Carriers Of Other Genotypes Research Articles

Association between Platelet-Derived Growth Factor Receptor Alpha Gene Polymorphisms and Platelet-Rich Plasma's Efficiency in Treating Lateral Elbow Tendinopathy-A Prospective Cohort Study.

Individual differences in the response to platelet-rich plasma (PRP) therapy can be observed among patients. The genetic background may be the cause of this variability. The current study focused on the impact of genetic variants on the effectiveness of PRP. The aim of the present study was to analyze the impact of single nucleotide polymorphisms (SNP) of the platelet-derived growth factor receptor alpha (PDGFRA) gene on the effectiveness of treating lateral elbow tendinopathy (LET) with PRP. The treatment's efficacy was analyzed over time (2, 4, 8, 12, 24, 52 and 104 weeks after the PRP injection) on 107 patients using patient-reported outcome measures (PROM) and achievement of a minimal clinically important difference (MCID). Four SNPs of the PDGFRA gene (rs7668190, rs6554164, rs869978 and rs1316926) were genotyped using the TaqMan assay method. Patients with the AA genotypes of the rs7668190 and the rs1316926 polymorphisms, as well as carriers of the T allele of rs6554164 showed greater effectiveness of PRP therapy than carriers of other genotypes. Moreover, the studied SNPs influenced the platelets' parameters both in whole blood and in PRP. These results showed that PDGFRA gene polymorphisms affect the effectiveness of PRP treatment. Genotyping the rs6554164 and the rs1316926 SNPs may be considered for use in individualized patient selection for PRP therapy.

Ala54Thr polymorphism of the fatty acid transporter gene (FABP2) in patients with type 2 diabetes mellitus in Yakutia

To study the contribution of the Ala54Thr genetic polymorphism of the FABP2 gene to the risk of developing type 2 diabetes mellitus among the Yakut population. The study included participants who filled out a questionnaire approved by the Local Committee on Biomedical Ethics at the Yakut Science Centre of complex medical problems and voluntarily signed an informed consent to conduct a genetic study. The sample consisted of 181 patients of the endocrinological department of the Republican Hospital No. 2 of the State Budgetary Institution "Center for Emergency Medical Care" with a diagnosis of type 2 diabetes. The comparison group was a sample of 336 volunteers without chronic diseases of the Yakut ethnicity. For molecular genetic analysis, genomic DNA samples were isolated from whole blood. Single nucleotide polymorphism was determined by polymerase chain reaction followed by analysis of restriction fragment length polymorphism. Study showed that polymorphism in the FABP2 gene has an impact on anthropometric parameters and blood biochemical parameters. The risk of developing type 2 diabetes was 1.7 times higher in carriers of the Ala/Thr genotype (odds ratio 1.755, 95% confidence interval - 1.212-2.542; p<0.005) compared with carriers of other genotypes. When comparing the average biochemical values, the levels of aspartate transaminase, alanine aminotransferase, glucose and total bilirubin in homozygous carriers of the Ala/Ala genotype were significantly lower than in carriers of other genotypes (р<0.05). Carriers of the heterozygous Ala/Thr genotype (р<0.05) had the highest level in terms of aspartate aminotransferase and alanine aminotransferase. The highest indicator of the average level of HbA1c and an indicator of total bilirubin were carriers of the Thr/Thr genotype (р<0.05). The high prevalence of the negative Thr allele among the Yakut population is probably associated with living conditions in the North, as well as in the traditional type of diet.

