Allele Genotype Research Articles

Associative study of maternal genetic variations with preeclampsia in Russian population: SNP-SNP interactions and haplotypes association

Preeclampsia is a pregnancy-associated hypertensive pathology that affects maternal and fetal quality of life. It was linked to several environmental and genetic factors including genetic polymorphisms. This study aimed to study the association, SNP-SNP interactions and haplotypes associations of thrombophilia, folate cycle and hypertension maternal genetic variations with preeclampsia risk in Russian women from Rostov region. 53 pregnant women diagnosed with preeclampsia were compared with 3108 women with relatively healthy pregnancy. DNA was extracted from blood samples and real time allele specific PCR was used for genotyping. MDR analysis was used for SNP-SNP interactions study. According to our data, F5(G1691A) and ITGB3(T1565C) mutant homozygotes were associated with higher risk of preeclampsia. MTRR (A66G) mutant allele (G) was shown as significant preeclampsia risk factor. ADD1 (G1378T) showed significantly higher frequency of mutant allele (T) and mutant homozygote genotype (TT) in preeclampsia patients comparing to control group. MDR showed that this polymorphism has the higher entropy among targeted variations which was confirmed by binary haplotypes association study. We have also examined linkage disequilibrium showing two haploblocks in between the studied genetic variations included MTHFR (C677T) and MTHFR (A1298C) block and AGT (T704C) with AGT (C521T) block. Results suggest several genetic variations and haplotypes as perspective maternal marker for preeclampsia which will contribute to improve prognosis tools and accordingly treatment and prevention possibilities.

Correlation of ACE insertion/deletion gene polymorphism with captopril effectiveness in Indonesian hypertensive patients.

Background: Hypertension is a prevalent health concern in Indonesia, with a high percentage of patients unresponsive to ACE inhibitor treatment. Methods: This multicenter case-control study investigated the correlation between ACE I/D and captopril effectiveness in Indonesian hypertensive patients. Hypertensive patients were divided into control (n=69) and case (n=73) groups. ACE I/D was identified using PCR and electrophoresis. Results: No significant differences in genotype frequencies or allele distribution were observed. The difference of blood pressure reduction among the three genotypes also lacked statistical significance. Conclusion: ACE I/D is not significantly associated with blood pressure reduction following captopril therapy in Indonesian hypertensive patients. These results underscore the limited predictive utility of ACE I/D in managing hypertension with captopril.

Molecular genetic indicators of the probability of early myocardial systolic dysfunction signs in doxorubicin chemotherapy in patients with breast cancer of moderate and low HFA-ICOS risk groups

Aim. To study the association of rs2232228 (HAS3 gene), rs2229774 (RARG gene), rs1056892 (CBR3 gene), rs1786814 (CELF4 gene), rs1695 (GSTP1 gene), rs8187710 (ABCC2 gene), rs7853758 (SLC28A3 gene), rs243865 (MMP­2 gene), rs243866 (MMP­2 gene), rs35068180 (MMP­3 gene), rs522616 (MMP­3 gene), rs679620 (MMP­3 gene), rs17576 (MMP­9 gene), rs3918242 (MMP­9 gene) with the probability of early doxorubicin cardiotoxicity signs in patients with breast cancer of moderate and low HFA-ICOS risk groups.Material and methods. The study included 100 patients (women, over 18 years old) diagnosed with breast cancer who received chemotherapy using doxorubicin.To identify early cardiotoxicity signs, echocardiography was performed before, immediately after and 12 months after the end of chemotherapy. The status of polymorphic variants of the studied genes was determined by real-time polymerase chain reaction.Results. Based on the decrease in global longitudinal myocardial strain (>12%) immediately after and 12 months after the end of chemotherapy, the patients were divided into two following groups: A — early signs of myocardial dysfunction can be diagnosed after the end of chemotherapy (19%); B — early signs of myocardial dysfunction are detected for the first time only 12 months after the chemotherapy end (17%). In patients from category A, a number of allelic variants and genotypes with potential as independent factors for predicting the early signs of myocardial dysfunction were identified, with an emphasis on targets involved in metabolism and detoxification of doxorubicin and its derivatives. In category B, the greatest differences in the frequencies of allelic variants and genotypes were found among target genes encoding matrix metalloproteinases involved in the processes of response to the intensification of oxidative stress caused by doxorubicin and its derivatives.Conclusion. In total, patients in the low- and moderate-risk groups can be divided into at least 2 categories based on molecular genetic testing. For these categories, the development of early signs of doxorubicin-related myocardial dysfunction before the start of chemotherapy can be predicted.

