CC Genotype Research Articles

Genetic variations associated with telomere length predict the risk of recurrence of non-oropharyngeal head and neck squamous cell carcinoma.

Genetic factors underlying lymphocyte telomere length (LTL) may provide insights into genomic stability and integrity, with direct links to susceptibility to cancer recurrence. Polymorphisms in telomere-associated genes are strongly associated with LTL and cancer risk, while few large studies have explored the associations between LTL-related polymorphisms and recurrence risk of non-oropharyngeal head and neck squamous cell carcinoma (non-OPHNSCC). Totally 1403 non-OPHNSCC patients were recruited and genotyped for 16 LTL-related polymorphisms identified by genome-wide association studies. Univariate and multivariate analyzes were performed to evaluate associations between the polymorphisms and non-OPHNSCC recurrence risk. Patients carrying rs755017 GA/GG, rs2487999 TC/TT, rs2736108 TC/TT, or rs6772228 AT/AA genotypes exhibited shorter DFS than those with the rs755017 AA, rs2487999 CC, rs2736108 CC, or s6772228 TT genotypes, respectively (all log-rank p < 0.05). Multivariable analysis confirmed an increased risk of recurrence for patients carrying rs755017 GA/GG, rs2487999 TC/TT, rs2736108 TC/TT, or rs6772228 AT/AA genotypes (adjusted hazard ratio [aHR]: 1.66, 95% confidence interval [CI]: 1.32-2.07; aHR: 1.77, 95% CI: 1.41-2.23; aHR: 1.56, 95% CI: 1.22-1.99; aHR: 1.52, 95% CI: 1.20-1.93, respectively). Further stratified analysis revealed stronger associations between these genotypes and recurrence risk in ever-smokers and patients undergoing chemoradiotherapy. The similar but particularly pronounced results were observed for the combined risk genotypes of the four significant polymorphisms. This is the first large study on non-OPHNSCC patients showing that LTL-related polymorphisms may modify risk of non-OPHNSCC recurrence individually and jointly, particularly when analyzed in the context of smoking status and personized treatment. Larger studies are needed to validate these results.

Risk of diabetes mellitus based on the interactive association between G6PD rs72554664 polymorphism and sex in Taiwan Biobank individuals

The presence of glucose-6-phosphate dehydrogenase (G6PD) deficiency may increase the risk of type 2 diabetes mellitus (T2DM), with differing prevalence between males and females. Although G6PD deficiency is an X-linked genetic condition, its interaction with sex regarding T2DM risk among the Taiwanese population has not been fully explored. This study aimed to investigate the association between G6PD deficiency and T2DM risk in the Taiwanese population, focusing on the potential influence of sex. Data were obtained from the Taiwan Biobank (TWB) database, involving 85,334 participants aged 30 to 70 years. We used multiple logistic regression analysis to assess the interaction between G6PD rs72554664 and sex in relation to T2DM risk. The T2DM cohort comprised 55.35% females and 44.65% males (p < 0.001). The TC + TT genotype of rs72554664 was associated with an increased risk of T2DM, with an odds ratio (OR) of 1.95 (95% CI: 1.39–2.75), and males showed an OR of 1.31 (95% CI: 1.19–1.44). Notably, the G6PD rs72554664-T allelic variant in hemizygous males significantly elevated the T2DM risk (OR), 4.57; p < 0.001) compared to females with the CC genotype. Our findings suggest that the G6PD rs72554664 variant, in conjunction with sex, significantly affects T2DM risk, particularly increasing susceptibility in males. The association of the G6PD rs72554664-T allelic variant with a higher risk of T2DM highlights the importance of sex-specific mechanisms in the interplay between G6PD deficiency and T2DM.

Correlations between growth differentiation factor 15 (GDF-15) serum levels and gene polymorphism with type 2 diabetes mellitus

PurposeTo date, the relationship between Growth Differentiation Factor 15 (GDF-15) gene polymorphism and the risk of type 2 diabetes mellitus (T2DM) has not been clarified. Our study aims to explore the association between serum GDF-15 levels and related gene polymorphism with the risk of T2DM in a Chinese rural Yao population. MethodsThis was a 1:1 case-control study with 179 T2DM patients and 179 age- and sex-matched control participants. Serum GDF-15 levels were measured by enzyme-linked immunosorbent assay, and polymorphisms (rs1059519, rs1059369, rs1804826 and rs1054564) were genotyped by MassArray mass spectrometry. ResultsSerum GDF-15 (sGDF-15) levels were higher in patients with T2DM and glycosylated hemoglobin (HbA1c) ≥ 6.5 % compared to that in controls (p < 0.001). The area under the curve (AUC) corresponding to sGDF-15 levels was 0.626. Serum GDF-15 was positively correlated with fasting plasma glucose (FPG) (rs = 0.150, p < 0.001) and HbA1c (rs = 0.160, p < 0.001). The frequency of GDF-15 gene rs1054564 GC + CC genotype was significantly associated with increased risk of T2DM compared to GG genotype (OR = 1.724, 95CI: 1.046–2.841, p = 0.033). Frequencies of rs1804826 T allele (β additive = 113.318, p = 0.026) and rs1054564 C allele (β additive = 247.282, p = 0.001, β dominant = 286.109, p = 0.001) was significantly correlated with higher sGDF-15. The rs1059519 C allele was negatively correlated with FPG (β recessive = −0.607, p = 0.047) and HbA1c (β recessive = −0.456, p = 0.020). ConclusionSerum GDF-15 levels were positively correlated with FPG and HbA1c. The GDF-15 rs1054564 GC + CC genotype was associated with a significantly higher T2DM risk. The rs1059519 C allele was negatively correlated with FPG and HbA1c.