Association of the circadian rhythm gene &lt;i&gt;ARNTL/BMAL1&lt;/i&gt; with personal anxiety among people aged 25–64 (WHO international program “MONICA-psychosocial (MOPSY)”)

Objective: to study associations between personal anxiety (PA) and single nucleotide polymorphism rs2278749 of the ARNTL gene among individuals aged 25–64 years living in Novosibirsk.Material and methods. Under the WHO program “MONICA-psychosocial (MOPSY)”, a random representative sample of the population aged 25–64 years in Novosibirsk was studied (725 men, mean age – 43.4±0.4 years, response – 71.3%; 710 women, mean age – 44.8±0.4 years, response – 72%). The general examination was carried out according to standard methods included in the protocol of the WHO program. To assess PA, a form of Spielberger self-assessment scales was proposed. Every second respondent underwent genotyping of the studied polymorphisms of the ARNTL gene.Results. The C/C genotype of the ARNTL gene was found in the general population in 60.7% of individuals (in 61.2% of men and 60.5% of women); the C/T genotype was found in 34.1% of individuals (in 35.1% of men and 33.5% of women) and the T/T genotype in the general population was found in 5.2% of individuals (in 3.7% of men and 6% women). The probability of PA development among carriers of the CT+TT genotypes of the ARNTL gene was 2 times higher (p&lt;0.05) in the general population and 2.4 times (p&lt;0.05) among women; among T allele carriers, it was 1.8 times higher (p&lt;0.05) in the population and 2.1 times (p&lt;0.05) among women. Carriers of the C/T genotype of the ARNTL gene were 30.3% more likely to believe that they almost always take everything too personally (p=0.024). Carriers of the C/T genotype (21%) almost always, and carriers of the T/T genotype (27.8%) often would like to be as happy as others (p=0.031). The answer “I often feel satisfaction” prevailed (38.2%) among the carriers of the C/C genotype, and the answer “Almost never feel satisfaction” among the carriers of the C/T genotype (5.9%) of the ARNTL gene (p=0.044) .Conclusion. It was found that the C/C genotype of the ARNTL gene was the most common in the population; the probability of PA occurrence among carriers of CT+TT genotypes, carriers of the T allele is 2 times higher than in carriers of other genotypes of the ARNTL gene.

Pharmacogenetics in treatment of anthracycline-induced cardiotoxicity in women without prior cardiovascular diseases

Aim. To evaluate the role of polymorphisms in adrenoceptor beta 1 (ADRB1) (Arg389Gly, rs1801253) and angiotensin-converting enzyme (ACE) (I/D, rs4343) genes in assessing the effectiveness of β-blocker (carvedilol) and ACE inhibitor (enalapril) therapy in women with anthracycline-induced cardiotoxicity (AIC) without prior cardiovascular diseases (CVD) during 12-month follow-up.Materials and methods. A total of 82 women (average age 45.0 (42.0; 50.0) years) with AIC and without prior CVD were included in the study. Echocardiography was performed and serum levels of NT-proBNP were determined at baseline and at 12 months after the enrollment. Gene polymorphisms in ADRB1 and ACE genes were evaluated by polymerase chain reaction at baseline.Results. Carriers of the G/G genotype in the ADRB1 gene and G/G genotype in the ACE (I/D, rs4343) gene showed a significant increase in left ventricular ejection fraction (LVEF), a decrease in the size of the left ventricle (LV) and left atrium (LA), and a fall in the NT-proBNP level. Carriers of other genotypes had further progression of AIC which was manifested through a decrease in LVEF and an increase in the size of LV and LA.Conclusion. Evaluation of gene polymorphisms in ADRB1 (Arg389Gly, rs1801253) and ACE (I/D, rs4343) genes may be recommended before treatment initiation for AIC in women without prior CVD to determine who will benefit from carvedilol and enalapril therapy, as well as to identify a priority group of patients for personalized intensification and optimization of treatment for decreasing development of adverse cardiovascular events.