Association of HLA alleles with cephalosporin allergy in the Taiwanese population

Cephalosporin antibiotics are widely used in clinical settings, but they can cause hypersensitivity reactions, which may be influenced by genetic factors such as the expression of Human leukocyte antigen (HLA) molecules. This study aimed to investigate whether specific HLA alleles were associated with an increased risk of adverse reactions to cephalosporins among individuals in the Taiwanese population. This retrospective case–control study analyzed data from the Taiwan Precision Medicine Initiative (TPMI) on 27,933 individuals who received cephalosporin exposure and had HLA allele genotyping information available. Using logistic regression analyses, we examined the associations between HLA genotypes, comorbidities, allergy risk, and severity. Among the study population, 278 individuals had cephalosporin allergy and 2780 were in the control group. Our results indicated that certain HLA alleles, including HLA-B*55:02 (OR = 1.76, 95% CI 1.18–2.61, p = 0.005), HLA-C*01:02 (OR = 1.36, 95% CI 1.05–1.77, p = 0.018), and HLA-DQB1*06:09 (OR = 2.58, 95% CI 1.62–4.12, p < 0.001), were significantly associated with an increased risk of cephalosporin allergy reactions. Additionally, the HLA-C*01:02 allele genotype was significantly associated with a higher risk of severe allergy (OR = 2.33, 95% CI 1.05–5.15, p = 0.04). This study identified significant associations between HLA alleles and an increased risk of cephalosporin allergy, which can aid in early detection and prediction of adverse drug reactions to cephalosporins. Furthermore, our study highlights the importance of HLA typing in drug safety and expanding our knowledge of drug hypersensitivity syndromes.

ACKR1 gene polymorphisms in Bombay blood group (Oh) individuals of Indian origin

BackgroundACKR1 blood group genes exhibit a high degree of polymorphisms with varying allele distribution seen among different populations and ethnic groups. The study aimed to genotype ACKR1 antigens and to establish FY allele frequency among the individuals with the Bombay (Oh) blood group phenotype. Materials and methodsACKR1 phenotype and genotype frequencies were estimated on 160 individuals typed as Oh and were compared with 100 non-oh blood donors from Mumbai, India by molecularly genotyping via PCR-RFLP. ResultsThe allelic and genotypic frequency of T(−67)C polymorphism showed the dominance of T allele and TT genotype [OR= 3.26 (0.59–17.99)] in both the study groups. The ACKR1 null (Fya-b-) phenotype was not found in the tested group. While the genotypic combination among the Oh group individuals was FYA/FYB (45.3 %), FYA/FYA (42.7 %), and FYB/FYB (12 %), in the non-Oh group donors, it was observed as FYA/FYB (53.3 %), FYA/FYA (39.1 %), and FYB/FYB (7.6 %).The haplotype TGGGC occurred in 38.4 % of the Oh group, but in non-Oh donors, it was found to be 50.9 % [OR = 1.820 (1.196–2.771)], and the difference was statistically significant (p = 0.005). Similarly, the TGGGT haplotype was found at a frequency of 12.7 % in non-Oh donors and 27.1 % in Oh group [OR= 0.411 (0.234–0.722)] (p = 0.001). ConclusionsThis study shows the prevalence of ACKR1 gene polymorphisms, including weak ACKR1 antigens in Oh individuals with a high frequency of haplotype TGGGC. The present study demonstrated for the first time the genotypes FyBweak, FyAweak and Fy Aweak/FyBESon RBC membranes in Indian subjects with Oh phenotype.

Association between polymorphisms of DNA repair genes and intracranial aneurysms: A systematic review and meta‑analysis.

Intracranial aneurysms (IAs) are present in ~2% of the general population, and genetic factors cannot be excluded for the risk of their development. The gene factors that result in the changes in the vascular extracellular matrix (ECM) may also be a key reason for IAs being hereditary. The VCAN gene [also known as chondroitin sulfate proteoglycan 2 (CSPG2)] plays various roles in maintaining ECM functions. The present systematic review and meta-analysis aimed to investigate all eligible articles involving IAs on the association with germ line SNPs of DNA repair genes (up to January, 2024). The total number of patients was 2,308 [987 cases (poor outcomes) and 1,321 controls (good outcomes)]. The results revealed that rs2287926 G/G genotype and G allele and rs251124 T/T genotype and minor allele T increased the risk of developing IAs. However, further studies are required to examine these gene polymorphisms as screening markers for IAs.