Association of germline HSD3B1 (c.1100) genotype with tumoral and clinical outcomes in breast and endometrial cancers.

10587 Background: A germline single-nucleotide polymorphism in HSD3B1 results in adrenal-permissive (c.1100 C) and adrenal-restrictive (c.1100 A) phenotypes with respect to androgen synthesis. In pre- and post-menopausal patients with breast cancer (n=3548 and 7871) and endometrial cancer (n=1588 and 8439), we annotated samples as adrenal permissive (CC/AC) or restrictive (AA) based on HSD3B1 variant status and then examined tumoral characteristics and clinical outcomes. Methods: We utilized tumors from the Caris Life Sciences Precision Oncology Alliance database and inferred germline HSD3B1 c.1100 genotype using variant allele frequencies (VAFs): c.1100 C VAF of 0% defined the AA genotype, VAF of 40-60% defined the AC genotype, and VAF of 100% defined the CC genotype. We explored associations of each HSD3B1genotypes with other genomic (WES) and transcriptomic (RNA-seq) features, as well as with survival outcomes. To performed consider menopausal status we used the patient’s age at the time of biopsy (&gt;55 indicating post-menopausal). Results: In breast cancer (BC) and endometrial cancer (EC), the permissive HSD3B1genotype had greater mRNA expression of the estrogen receptor ( ESR1) and co-alterations of the TP53 (p&lt;0.0001). In post-menopausal ECs, the permissive genotype was associated with increased alterations in the PI-3-kinase pathway ( PTEN, PIK3CA, PIK3R1, p&lt;0.0001). In pre-menopausal HER2+ BCs, the restrictive genotype was associated with worse survival (HR=1.40, 95% CI = 1.05-1.85, p=0.027) and exhibited increases in hallmark GSEA signatures including epithelial-to-mesenchymal transition. Post-menopausal basal BCs with the permissive genotype had numerically higher PD-L1 protein expression (50% vs 13%) and less PI-3-kinase alterations ( PTEN, PIK3R1, p&lt;0.01). Post-menopausal clear cell ECs with the restrictive genotype exhibited worse survival (HR=1.60, 95% CI=1.07-2.38, p=0.03) and were 3-fold more likely to be TMB-high or MSI-high (p&lt;0.05). Distinctly, post-menopausal endometrioid ECs of the restrictive genotype were less likely to be TMB- or MSI-high (p&lt;0.05). Conclusions: Breast and endometrial cancers can be classified as adrenal-permissive or -restrictive based on HSD3B1 c.1100 genotype. This classification distinguishes clinical outcomes and tumoral features, particularly when stratifying by menopausal status. Importantly, these genotypes are differentially associated with druggable pathways (PI-3-kinase) and markers of immune sensitivity (PD-L1, TMB, MSI). [Table: see text]

Correlation Analysis between STING Promoter Polymorphism and Susceptibility to Infection after Chemotherapy for Multiple Myeloma

To investigate the correlation between the stimulator of interferon genes (STING ) promoter polymorphism and the susceptibility to infection after chemotherapy for multiple myeloma. A total of 102 patients who had undergone chemotherapy for multiple myeloma in our hospital from January 2016 to July 2022 were selected. Depending on the presence or absence of infection after chemotherapy, the enrolled patients were divided into infection group (53 cases) and non-infection group (49 cases). The infection sites and distribution characteristics of pathogenic bacteria of the infection group were analyzed. The genotype distribution of STING gene promoter rs587777609 was compared between the two groups, and the risk factors of infection after chemotherapy for multiple myeloma were analyzed. For infection site, digestive system, respiratory system, urinary system, skin and mucous membranes accounted for 43.40%, 26.42%, 20.75%, and 9.43%, respectively. For pathogenic bacteria, Gram-negative bacteria, Gram-positive bacteria and fungi accounted for 57.14%, 26.98%, and 15.87%, respectively. The CC genotype frequency of STING gene rs587777609 locus in the infection group was lower than that in the non-infection group, while the TT genotype frequency was higher than that in the non-infection group (P < 0.05). The proportions of patients with diabetes, chronic obstructive pulmonary disease, renal insufficiency, serum albumin level< 35 g/L, ISS stage III, mechanical ventilation, and indwelling catheter in the infection group were higher than those in the non-infection group (P < 0.05). Multivariate logistic regression analysis showed that diabetes (OR =1.992), serum albumin level< 35 g/L (OR =2.782), ISS stage III (OR =2.707), mechanical ventilation (OR =3.031), and TT genotype (OR =2.401) were risk factors of infection after chemotherapy for multiple myeloma (P < 0.05). There is a correlation between STING promoter polymorphism and the susceptibility to infection after chemotherapy for multiple myeloma, and patients with TT genotype have a higher risk of infection.

