with CTD (OR=3.17 and OR=11.28), the TT genotype was also associated with the isolated form of CTD (OR=3.74). The GT genotype of the rs73611720 locus of the GDF5 gene was associated with isolated CTD (OR=4.15). No statistically significant associations were found for polymorphic variants rs11540149 (VDR), rs2268578 and rs3759222 (LUM), rs3130342 (TNXB). Conclusion: The G allele of locus rs3734444 of the BMP5 gene is a potential risk marker for JH in general, the A allele of locus rs1470527 is an isolated JH, the GT genotype of locus rs73611720 of the GDF5 gene is a marker for isolated CTD, the T allele of locus rs11144134 of the TRPM6 gene is a marker for JH combined with CTD.

Polymorphism in the matrix metallopeptidase genes is associated with coronary artery disease risk with concomitant metabolic syndrome

Background: Metabolic syndrome (MS) and its components are the reasons of the development and progression of cardiovascular diseases. Nowadays, the association between coronary artery disease and MS remains ambiguous. The central role of matrix metallopeptidases (MMP) in the metabolism of connective tissue proteins, cell matrix remodeling, tissue repair and other complex biochemical processes has been shown, which implies their involvement in the pathogenesis of cardiovascular diseases. The aim of the study: To study the associations of polymorphic variants in the MMP genes with the risk of stable coronary artery disease with concomitant metabolic syndrome. Materials and methods: 170 patients with stable coronary artery disease concomitant with a visceral type of obesity in combination with two or more pathological conditions (elevated serum blood glucose level, elevated serum blood cholesterol level, hypertension) were included in the case group. Conditionally healthy volunteers (n=182) were recruited in the control group. Genotyping of five polymorphic sites in the four genes MMP1 (rs514921), MMP3 (rs6796620 and rs626750), MMP9 (rs17576) and TIMP2 (rs2277698) was performed by real-time PCR. The serum blood level of MMP was measured by ELISA. Gene-gene interactions were analyzed using MDR v.3.0.2 software. Results: The frequency of heterozygous C/T genotype in the MMP3 gene (rs626750) was higher in the control group (37.90%) compared to the case group (23.20%), which indicates its protective effect on the risk of coronary artery disease with concomitant metabolic syndrome (OR=0.47, 95%CI 0.29-0.75). 2.6-fold increased risk of coronary artery disease with concomitant metabolic syndrome was demonstrated for carriers of the A/G genotype in the TIMP2 gene (rs2277698) according to the codominant inheritance model. We found no associations of polymorphic variants in the MMP1 (rs514921), MMP3 (rs626750), MMP9 (rs17576) and TIMP2 (rs2277698) genes with the serum blood level of MMP, as well as their inhibitors. Four-loci model of gene-gene interactions (MMP9 (rs17576) – MMP3 (rs626750) – MMP1 (rs514921) – TIMP2 (rs2277698)) characterized by high sensitivity, specificity and risk effect to the coronary artery disease with concomitant metabolic syndrome development was discovered. Conclusion: This study revealed the association of polymorphic variants in the MMP genes and their inhibitors with the risk of coronary artery disease with concomitant metabolic syndrome. In addition, a four-locus model of intergenic interactions with high sensitivity and specificity was obtained.

Efficacy of combined antihypertensive therapy in patients with type 2 diabetes mellitus and non-alcoholic fatty liver disease with various polymorphisms of the CYP2C9 gene

Background. The difficulty of achieving target blood pressure (BP) levels in patients with arterial hypertension (AH) is often due to their type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). In turn, taking into account the individual genetic characteristics of the body helps to personalize treatment and make it more effective. Aim. To compare the antihypertensive efficacy of a fixed combination of amlodipine and olmesartan medoxomil (Aml/Ol-M) in patients with hypertension and T2DM, with and without NAFLD, depending on the polymorphism of the CYP2C9 gene. Materials and methods. The study included 139 patients with uncontrolled hypertension and concomitant T2DM; after diagnosis of NAFLD, they were randomized into 2 groups: without NAFLD (group 1, n=70), with NAFLD (group 2, n = 69). After discontinuation of previous ineffective antihypertensive therapy, they were prescribed a combination of Aml/Ol-M in doses of 5-10/20-40 mg/day. At baseline, 4, 8, 12 and 24 weeks, their office BP levels were determined; Also, at the initial visit and after 24 weeks of treatment, the main indicators of 24-hour blood pressure monitoring (ABPM) were measured. Patients who did not reach the blood pressure target within 12 weeks of therapy were excluded from the study. Those who continued to participate in the amplifierThe Rotor Gene-Q allele discrimination method revealed the following distribution of polymorphic variants of the CYP2C9 gene: *1/*1 was found in 52 and 47, *1/*2 – in 6 and 5, *1/*3 – in 5 and 6 subjects, for groups 1 and 2, respectively. Results. The initial levels of office BP values were significantly higher in patients of group 2 and amounted to 153,5 mm Hg for systolic and 93 mm Hg for diastolic blood pressure, compared with 145 mm Hg and 88 mm Hg those included in group 1. After 12 weeks of therapy, the achievement of target blood pressure was registered in 63 (90 %) patients of group 1 and in 58 (84,1 %) of group 2. After 24 weeks of observation, in both groups a beneficial effect of the studied combination of drugs on all indicators of ABPM was noted, but a more pronounced improvement was noted in patients with NAFLD. Along with this, significant improvements in daily blood pressure profiles were registered in both groups 1 and 2: an increase in the number of patients with the “dipper” profile and a decrease in the number of patients with the pathological “non-dipper” profile. The antihypertensive effectiveness of Aml/Ol-M has been demonstrated for all isolated allelic variants of the CYP2C9 gene. Conclusions. A 24-week study with the use of Aml/Ol-M demonstrated a high incidence of achieving office BP target values in patients with hypertension and T2DM, with and without NAFLD. However, a more pronounced decrease in ABPM levels was found in patients with NAFLD. Carriage of any of the identified polymorphic gene variantsCYP2C9 had no effect on the clinical effects of the studied combination.