Preimplantation Genetic Testing of Spinocerebellar Ataxia Type 3/Machado-Joseph Disease-Robust Tools for Direct and Indirect Detection of the ATXN3 (CAG)n Repeat Expansion.

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a neurodegenerative disorder caused by the ATXN3 CAG repeat expansion. Preimplantation genetic testing for monogenic disorders (PGT-M) of SCA3/MJD should include reliable repeat expansion detection coupled with high-risk allele determination using informative linked markers. One couple underwent SCA3/MJD PGT-M combining ATXN3 (CAG)n triplet-primed PCR (TP-PCR) with customized linkage-based risk allele genotyping on whole-genome-amplified trophectoderm cells. Microsatellites closely linked to ATXN3 were identified and 16 markers were genotyped on 187 anonymous DNAs to verify their polymorphic information content. In the SCA3/MJD PGT-M case, the ATXN3 (CAG)n TP-PCR and linked marker analysis results concurred completely. Among the three unaffected embryos, a single embryo was transferred and successfully resulted in an unaffected live birth. A total of 139 microsatellites within 1 Mb upstream and downstream of the ATXN3 CAG repeat were identified and 8 polymorphic markers from each side were successfully co-amplified in a single-tube reaction. A PGT-M assay involving ATXN3 (CAG)n TP-PCR and linkage-based risk allele identification has been developed for SCA3/MJD. A hexadecaplex panel of highly polymorphic microsatellites tightly linked to ATXN3 has been developed for the rapid identification of informative markers in at-risk couples for use in the PGT-M of SCA3/MJD.

Effect of Sacubitril/Valsartan on Cognitive Function in Patients With Heart Failure With Preserved Ejection Fraction: A Prespecified Analysis of PARAGON-HF.

A hypothetical concern has been raised that sacubitril/valsartan might cause cognitive impairment because neprilysin is one of several enzymes degrading amyloid-β peptides in the brain, some of which are neurotoxic and linked to Alzheimer-type dementia. To address this, we examined the effect of sacubitril/valsartan compared with valsartan on cognitive function in patients with heart failure with preserved ejection fraction in a prespecified substudy of PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). In PARAGON-HF, serial assessment of cognitive function was conducted in a subset of patients with the Mini-Mental State Examination (MMSE; score range, 0-30, with lower scores reflecting worse cognitive function). The prespecified primary analysis of this substudy was the change from baseline in MMSE score at 96 weeks. Other post hoc analyses included cognitive decline (fall in MMSE score of ≥3 points), cognitive impairment (MMSE score <24), or the occurrence of dementia-related adverse events. Among 2895 patients included in the MMSE substudy with baseline MMSE score measured, 1453 patients were assigned to sacubitril/valsartan and 1442 to valsartan. Their mean age was 73 years, and the median follow-up was 32 months. The mean±SD MMSE score at randomization was 27.4±3.0 in the sacubitril/valsartan group, with 10% having an MMSE score <24; the corresponding numbers were nearly identical in the valsartan group. The mean change from baseline to 96 weeks in the sacubitril/valsartan group was -0.05 (SE, 0.07); the corresponding change in the valsartan group was -0.04 (0.07). The mean between-treatment difference at week 96 was -0.01 (95% CI, -0.20 to 0.19; P=0.95). Analyses of a ≥3-point decline in MMSE, decrease to a score <24, dementia-related adverse events, and combinations of these showed no difference between sacubitril/valsartan and valsartan. No difference was found in the subgroup of patients tested for apolipoprotein E ε4 allele genotype. Patients with heart failure with preserved ejection fraction in PARAGON-HF had relatively low baseline MMSE scores. Cognitive change, measured by MMSE, did not differ between treatment with sacubitril/valsartan and treatment with valsartan in patients with heart failure with preserved ejection fraction. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

Geographical distribution of MTHFR C677T gene polymorphisms among the reproductive-age women in Chinese Han populations: based on migration