Homocysteine concentration in coronary artery disease and severity of coronary lesions.

Our previous study reckons that the impact of the rs1801133 variant of 5,10-methylenetetrahydrofolate reductase (MTHFR) on coronary artery disease (CAD) is possibly mediated by cardiometabolic disorder. This study is performed to verify this hypothesis. Four hundred and thirty CAD patients and 216 CAD-free individuals were enrolled in this case-control study. The rs1801133 variant was genotyped by PCR-RFLP. Severity of coronary lesions was evaluated by number of stenotic coronary vessels and extent of coronary stenosis. The rs1801133 T allele significantly increased homocysteine levels in patients with CAD and CAD-free individuals. Individuals with the T allele of rs1801133 had an increased risk of developing CAD. In contrast, individuals with the TT genotype of rs1801133 were at high risk of multiple vessel lesions. The carriers of CT genotype had higher levels of systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDL-C), and high-sensitivity C-reactive protein (hs-CRP), and lower levels of apolipoprotein A1 (APOA1) than those with CC genotype in male patients with CAD. The receiver operating characteristic (ROC) curve and precision-recall (PR) curve indicated that hyperhomocysteinemia was sensitive to predict the severity of CAD. Multivariate logistic regression revealed that homocysteine, rs1801133, age, smoking, weight, body mass index (BMI), lipoprotein(a) [Lp(a)], and hs-CRP were independent risk factors for CAD. The increased risk of CAD and severity of coronary lesions associated with rs1801133 in the Chinese Han population were attributed, at least partly, to high homocysteine levels. Hyperhomocysteinemia had a high predictive value for severe CAD or multiple vessel lesions.

Impact of TNFRSF1B (rs3397, rs1061624 and rs1061622) and IL6 (rs1800796, rs1800797 and rs1554606) Gene Polymorphisms on Inflammatory Response in Patients with End-Stage Kidney Disease Undergoing Dialysis.

We aimed to study the impact of polymorphisms in the genes encoding interleukin-6 (IL6) and tumor necrosis factor receptor-2 (TNFR2), reported to be mortality risk predictors, in patients with end-stage kidney disease (ESKD) undergoing dialysis. TNFRSF1B (rs3397, rs1061624, and rs1061622) and IL6 (rs1800796, rs1800797, and rs1554606) polymorphisms were studied in patients with ESKD and controls; the genotype and allele frequencies and the associations with inflammatory and erythropoiesis markers were determined; deaths were recorded throughout the following two years. The genotype and allele frequencies for the TNFRSF1B rs3397 polymorphism were different in these patients compared to those in the controls and the global and European populations, and patients with the C allele were less common. Patients with the CC genotype for TNFRSF1B rs3397 presented higher hemoglobin and erythrocyte counts and lower TNF-α levels, suggesting a more favorable inflammatory response that seems to be associated with erythropoiesis improvement. Patients with the GG genotype for TNFRSF1B rs1061622 showed lower serum ferritin levels. None of the TNFRSF1B (rs3397, rs1061624, and rs1061622) or IL6 (rs1800796, rs1800797, and rs1554606) polymorphisms had a significant impact on the all-cause mortality rate of Portuguese patients with ESKD.

Relationship of Toll-Like Receptor 7, 9, and 10 Polymorphisms and the Severity of Coronavirus Disease 2019.

Coronavirus disease 2019 (COVID-19) is a pandemic that is still affecting people and has caused many deaths. Toll-like receptors (TLRs) have an important role in the binding of disease agents to the host cell, disease susceptibility and severity, and host disease resistance. In this study, we investigated the frequencies of TLR7 (C.4-151 A/G), TLR9 (T-1486C and G2848A), and TLR10 (720A/C and 992T/A) single nucleotide polymorphisms in 150 cases with COVID-19 and 171 control samples. We also examined whether TLR7, TLR9, and TLR10 were related to COVID-19 severity. Furthermore, we analyzed the association between COVID-19 and some clinical parameters. Polymerase chain reaction based on restriction fragment length polymorphisms performed for the TLR7, TLR9, and TLR10 single nucleotide polymorphisms. TLR7 C.4-151 A/G G allele and GG genotype; TLR9 T-1486C C allele and TC, CC genotypes; and TLR10 720A/C C allele; TLR10 992T/A A allele and AA genotype frequencies were statistically significant in cases with COVID-19 compared with controls (P < 0.05*). In addition, there was a statistically significant difference in the distribution of TLR7, TLR9, and TLR10 allele and genotype frequencies between the severity groups (P < 0.05*). Our findings suggest that TLR7, TLR9, and TLR10 polymorphisms may be crucial for the clinical course and susceptibility to infection.

Single-Base Gene Variants in MIR-146A and SCN1A Genes Related to the Epileptogenic Process in Drug-Responsive and Drug-Resistant Temporal Lobe Epilepsy-A Preliminary Study in a Brazilian Cohort Sample.