Association of ORMDL3 single nucleotide polymorphic variants with bronchial asthma in Pathan population

BackgroundSingle nucleotide polymorphic variants of chromosome 17q21 potential candidate genes have been found to associate with asthma predisposition in many ethnically diverse populations. Identifying the potential SNPs, that are associated with asthma in a certain population, may lead to early diagnosis of genetic predisposition, thus reducing the treatment cost by timely management. This research work was planned to study the association of SNPs residing on chromosome 17q21, with asthma, in the Pathan population of Pakistan. MethodsSixty- two physician-diagnosed bronchial asthma cases and one hundred, age and gender-matched, control subjects of the Pathan ethnic group were enrolled for this study. Five SNPs from 17q21 were analyzed for their association with asthma by the Single Base Extension method using capillary-based electrophoresis. Allelic, dominant and recessive genotypic association analyses were done by PLINK and SHEsis plus version beta software, followed by Haploview v4.1 analysis of relevant haplotypes. ResultsOut of five studied SNPs, rs8076131 was significantly associated with bronchial asthma whereas rs9894164 tended to show a marginal association. Haplotype ‘TATT’ seemed to be a marginal risk factor associated with bronchial asthma in the studied population. Conclusionrs8076131 may be used as a predictive indicator of Bronchial Asthma development in risk allele carriers of Pathan ethnicity.

Structural variants contribute to phenotypic variation in maize.

Comprehensively identifying the loci shaping trait variation has been challenging, in part because standard approaches often miss many types of genetic variants. Structural variants, especially transposable elements are likely to affect phenotypic variation but we need better methods in maize for detecting polymorphic structural variants and TEs using short-read sequencing data. Here, we used a whole genome alignment between two maize genotypes to identify polymorphic structural variants and then genotyped a large maize diversity panel for these variants using short-read sequencing data. We characterized variation of SVs within the panel and identified SV polymorphisms that are associated with life history traits and genotype-by-environment interactions. While most of the SVs associated with traits contained TEs, only one of the SV's boundaries clearly matched TE breakpoints indicative of a TE insertion, whereas the other polymorphisms were likely caused by deletions. All of the SVs associated with traits were in linkage disequilibrium with nearby single nucleotide polymorphisms (SNPs), suggesting that this method did not identify variants that would have been missed in a SNP association study.

The longevity-associated BPIFB4 gene guarantees vascular homeostasis and immune protection through platelets.

Beyond their activity in hemostasis and thrombosis, recent advances attribute platelets a pro-youthful role capable to attenuate immune senescence and age-related neuroinflammation. Previous studies from our group associated a polymorphic haplotype variant in the BPIFB4 gene (LAV-BPIFB4) with exceptional longevity. Transfer of the LAV-BPIFB4 in preclinical models has proved strategic to cope with frailty conditions, aging-related events, e.g., cardiovascular ones, and immune dysfunction mainly through a favorable conditioning of the immune system. However, whether platelets participate in LAV-BPIFB4 therapeutic action is currently unknown.Herein, we discovered that platelets were instrumental in boosting the favorable health outcomes of the systemic AAV-LAV-BPIFB4 gene transfer in vivo, as the α-CD42b platelet depletion completely abolished the vascular protective action of LAV-BPIFB4 and suppressed its pro-resolutive CD206 + anti-/CD86 + pro-inflammatory Ly6C + monocyte skewing to LPS stimulation. Of note, this is associated with a huge drop in the protective levels of BPIFB4 in the plasma of AAV-LAV-BPIFB4-injected C57BL/6 mice, indicating that plasma circulating platelets may be a reservoir of the BPIFB4 protein. Indeed, we noticed that BPIFB4 was released by human platelets, a process that is amplified in LAV-allele carrier donors. Accordingly, lentivirus-mediated overexpression of human LAV-BPIFB4 isoform, but not WT-BPIFB4 isoform was able in leading differentiated megakaryocytes to release more platelet-like-particles enriched for BPIFB4. In addition, in vitro, the M2 macrophage polarization increased when releasate from platelets, and even more from LAV pre-stimulated once, was added in monocyte cell culture. Our data suggest that platelet release of BPIFB4 and of yet-to-be-determined unidentified factors mediates the therapeutic efficacy of LAV-BPIFB4 treatment.

HLA-G Polymorphic Variation (G*0104N exon 3) Confers Potential Risk for Recurrent Pregnancy Losses: A Study in a High Incidence Zone (Kashmir, North India)

<i>HLA-G</i> Polymorphic Variation (G*0104N exon 3) Confers Potential Risk for Recurrent Pregnancy Losses: A Study in a High Incidence Zone (Kashmir, North India)