BackgroundMethylenetetrahydrofolate reductase (MTHFR) is essential for the metabolism of folic acid and homocysteine. The MTHFR C677T polymorphism is associated with several disorders. Our study aims to explore the geographical distributions of the MTHFR C677T polymorphism of women in China and how migration affected the polymorphism in Suzhou.MethodsA total of 7188 women of reproductive age were recruited in Suzhou of the study. Subjects were classified according to their native places after data extraction. MTHFR C677T gene polymorphisms were detected by quantitative PCR with genomic DNA isolated from blood samples.ResultsThe frequencies of the 677T allele and 677TT genotype were higher in northern China than that in southern China and decreased in geographical gradients from north to south. The frequencies were considerably higher in the migrant population than that in the indigenous population of Suzhou. The migrant population have gradually changed the prevalence in Suzhou.ConclusionsOur study suggested that the prevalence of MTHFR C677T polymorphisms among women varied across different geographical regions in Chinese Han populations. The 677T allele frequencies of the northern populations were significantly higher than those of the southern populations. The migrant population gradually changed the prevalence of the MTHFR C677T polymorphism in Suzhou.

A Perspective Study on Therapeutic Drug Monitoring of Voriconazole in Pediatric Patients with Hematologic Disorders

Background: The incidence of invasive aspergillosis and the administration of voriconazole have risen among immunocompromised patients. Objectives: This study aimed to evaluate serum voriconazole concentration and its corresponding influential factors in pediatric patients with hematologic disorders. Methods: A total of 132 blood samples were collected from 44 pediatric patients with hematologic disorders infected with invasive aspergillosis and treated with voriconazole. Among these patients, 20.5% were classified as having proven invasive aspergillosis, 77.2% as probable, and 2.3% as possible. Voriconazole serum levels were evaluated using HPLC on the 3rd, 5th, and 7th days of treatment. Genotyping of the CYP2C19 alleles (*2, *3, and *17) was performed, and demographic and clinical data were gathered from records between 2018 to 2020. Results: The voriconazole concentration in 70.5% of patients and 77.3% of treatment cases (complete or partial) ranged from 1 to 5.5 µg/mL. Adverse events were observed in 4.5% of the patients. Genotyping of CYP2C19 genes revealed CYP2C19*1*1 (5.4%), CYP2C19*1*17 (16.2%), CYP2C19*1*2 (51.4%), and CYP2C19*2*17 (27%). Multivariate analysis using linear regression demonstrated that serum voriconazole concentration increased by 0.037 µg/mL per year of age and by 0.06 µg/mL for each unit increase in C-reactive protein (on the 3rd day of voriconazole therapy). Additionally, an increase in alanine aminotransferase level by 1 unit decreased the mean voriconazole concentration by 0.03 µg/mL. Of these patients, 65.9% were completely treated, 11.4% were partially treated, and 22.7% died. Conclusions: Serum voriconazole concentrations varied among pediatric hematologic patients receiving standard doses, with age, C-reactive protein, and alanine aminotransferase levels affecting the concentration of voriconazole in the sera of pediatric patients.

Associations of TRAF2 (rs867186), TAB2 (rs237025), IKBKB (rs13278372) Polymorphisms and TRAF2, TAB2, IKBKB Protein Levels with Clinical and Morphological Features of Pituitary Adenomas.

The aim of this study was to determine associations of TRAF2 (rs867186), TAB2 (rs237025), IKBKB (rs13278372) gene polymorphisms and TRAF2, TAB2, IKBKB protein levels with clinical and morphological features of pituitary adenomas (PAs). This case-control study included 459 individuals divided into two groups: a control group (n = 320) and a group of individuals with PAs (n = 139). DNA from peripheral blood leukocytes was isolated using salt precipitation and column method. Real-time PCR was used for TRAF2 (rs867186), TAB2 (rs237025), and IKBKB (rs13278372) SNP genotyping, and TRAF2, TAB2, IKBKB protein concentration measurements were performed by immunoenzymatic analysis tests using a commercial ELISA kit according to the manufacturer's recommendations. The labeling index Ki-67 was determined by immunohistochemical analysis using a monoclonal antibody (clone SP6; Spring Bioscience Corporation). Statistical data analysis was performed using the programs "IMB SPSS Statistics 29.0". We found significant differences in TRAF2 (rs867186) genotypes (AA, AG, GG) between groups: 79.1%, 17.3%, 3.6% vs. 55.3%, 20.9%, 23.8% (p < 0.001). The G allele was less frequent in the PA group than in controls (12.2% vs. 34.2%, p < 0.001). The AG and GG genotypes reduced PA occurrence by 1.74-fold and 9.43-fold, respectively, compared to AA (p < 0.001). In the dominant model, GG and AG genotypes reduced PA odds by 3.07-fold, while in the recessive model, the GG genotype reduced PA odds by 8.33-fold (p < 0.001). Each G allele decreased PA odds by 2.49-fold in the additive model (p < 0.001). Microadenomas had significant genotype differences compared to controls: 81.3%, 18.8%, 0.0% vs. 55.3%, 20.9%, 23.8% (p < 0.001), with the G allele being less frequent (9.4% vs. 34.2%, p < 0.001). In macroadenomas, genotype differences were 78%, 16.5%, 5.5% vs. 55.3%, 20.9%, 23.8% (p < 0.001), and the G allele was less common (13.7% vs. 34.2%, p < 0.001). The dominant model showed that GG and AG genotypes reduced microadenoma odds by 3.5-fold (p = 0.001), and each G allele reduced microadenoma odds by 3.1-fold (p < 0.001). For macroadenomas, the GG genotype reduced odds by 6.1-fold in the codominant model (p < 0.001) and by 2.9-fold in GG and AG genotypes combined compared to AA (p < 0.001). The recessive model indicated the GG genotype reduced macroadenoma odds by 5.3-fold (p < 0.001), and each G allele reduced odds by 2.2-fold in the additive model (p < 0.001). The TRAF2 (rs867186) G allele and GG genotype are significantly associated with reduced odds of pituitary adenomas, including both microadenomas and macroadenomas, compared to the AA genotype. These findings suggest a protective role of the G allele against the occurrence of these tumors.