The drug-resistant temporal lobe epilepsy (TLE) has recently been associated with single nucleotide variants (SNVs) in microRNA(miR)-146a (MIR-146A) (rs2910164) and Sodium Voltage-Gated Channel Alpha Subunit 1 (SCN1A) (rs2298771 and rs3812718) genes. Moreover, no studies have shown an association between these SNVs and susceptibility to drug-resistant and drug-responsive TLE in Brazil. Thus, deoxyribonucleic acid (DNA) samples from 120 patients with TLE (55 drug-responsive and 65 drug-resistant) were evaluated by real-time polymerase chain reaction (RT-PCR). A total of 1171 healthy blood donor individuals from the Online Archive of Brazilian Mutations (ABraOM, from Portuguese Arquivo Brasileiro On-line de Mutações), a repository containing genomic variants of the Brazilian population, were added as a control population for the studied SNVs. MIR-146A and SCN1A relative expression was performed by quantitative RT-PCR (qRT-PCR). The statistical analysis protocol was performed using an alpha error of 0.05. TLE patient samples and ABraOM control samples were in Hardy-Weinberg equilibrium for all studied SNVs. For rs2910164, the frequencies of the homozygous genotype (CC) (15.00% vs. 9.65%) and C allele (37.80% vs. 29.97%) were superior in patients with TLE compared to controls with a higher risk for TLE disease [odds ratio (OR) = 1.89 (95% confidence interval (95%CI) = 1.06-3.37); OR = 1.38 (95%CI = 1.04-1.82), respectively]. Drug-responsive patients also presented higher frequencies of the CC genotype [21.81% vs. 9.65%; OR = 2.58 (95%CI = 1.25-5.30)] and C allele [39.09% vs. 29.97%; OR = 1.50 (95%CI = 1.01-2.22)] compared to controls. For rs2298771, the frequency of the heterozygous genotype (AG) (51.67% vs. 40.40%) was superior in patients with TLE compared to controls with a higher risk for TLE disease [OR = 2.42 (95%CI = 1.08-5.41)]. Drug-resistant patients presented a higher AG frequency [56.92% vs. 40.40%; OR = 3.36 (95%CI = 1.04-17.30)] compared to the control group. For rs3812718, the prevalence of genotypes and alleles were similar in both studied groups. The MIR-146A relative expression level was lower in drug-resistant compared to drug-responsive patients for GC (1.6 vs. 0.1, p-value = 0.049) and CC (1.8 vs. 0.6, p-value = 0.039). Also, the SCN1A relative expression levels in samples from TLE patients were significantly higher in AG [2.09 vs. 1.10, p-value = 0.038] and GG (3.19 vs. 1.10, p-value < 0.001) compared to the AA genotype. In conclusion, the rs2910164-CC and rs2298771-AG genotypes are exerting significant risk influence, respectively, on responsive disease and resistant disease, probably due to an upregulated nuclear factor kappa B (NF-kB) and SCN1A loss of function.

Molecular investigation of vitamin D receptor (VDR) genetic variants and their impact on VDR mRNA and serum vitamin D levels in allergic rhinitis in an Indian population: A case-control study.

Vitamin D deficiency is widespread and poses a significant health concern, as emerging research links it to allergic diseases owing to its immunomodulatory functions. The optimal functioning of vitamin D and its activation depend on its nuclear receptor, vitamin D receptor (VDR). Genetic variants of VDR have been explored as potential factors in autoimmune and allergic diseases, with limited studies on their association with allergic rhinitis (AR). The present investigation aims to analyse the role of three VDR genetic variants - TaqI, FokI and BsmI - in AR susceptibility and their impact on VDR mRNA and serum vitamin D levels. A total of 550 subjects, consisting of 250 AR cases and 300 age- and gender-matched controls, underwent genotyping by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). VDR mRNA and vitamin D levels were determined by quantitative real-time PCR and chemiluminescence, respectively. Although TaqI did not exhibit significant differences, FokI demonstrated a noteworthy association with AR, particularly with the CC genotype (odds ratio [OR]: 3.34; confidence interval [CI]: 1.79-6.23). Similarly, BsmI revealed an increased risk for AR, with the GA+AA genotypes showing a 2.2-fold elevated risk (OR: 2.20; CI: 1.53-3.16). VDR mRNA expression was threefold lower in AR patients (p<.0001), accompanied by reduced serum vitamin D levels (p<.0001). In addition, CC (p=.01) and AA (p=.02) genotypes of FokI and BsmI were associated with reduced VDR mRNA levels, whereas TaqI showed no such association. Similarly, heterozygous genotypes of TaqI and FokI, as well as homozygous AA of BsmI, correlated with lower serum vitamin D levels (p<.001). This study emphasizes the intricate relationship among VDR genetic variations, altered VDR activity, immune modulation and vitamin D metabolism in AR. Further research involving diverse populations is crucial for confirming and generalizing these findings, paving the way for personalized therapeutic interventions in vitamin D-related disorders.