GENETIC DETERMINANTS OF CARBOHYDRATE METABOLISM: INTRA- AND INTERETHNIC VARIABILITY OF THE LACTASE LCT, TREHALASE TREH AND SUCRASE-ISOMALTASE SI GENES IN THE EVENKI AND OTHER INDIGENOUS PEOPLES OF SIBERIA

Introduction. The authors consider the features of genetic determinants of disaccharide assimilation as the corollary of adaptation to the environment. The aim of the study was to assess the polymorphism of the genes that determine activity of disaccharidase enzymes lactase (LCT, rs4988235), trehalase (TREH, rs2276064) and sucrase-isomaltase (SI, rs781470490) in different territorial groups of Evenks. Materials and methods. Biomaterial samples from 1365 unrelated individuals representing 15 ethno-territorial population groups in European Russia, Siberia, and the Far East of the Russian Federation were genotyped. "Focus" groups include "Western" (N=65), "Transbaikal" (N=50), and "Okhotsk" (N=81) Evenks (Krasnoyarsk Krai, Northern Transbaikalia, Okhotsk-Aldan region). The other study groups allow us to assess the specificity of the distribution of genetic determinants of disaccharide assimilation in populations that differ from racial, ecological, and subsistence perspectives. Results. The Evenki territory subgroups do not differ from each other in terms of allele frequencies and genotype distribution of LCT (p&gt;0.2) and TREH (p&gt;0.8) and are similar to Yakuts, Buryats, Mongols, and populations of the Far East and Chukotka. The SI delAG deletion was not found in the Western Evenki subgroup. Discussion. A question of similarity between taiga hunters Evenks to cattle breeders Buryats, Mongols, and Yakuts in terms of C*LCT frequencies requires further elaboration. Possible explanations may include a weakening of selection for the T*LCT allele due to the shift in traditional diet toward replacement of fresh milk with fermented dairy products, high activity of specific intestinal microflora, or the existence of other lactase synthesis genetic determinants, besides LCT*C/T-13910. The evolutionary origins of the clinal variation in the TREH gene allele frequencies, which appears to be associated with the expression of the Mongoloid ancestral component in the gene pool of populations in Northern Eurasia, remain unclear. It seems appropriate to conduct genetic screening in the indigenous populations of the Russian Far East in order to assess the prevalence of SI delAG deletion as an inducer of the sucrase-isomaltase deficiency.

Apolipoprotein E E3/E4 genotype is associated with an increased risk of premature coronary artery disease

ObjectiveDyslipidemia is one of the causes of coronary heart disease (CAD), and apolipoprotein E (APOE) gene polymorphism affects lipid levels. However, the relationship between APOE gene polymorphisms and premature CAD (PCAD, male CAD patients with ≤ 55 years old and female with ≤ 65 years old) risk had different results in different studies. The aim of this study was to assess this relationship and to further evaluate the relationship between APOE gene polymorphisms and PCAD risk in the Hakka population.MethodsThis study retrospectively analyzed 301 PCAD patients and 402 age matched controls without CAD. The APOE rs429358 and rs7412 polymorphisms were genotyped by polymerase chain reaction (PCR) -chip technique. The distribution of APOE genotypes and alleles between the case group and the control group was compared. The relationship between APOE genotypes and PCAD risk was obtained by logistic regression analysis.ResultsThe frequency of the APOE ɛ3/ɛ4 genotype (18.9% vs. 10.2%, p = 0.001) and ε4 allele (11.1% vs. 7.0%, p = 0.007) was higher in the PCAD patients than that in controls, respectively. PCAD patients with ɛ2 allele had higher TG level than those with ɛ3 allele, and controls carried ɛ2 allele had higher HDL-C level and lower LDL-C level than those carried ɛ3 allele. Regression logistic analysis showed that BMI ≥ 24.0 kg/m2 (BMI ≥ 24.0 kg/m2 vs. BMI 18.5–23.9 kg/m2, OR: 1.763, 95% CI: 1.235–2.516, p = 0.002), history of smoking (Yes vs. No, OR: 5.098, 95% CI: 2.910–8.930, p < 0.001), ɛ3/ɛ4 genotype (ɛ3/ɛ4 vs. ɛ3/ɛ3, OR: 2.203, 95% CI: 1.363–3.559, p = 0.001), ε4 allele (ε4 vs. ε3, OR: 2.125, 95% CI: 1.333–3.389, p = 0.002), and TC level (OR: 1.397, 95% CI: 1.023–1.910, p = 0.036) were associated with PCAD.ConclusionsIn summary, BMI ≥ 24.0 kg/m2, history of smoking, APOE ɛ3/ɛ4 genotype, and TC level were independent risk factors for PCAD. It means that young individuals who are overweight, have a history of smoking, and carried APOE ɛ3/ɛ4 genotype had increased risk of PCAD.

Androgen receptor-mediated pharmacogenomic expression quantitative trait loci: implications for breast cancer response to AR-targeting therapy

BackgroundEndocrine therapy is the most important treatment modality of breast cancer patients whose tumors express the estrogen receptor α (ERα). The androgen receptor (AR) is also expressed in the vast majority (80–90%) of ERα-positive tumors. AR-targeting drugs are not used in clinical practice, but have been evaluated in multiple trials and preclinical studies.MethodsWe performed a genome-wide study to identify hormone/drug-induced single nucleotide polymorphism (SNP) genotype - dependent gene-expression, known as PGx-eQTL, mediated by either an AR agonist (dihydrotestosterone) or a partial antagonist (enzalutamide), utilizing a previously well characterized lymphoblastic cell line panel. The association of the identified SNPs-gene pairs with breast cancer phenotypes were then examined using three genome-wide association (GWAS) studies that we have published and other studies from the GWAS catalog.ResultsWe identified 13 DHT-mediated PGx-eQTL loci and 23 Enz-mediated PGx-eQTL loci that were associated with breast cancer outcomes post ER antagonist or aromatase inhibitors (AI) treatment, or with pharmacodynamic (PD) effects of AIs. An additional 30 loci were found to be associated with cancer risk and sex-hormone binding globulin levels. The top loci involved the genes IDH2 and TMEM9, the expression of which were suppressed by DHT in a PGx-eQTL SNP genotype-dependent manner. Both of these genes were overexpressed in breast cancer and were associated with a poorer prognosis. Therefore, suppression of these genes by AR agonists may benefit patients with minor allele genotypes for these SNPs.ConclusionsWe identified AR-related PGx-eQTL SNP-gene pairs that were associated with risks, outcomes and PD effects of endocrine therapy that may provide potential biomarkers for individualized treatment of breast cancer.

Multi-omic characterization of allele-specific regulatory variation in hybrid pigs

Hybrid mapping is a powerful approach to efficiently identify and characterize genes regulated through mechanisms in cis. In this study, using reciprocal crosses of the phenotypically divergent Duroc and Lulai pig breeds, we perform a comprehensive multi-omic characterization of regulatory variation across the brain, liver, muscle, and placenta through four developmental stages. We produce one of the largest multi-omic datasets in pigs to date, including 16 whole genome sequenced individuals, as well as 48 whole genome bisulfite sequencing, 168 ATAC-Seq and 168 RNA-Seq samples. We develop a read count-based method to reliably assess allele-specific methylation, chromatin accessibility, and RNA expression. We show that tissue specificity was much stronger than developmental stage specificity in all of DNA methylation, chromatin accessibility, and gene expression. We identify 573 genes showing allele specific expression, including those influenced by parent-of-origin as well as allele genotype effects. We integrate methylation, chromatin accessibility, and gene expression data to show that allele specific expression can be explained in great part by allele specific methylation and/or chromatin accessibility. This study provides a comprehensive characterization of regulatory variation across multiple tissues and developmental stages in pigs.