The impact of SLCO1B1 single nucleotide polymorphism and non-genetic factors on statin-induced myopathy

Abstract Funding Acknowledgements None. Background Statins, also known as HMG CoA Reductase Inhibitors, are a class of drugs considered the drug of choice for treating hypercholesterolemia. Statins are well tolerated; however, they may cause severe myopathy in 20% to 30% of patients, due to the individual variation regarding its efficacy and related adverse effects. Of these, comes the Single Nucleotide Polymorphism (SNP) T521C of the SLCO1B1 gene that encodes the protein involved in the trafficking of statins from the blood to hepatocytes which is called Organic Anion Transport Protein 1B1 (OATP1B1). The T521C single nucleotide polymorphism (SNP) results in a substitute of valine with alanine resulting in a decreased or lack of functional protein. Purpose The aim is to determine the frequency of the high-risk C allele and to define its impact on statin-induced myopathy in Syrian patients on statins. In addition to the non-genetic factors that may affect the ability to develop statin-induced myopathy. Methods This was an observational case-control study that had ethical approval from Damascus University (No.433/ 2020). The case group included 44 patients on statins who experienced myopathy, 18 patients who had increased creatinine kinase levels (CK), and 26 patients with normal CK levels, while the control group encompassed 56 patients who were taking statins and had no muscular adverse events. The DNA was extracted from each sample and then genotyped using standard sequencing of specific PCR products using a specific pair of primers. Results The age of patients in the case arm ranged between 27 and 84 years with an average ± SD of (58.2 ± 12.7 years), 70% of them were males. In comparison with (53.34 ± 12.4 years) in the control arm, 66% of them were males without a statistically significant differences (p=0.672, 0.057) respectively. The statin type and dose have a statistically non-significant effect, the average statin dose in the case arm and the control arm was 26.02 mg and 31.27 mg respectively (p=0.072). While the statin type treatment varied as 59% used atorvastatin and 39% used rosuvastatin in the case group compared with 71% used atorvastatin and 27% used rosuvastatin in the control group, without a statistically significant difference (p=0.252). The frequency of the C allele reaches 19.3% and is distributed in three genotypes: wild-type TT (68%), heterozygote TC (25%), and homozygote CC (7%) in the case arm, while it does not exceed 8% in the control arm with the absence of the CC genotype. Only a statistically significant difference was found in the frequency of the CC genotype between these two groups (p=0.047). Conclusion Our study is the first to identify the frequency of the 521T&amp;gt;C SNP of the SLCO1B1 gene in Syrian patients taking statins. Our data reveals a high prevalence of risk allele C in the patients who suffer from statin-induced myopathy with a statically significant difference from the control arm (p=0.026).

Meta-analyses of the relationship between five CXCL8 gene polymorphisms and overall cancer risk, and a case-control study of oral cancer

BackgroundC-X-C motif chemokine ligand (CXCL8), also known as interleukin-8, is a prototypical CXC family chemokine bearing a glutamic acid-leucine-arginine (ELR) motif that plays key roles in the onset and progression of a range of cancers in humans. Many prior studies have focused on exploring the relationship between CXCL8 gene polymorphisms and the risk of cancer. However, the statistical power of many of these reports was limited, yielding ambiguous or conflicting results in many cases.MethodsAccordingly, the PubMed, Wanfang, Scopus and Web of Science databases were searched for articles published until July 20, 2023 using the keywords ‘IL-8’ or ‘interleukin-8’ or ‘CXCL8’, ‘polymorphism’ and ‘cancer’ or ‘tumor’. Odds ratios (ORs) and 95% confidence intervals (CIs) were utilized to examine the association. The CXCL8 +781 polymorphism genotypes were assessed with a TaqMan assay.ResultsAbout 29 related publications was conducted in an effort to better understand the association between these polymorphisms and disease risk. The CXCL8 -353A/T polymorphism was associated with an increased overall cancer risk [A vs. T, odds ratio (OR) = 1.255, 95% confidence interval (CI) (1.079–1.459), Pheterogeneity = 0.449, P = 0.003]. The CXCL8 +781 T/C allele was similarly associated with a higher risk of cancer among Caucasians [TT vs. TC + CC, OR = 1.320, 95%CI (1.046–1.666), Pheterogeneity = 0.375, P = 0.019]. Furthermore, oral cancer patients carrying the CXCL8 +781 TT + TC genotypes exhibited pronounced increases in serum levels of CXCL8 as compared to the CC genotype (P < 0.01), and also shown similar trend as compared to genotype-matched normal controls (P < 0.01). Finally, several limitations, such as the potential for publication bias or heterogeneity among the included studies should be paid attention.ConclusionCurrent study suggested that the CXCL8 -353 and +781 polymorphisms may be associated with a greater risk of cancer, which might impact cancer prevention, diagnosis, or treatment through the different expression of CXCL8. At the same time, the +781 polymorphism may further offer value as a biomarker that can aid in the early identification and prognostic evaluation of oral cancer.