Relationship between the serum level, polymorphism and gene expression of IL-33 in samples of recurrent miscarriage Iraqi women infected with toxoplasmosis

One of the many warm-blooded hosts that toxoplasmosis-causing intracellular protozoan parasite Toxoplasma gondii can infect is humans. Cytokines are crucial to stimulate an effective immune response against T. gondii. Interleukin-33 (IL-33) is a unique anti-inflammatory cytokine that suppresses the immune response. The levels of cytokine gene expression are regulated by genetics, and the genetic polymorphisms of these cytokines play a functional role in this process. Single nucleotide polymorphisms (SNPs) are prognostic indicators of illnesses. This study aimed to determine whether toxoplasmosis interacts with serum levels of IL-33 and its SNP in miscarriage women as well as whether serum levels and IL-33 gene expression are related in toxoplasmosis-positive miscarriage women. Two hundred blood samples from patients and controls were collected from AL-Alawiya Maternity Teaching Hospital and AL-Yarmouk Teaching Hospital in Baghdad, Iraq from 2021 to 2022 in order to evaluate the serum level of IL-33 using ELISA test. For the SNP of IL-33, the allelic high-resolution approach was utilized, and real time-PCR was performed to assess gene expression. The results showed that compared to healthy and pregnant women, recurrent miscarriage with toxoplasmosis and recurrent miscarriage women had lower IL-33 concentrations. Additionally, there were significant differences among healthy women, pregnant women, and women with repeated miscarriage who experienced toxoplasmosis. Furthermore, no differences between patients and controls were revealed by gene expression data. The results revealed that recurrent miscarriage, pregnancy, and healthy women all had a slightly higher amount of the IL-33 gene fold. Additionally, the SNP of IL-33 data demonstrated that there was no significant genetic relationship between patients and controls. Recurrent miscarriage women with toxoplasmosis have showed significant differences from pregnant women in the genotypes GG and AA as well as the alleles A and G. There were notable variations between recurrent miscarriage with and without toxoplasmosis in terms of the genotypes AA and AC. The genotypes GG, AA, and allele A in recurrent miscarriage women with toxoplasmosis and recurrent miscarriage women is a protective factor. Taking together, there was a statistically significant negative correlation between toxoplasmosis and IL-33 gene expression, which calls for more quantitative investigation in order to fully comprehend the interaction of mRNA and protein.

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.

Association of LPP and ZMIZ1 Gene Polymorphism with Celiac Disease in Subjects from Punjab, Pakistan.

Celiac disease (CD) is a complicated autoimmune disease that is caused by gluten sensitivity. It was commonly believed that CD only affected white Europeans, but recent findings show that it is also prevailing in some other racial groups, like South Asians, Caucasians, Africans, and Arabs. Genetics plays a profound role in increasing the risk of developing CD. Genetic Variations in non-HLA genes such as LPP, ZMIZ1, CCR3, and many more influence the risk of CD in various populations. This study aimed to explore the association between LPP rs1464510 and ZMIZ1 rs1250552 and CD in the Punjabi Pakistani population. For this, a total of 70 human subjects were selected and divided into healthy controls and patients. Genotyping was performed using an in-house-developed tetra-amplification refractory mutation system polymerase chain reaction. Statistical analysis revealed a significant association between LPP rs1464510 (χ2 = 4.421, p = 0.035) and ZMIZ1 rs1250552 (χ2 = 3.867, p = 0.049) and CD. Multinomial regression analysis showed that LPP rs1464510 A allele reduces the risk of CD by ~52% (OR 0.48, CI: 0.24-0.96, 0.037), while C allele-carrying subjects are at ~2.6 fold increased risk of CD (OR 3.65, CI: 1.25-10.63, 0.017). Similarly, the ZMIZ1 rs1250552 AG genotype significantly reduces the risk of CD by 73% (OR 0.26, CI: 0.077-0.867, p = 0.028). In summary, Genetic Variations in the LPP and ZMIZ1 genes influence the risk of CD in Punjabi Pakistani subjects. LPP rs1464510 A allele and ZMIZ1 AG genotype play a protective role and reduce the risk of CD.