Frequency of CYP2C19, P2RY12, ITGB3, ITGA2, and eNOS3 gene polymorphism in patients with myocardial infarction

The aim of the study was to assess the distribution of polymorphic variants G681A (*2) of the CYP2C19 gene, H1/H2 of the P2RY12 gene, T1565C of the ITGB3 gene, C807T of the ITGA2 gene, and T786C of the eNOS3 gene in the population of the Grodno region, and to study their associations with myocardial infarction (MI). The study of the population consists of 493 people, including 400 patients with MI aged 31 to 74 years and 93 people of the control group aged 32 to 60 years. Research data (clinical and genotyping performed by polymerase chain reaction) were analyzed using STATISTICA 10.0 software. The prevalence of carriage of genotypes associated with high residual platelet reactivity and variability in response to dual antiplatelet therapy among patients with MI was 25.2 % for the G681A polymorphic locus of the CYP2C19 gene (GA + AA), and for the H1/H2 polymorphic locus of the P2RY12 gene (H1/H2 + H2/H2) – 40.0 %, for the C807T polymorphic locus of the ITGA2 gene (CT + TT) – 65.8, for the T1565C polymorphic locus of the ITGB3 gene (TC + CC) – 25.5, for the polymorphic locus T786C of the eNOS gene (TC + CC) – 69.2 %. Among the individuals of the control group, the frequency of occurrence of these genotypes was 18.3, 46.2, 60.2, 37.6, 48.4 %, respectively. In patients with MI, compared to the control group, the TT genotype of the eNOS gene was less common (χ2 = 13.6, p = 0.0002), the CC genotype of the eNOS gene (χ2 = 5.4, p = 0.02) and the allele 786C of the eNOS gene (χ2 = 15.1, p = 0.0001) were more often detected. The carriage of the 786C allele of the eNOS gene increased the risk of MI in the studied population (OR = 2.0, 95 % CI: 1.41‒2.82, p = 0.0001). Gender differences were not found in the distribution of genotypes and alleles within the studied groups. There were no differences in carriage by the number of combinations of minor alleles between the control group and patients with MI. The most common combinations of minor alleles in both groups were comparable.

#1625 Influence of polymorphisms in genes for interleukin-6 and interleukin-10 on dialysis patients survival

Abstract Background and Aims Chronic inflammation is an important non-traditional risk factor for morbidity and mortality in patients with terminal kidney disease. Associated occurrence of malnutrition, inflammation and atherosclerosis was observed in patients on dialyses and marked as MIA syndrome, a vicious circle in which pro inflammatory cytokines play a key role. It is known that there were individual differences in creation of cytokines, and it is assumed that polymorphisms in the promoter regions of cytokine genes can have a key role in the predisposition to chronic inflammation and its consequences. We investigated association between interleukin-6 -174 G&amp;gt;C, interleukin-10 -1082 G&amp;gt;A, inteleukin-10 -819 T&amp;gt;C genotypes with the survival of patients with terminal renal failure. Method In this study, a total of 128 patients were examined, 77 on the regular hemodialysis (HD) and 51 on the peritoneal dialysis (PD) program of the UKCS Nephrology Clinic in Belgrade. Age, gender, BMI, duration of HD/PD, C-reactive protein (CRP), albumin and IL-6 and IL-10 concentration in serum were analyzed. Analysis of IL6 -174G&amp;gt;C and IL10 -819T&amp;gt;C polymorphisms was performed by the allele-specific PCR method, and analysis of the IL10 -1082G&amp;gt;A polymorphism by the PCR/RFLPs method. The patients were followed for 36 months and during that time 37 patients died. Results Univariate analysis showed that significant predictors of mortality were age (OR= 1.16,95%CI 1.061-1.269, p=0.001), albumin concentration (OR= 0.81, 95%CI 0.656-0.999, p=0.049), CRP (OR= 1.06, 95%CI 1003-1.124, p=0.039) and IL-6 (OR= 1.12, 95%CI 1.038-1.216, p=0.004), as well as IL-6176G&amp;gt;C gene polymorphism (OR= 0.82, 95%CI 0.097-0.805, p=0.018), while in multivariate logistic model separated only the concentration of IL-6 and the polymorphism in the gene for IL-6 -174 G&amp;gt;C. Estimated arithmetic mean of survival in subjects with the IL-6 -174GG genotype was 33.1 months (95%CI 30.8-35.3), GC 34.6 months (95% CI 33.6-35.7) and CC 26.1 (95% CI 20.0-32.2). There is statistically significant difference in survival time in relation to IL-6 -174 G&amp;gt;C genotype (chi-square=11.398; p=0.003). Estimated arithmetic mean survival in patients with the IL-10 -1082 GG genotype was 32.6 months (95% CI 30.5-35.2), in GA 31.5 (95% CI 29.2-33.8) and in AA 36.0 (95% CI 35.9-36.1). Exists statistically significant difference in survival time in relation to 1082G&amp;gt;A genotype (chi-square=9.669; p=0.008). Conclusion Monitoring of survival in 128 patients during 36 months showed that significant worse survival was experienced in patients with IL -6 -174 CC genotype, while polymorphisms in IL 10 gene-1082 G&amp;gt;A and -819T&amp;gt;C did not significantly affect survival. In this group of patients, beside IL-6-174 CC genotype, concentrations of IL-6, C reactive protein and albumin were significant predictors of mortality as well as Kt/V.

#1463 Assessment of salt-sensitive hypertension in a novel Lanosterol Synthase knock-in mouse model

Abstract Background and Aims The diversity in blood pressure (BP) response to various salt intakes, known as Salt Sensitivity (SS), exhibits significant differences among individuals within the hypertensive subjects relative to the general population. Hypertension (HT) and SS are correlated to elevated levels of plasma Endogenous Ouabain (EO). We aimed at delineating the role of the missense variation rs2254524 (Val642Leu; C&amp;gt;A) within the Lanosterol Synthase gene (LSS), encoding for an enzyme involved in steroid biosynthesis. Individuals with the AA LSS variant, adherent to a low-salt diet, had a more significant BP reduction compared to those with CC genotype. Method Utilising CRISPR-Cas9, we established a knock-in mouse model carrying the analogous LssV643L/V643L. Male mice were subjected to a normal-salt diet (0.5% NaCl), high-salt diet (4% NaCl), or low-salt diet (&amp;lt;0.03% Na) and BP was monitored every two days using a tail-cuff system for 10 days. Blood and urine were collected separately in metabolic cages. Results Homozygous mice for Lss mutation demonstrated normal viability and healthy phenotype, undistinguishable from the WT. At baseline, the Lss AA mice were affected by a significant augmentation in kidney weight at 3 and 12 months of age, relative to WT. The Lss V643L does not influence EO levels or systolic BP (SBP), specifically at 3 and 12 months, but affects the SBP response to dietary salt. AA mice showed a high SBP in a high-salt diet against control diet at the same time intervals. Moreover, the Lss variant impacted the pressure-natriuresis relationship, with the mutated AA strain showing a less steep curve both in control diet versus the high-salt diet and in control diet versus the low-salt diet, displaying the SS phenotype of the AA mice. The 12-month-old mice in high-salt diet displayed cardiac hypertrophy with the AA genotype exhibiting an elevated prevalence of cardiac fibrosis. The level of Lss mRNA decreased in the adrenal glands in response to a high-salt diet. RNASeq analysis identified distinct patterns in several Slc genes, Cbr2 and Arhgap26 within the kidneys of these mice, in control or high-salt dietary conditions. Conclusion The established LssV643L/V643L mouse model effectively mirrors the SS-HT phenotype. Our findings highlight the significance of the Lss in modulating BP in response to salt stimuli suggesting a potential organ damage pathway requiring further exploration in older mice.

Farnesyl Diphosphate Synthase Gene Associated with Loss of Bone Mass Density and Alendronate Treatment Failure in Patients with Primary Osteoporosis.

Aminobisphosphonates (NBPs) are the first-choice medication for osteoporosis (OP); NBP treatment aims at increasing bone mineral density (BMD) by inhibiting the activity of farnesyl diphosphate synthase (FDPS) enzyme in osteoclasts. Despite its efficacy, inadequate response to the drug and side effects have been reported. The A allele of the rs2297480 (A > C) SNP, found in the regulatory region of the FDPS gene, is associated with reduced gene transcription. This study evaluates the FDPS variant rs2297480 (A > C) association with OP patients' response to alendronate sodium treatment. A total of 304 OP patients and 112 controls were enrolled; patients treated with alendronate sodium for two years were classified, according to BMD variations at specific regions (lumbar spine (L1-L4), femoral neck (FN) and total hip (TH), as responders (OP-R) (n = 20) and non-responders (OP-NR) (n = 40). We observed an association of CC genotype with treatment failure (p = 0.045), followed by a BMD decrease in the regions L1-L4 (CC = -2.21% ± 2.56; p = 0.026) and TH (CC = -2.06% ± 1.84; p = 0.015) after two years of alendronate sodium treatment. Relative expression of the FDPS gene was also evaluated in OP-R and OP-NR patients. Higher expression of the FDPS gene was also observed in OP-NR group (FC = 1.84 ± 0.77; p = 0.006) when compared to OP-R. In conclusion, the influence observed of FDPS expression and the rs2897480 variant on alendronate treatment highlights the importance of a genetic approach to improve the efficacy of treatment for primary osteoporosis.

Identification of FASN Gene Polymorphisms, Expression and Their Relationship with Body Size Traits in Guizhou White Goat (Capra hircus) with Different Genders.

To investigate the nucleotide variation sites (SNPs) and expression differences of the fatty acid synthase gene (FASN) in Guizhou white goats, the relationship between the variation and body size traits was investigated. In this study, DNA was extracted from the blood of 100 samples of white goats from different regions in Guizhou province, China, and the variation sites were screened using pooled sequencing by mixing DNA samples, and 242 blood samples with body size traits were used for association analysis. The allele frequency, genotype frequency, homozygosity, heterozygosity and effective gene number were calculated by using PopGene 32.0 software, the population polymorphism information content was calculated by using PIC software (Version 0.6), and the state of genetic balance of the genes was analyzed by using the chi-square test. The mRNA of FASN gene expression levels in male and female goats were investigated by using real-time fluorescence quantitative PCR (RT-qPCR). The general linear mixed model of MINTAB software (Version 16.0) was used to analyze the association between FASN gene nucleotide mutation sites and body size traits. The results showed that there was one nucleotide mutation site g.141 C/T in the target fragment of FASN gene amplification, and revealed two alleles, C and T, and three genotypes CC, CT and TT. The genotype frequencies for CC, CT and TT were 0.4308, 0.4205 and 0.1487, respectively. The allele frequencies for C and T were 0.6410 and 0.3590, respectively. The genetic homozygosity (Ho) was higher than the heterozygosity (He). The χ2 test showed that the mutation site was in the Hardy-Weinberg equilibrium state (p > 0.05). The RT-qPCR results showed that the FASN gene had different expression levels in the longissimus dorsi muscle of male and female goats, and its expression was significantly higher in male goats than in female goats. The association analysis results showed that the mutation of the FASN gene had different effects on body size traits of male and female goats, and the presence of the populations of the T allele and the TT genotype recorded higher body size traits (body weight, heart girth and wither height) in female populations. Therefore, the site of the FASN gene can be used as a candidate marker for the early selection of growth traits in Guizhou white goats.