Study of gene polymorphisms in Toll-like receptor 2 in patients with acute lymphoblastic leukemia

ObjectivesAcute Lymphoblastic Leukemia (ALL) is a multifactorial disease that results from the interaction between multiple genetic factors. ALL is characterized by uncontrolled production of hematopoietic precursor cells of the lymphoid progenitors within the bone marrow. The development of hematological malignancies has been associated with malignant-like cells that express low levels of immunogenic surface molecules, thus, facilitating their escape from cellular antineoplastic immune responses. This risk may be partly influenced by variations in polymorphic genes that control immune function and regulation. Toll-like receptors (TLRs) are well known pattern recognition receptors playing key role in innate immune response. Abnormal expression and dysregulation of TLRs will provide an opportunity for cancer cells to escape from the immune system and enhance their proliferation and angiogenesis. Toll-like receptor 2 (TLR2) play an essential role in innate immunity. Single nucleotide polymorphisms (SNPs) are present in a number of TLR genes and have been associated with various disorders. MethodsIn this study, 265 subjects have been divided into two groups included 150 patients with ALL and115 healthy volunteers. All subjects were genotyped using TaqMan PCR techniques. In total, Five SNPs were statistically evaluated in the TLR2 (rs1898830 A/G, rs3804099 T/C, rs3804100 T/C, rs1339 T/C, and rs1337 C/G), which may influence the susceptibility of ALL. Minor allele frequency and genotype distribution were compared across the study groups, and the relative risk and differences between patients and controls were estimated. Moreover, the mRNA expression level was evaluated in patients with ALL and the matched healthy individuals by Real-Time Quantitative Reverse Transcription PCR (qRT-PCR). ResultsTLR2 rs1898830 A/G; rs3804099 T/C; rs3804100 T/C; rs1339 T/C, were significantly decrease the risk in our population, overall and for certain subtypes and ALL samples exhibited significant increase in the mRNA levels of TLR2. ConclusionsThis study shows that TLR2 could be an independent prognostic factor of ALL risks in the Saudi population. Suggesting that genetic variation in genes associated with an immune response may be important in the etiology of ALL. In addition, the results herein revealed that TLR2 overexpression is associated with ALL and has diverse biological significance in the context of the complex relationship between inflammation and cancer development. Therefore, these data could open further studies to explore the possible clinical relevance of TLRs as pathological markers for Leukemia and enhance the strategies regarding hematological malignancies prevention based on their gene expression.

HLA-DQA1*05 Allele Carriage and Anti-TNF Therapy Persistence in Inflammatory Bowel Disease

Abstract Introduction Carriage of the HLA-DQA1*05 allele is associated with development of antidrug antibodies (ADAs) to antitumor necrosis factor (anti-TNF) therapy in patients with Crohn’s disease. However, ADA is not uniformly associated with treatment failure. We aimed to determine the impact of carriage of HLA-DQA1*05 allele on outcome of biologic therapy evaluated by drug persistence. Methods A multicenter, retrospective study of 877 patients with inflammatory bowel disease (IBD) treated with anti-TNF therapy with HLA-DQA1*05 genotypes were generated by imputation from whole genome sequence using the HIBAG package, in R. Primary end point was anti-TNF therapy persistence, (time to therapy failure), segregated by HLA-DQA1*05 allele genotype and development of a risk score to predict anti-TNF therapy failure, incorporating HLA-DQA1*05 allele genotype status (LORisk score). Results In all, 877 patients receiving anti-TNF therapy were included in our study; 543 (62%) had no copy, 281 (32%) one copy, and 53 (6%) 2 copies of HLA-DQA1*05 allele. Mean time to anti-TNF therapy failure in patients with 2 copies of HLA-DQA1*05 allele was significantly shorter compared with patients with 0 or 1 copy at 700 days’ follow-up: 418 vs 541 vs 513 days, respectively (P = .012). Factors independently associated with time to anti-TNF therapy failure included carriage of HLA-DQA1*05 allele (hazard ratio [HR], 1.2, P = .02; female gender HR, 1.6, P &amp;lt; .001; UC phenotype HR, 1.4, P = .009; and anti-TNF therapy type [infliximab], HR, 1.5, P = .002). The LORisk score was significantly associated with shorter time to anti-TNF therapy failure (P &amp;lt; .001). Conclusions Carriage of 2 HLA-DQA1*05 alleles is associated with less favorable outcomes for patients receiving anti-TNF therapy with shorter time to therapy failure. HLA-DQA1*05 genotype status in conjunction with clinical factors may aid in therapy selection in patients with IBD.