Association of the Complement Factor H Y402H Polymorphism and Response to Anti-Vascular Endothelial Growth Factor Treatment in Age-Related Macular Degeneration: An Updated Meta-Analysis.

Anti-vascular endothelial growth factor (anti-VEGF) agents have a variable effect on patients with age-related macular degeneration (AMD) that has been attributed to several causes, including genetic factors. We evaluated the effects of Complement Factor H (CFH) rs1061170/Y402H polymorphism on the response to anti-VEGF therapy among AMD patients. PubMed, Scopus, EMBASE, Web of Science, and Google Scholar were used for a literature search. Pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were estimated to assess the effects of CFH Y402H polymorphism on the response to anti-VEGF therapy in AMD. I2 was used to present the amount of heterogeneity. We used STATA version 14.0 software. Twenty-five papers reporting data for 4,681 patients were included in this study. Better response to anti-VEGF therapy was seen in T over C (OR = 1.25, 95% CI = 1.04-1.50), TT over CC (OR = 1.60, 95% CI = 1.06-2.4), and TT + TC over CC (OR = 1.68, 95% CI = 1.23-2.28) genotypes. There was no significant difference in the three other genetic models (TT vs. TC, TT vs. TC + CC, TC vs. TT + CC). In Asians, no significant difference was observed in all six genetic models. Ranibizumab and bevacizumab had similar efficacy; however, conbercept was more effective in homozygous genotypes. The literature indicated that TT and TC genotypes and T allele were associated with a better functional response, while the CC genotype and C alleles had a better anatomical response. The combination of risk alleles in ARMS2 A69S (rs10490924), VEGF-A (rs699947), and VEGF-A (rs833069) with Y420H is a predictor of non-respondents. In patients with AMD, the CFH Y402H is a predictor of the response to anti-VEGF agents and should be considered in the treatment plan.

Analysis of Genes Involved in Oxidative Stress and Iron Metabolism in Heart Failure: A Step Forward in Risk Stratification.

Heart failure (HF) is a clinical syndrome characterized by cardinal symptoms that may be accompanied by signs. It results from structural and/or functional abnormalities of the heart leading to elevated intracardiac pressures and/or inadequate cardiac output at rest and/or during exercise. The prevalence of iron deficiency and anemia justifies the current guidelines recommendation of screening. Genes HP, ACE, MTHFR, HFE, and CYBA are involved in oxidative mechanisms, iron metabolism, and hematologic homeostasis. This study investigatesthe contribution of variants Hp1/2 (HP), I/D (ACE), C677T (MTHFR), C282Y and H63D (HFE), and C242T (CYBA) to the development of HF, either independently or in epistasis. We used a database of 389 individuals, 143 HF patients, and 246 healthy controls. Genotypes were characterized throughPAGE electrophoresis, PCR, PCR-RFLP, and multiplex-ARMS. Data analysis was performed with the SPSS® 26.0 software(IBM Corp., Armonk, NY). We observed a significant association between theMTHFR gene and HF predisposition.The presence of allele T and genotype CT constituted risk, whilegenotype CC granted protection. Epistatic interactions revealed risk between genotype II of the ACE gene and genotypes CC (C282Y) or HH (H63D) of theHFE gene. Risk was also observed for interactions between genotype CC (CYBA)and genotypes 2-2 (HP), CT (MTHFR), or HH (HFE-H63D). We concluded that genes HP, ACE, MTHFR, HFE, and CYBA contribute to the susceptibility for HF, individually or in epistasis. This study contributes to the clarification of the role that genes involved in oxidative mechanisms and iron metabolism play in the physiopathology of HF. It is, therefore, a step forward in risk stratification and personalized medicine.

Right thalamic volume mediates impact of the dopamine beta-hydroxylase gene on the endowment effect

The endowment effect is a tendency that individuals overvalue items belonging to them relative to those items that do not. Previous studies showed a strong relation between the dopamine beta-hydroxylase (DBH) gene and the endowment effect (EE), and a link between EE and task-based functional MRI activation in multiple brain regions. However, the role of brain structure on EE remains unclear. In this study, we have explored whether regional brain volume mediate the effect of the DBH gene on EE. Results showed that rs1611115, single-nucleotide polymorphisms (SNPs) at DBH loci, were significantly associated with right thalamus volume and the endowment effect in males but not in female participants. Specifically, male DBH rs1611115 T-carriers had larger right thalamus volume compared to carriers of CC genotype and exhibited a greater endowment effect. Importantly, we found that right thalamus volume mediated the effect of rs1611115 on the endowment effect in male participants. This study demonstrated how thalamic volume plays an important mediating role between genetics and decision-making in humans.