Association of ID polymorphism of the CASP8 gene with vibration disease

Introduction. The study of the contribution of molecular genetic markers to the formation of occupational diseases is currently an urgent direction in occupational health. It is considered proven that the development and course of occupational diseases depends not only on the occupational risk, but also on the individual characteristics of the body of workers. The study of molecular genetic markers makes it possible to determine the risk groups of early development and unfavorable course of occupational diseases in the post-contact period. The study aims to explore the association of the ID polymorphism of the CASP8 gene with vibration disease, the timing of its development and some biochemical parameters. Materials and methods. We have examined eighty men with vibration disease. Of these: twenty three people with early stages of disease development (work experience under the influence of industrial vibration for less than fifteen years), fifty-seven people with late stages of disease development (work experience under the influence of industrial vibration for more than fifteen years). The scientists have carried DNA extraction from blood by the phenol-chloroform method. In the caspase 8 gene (CASP8) in the promoter we have checked the presence/absence of detention in 6 bp652 AGTAAG ins/del (rs3834129) using PCR.The researchers carried out the frequencies of the genotype and alleles of the I/D polymorphism of the CASP8 gene in the studied groups. Results. The authors found that the genotype ID of the rs3834129 polymorphism of the CASP8 gene is significantly more common in the group of patients with late-onset vibration disease (VD). The researchers found when studying some indicators of connective tissue metabolism, that the level of uronic acids (UC) was significantly lower in carriers of the genotype ID polymorphism of the CASP8 gene compared with carriers of other genotypes. Conclusion. The carriage of the genotype ID of the rs3834129 polymorphism of the CASP8 gene is a marker associated with resistance to the formation of VB in workers of vibration-hazardous professions, as well as with a low level of activity of fibroplastic processes. Limitations. The relatively small size of the studied groups. Ethics. The authors have conducted the study in compliance with the Ethical principles of conducting medical research with the participation of a person as a subject and the rules of clinical practice in the Russian Federation approved by Order of the Ministry of Health of the Russian Federation No. 266 of 19.06.2003. The conclusion of the Ethical Committee at the Federal State Budgetary Educational Institution of the Ministry of Health of the Russian Federation (Protocol No. 65 of 27.05.2014) and informed consent of patients was received.

Clinical and genetic associations of the CLOCK circadian rhythm gene and depressive disorders in patients with alcohol dependence syndrome during the period of alcohol abstinence

About 20% of patients with depression are diagnosed with alcohol dependence, and alcohol dependent individuals are at a higher risk of developing depression. A number of authors point to the relationship of CLOCK gene activity with both affective disorders and alcohol use/dependence disorders; in particular, variations in the CLOCK gene at the evidence level link to depression and stress.Objective: to establish clinical and genetic associations of the CLOCK circadian rhythm gene and depressive disorders during the period of abstinence in patients with alcohol dependence syndrome.Patients and methods. From June 2019 to December 2022, 402 patients (mean age 42.47±7.5 years) were examined, who underwent outpatient follow-up at a narcological dispensary not earlier than 1 month after and not later than 2 months after discharge from the hospital. All patients were diagnosed with middle-stage alcohol dependence syndrome, early remission phase. Depending on the presence of an episode of depression at the time of the examination, the main group (patients with a depressive disorder; n=128) and a comparison group (patients without a depressive disorder; n=274) were formed. Clinical interviews and psychometric study using the Montgomery–Asberg Depression Scale, were conducted for all the subjects. All subjects provided 10 ml venous blood samples for molecular, genetic and biochemical studies.Results and discussion. Correlations were found between the carriage of the TT genotype of the CLOCK gene in patients with alcohol dependence and concomitant clinical depression. Carrying the TT genotype of the CLOCK gene is presumably associated with the predominance of the following symptoms of depression, which demonstrated statistically significant differences: loss of appetite, impaired concentration, apathy, as well as with a higher overall score on the MADRS depression scale. The established association between the CLOCK gene and depression in people with alcohol dependence can be considered as a vulnerability factor in relation to the development of depression in patients with the underlying disease – alcohol dependence syndrome.Conclusion. The CLOCK gene is associated with the development of depression in patients suffering from alcohol dependence. Carriers of the TT genotype of the CLOCK gene (rs1801260) to a greater extent than carriers of other genotypes are characterized by the development of comorbid depression, as well as the predominance of such clinical symptoms as loss of appetite, impaired concentration, apathy, and a higher overall score on the MADRS depression scale.

CYP2C19 gene polymorphism and its impact on the long-term prognosis after myocardial infarction

Background: Despite advanced in interventional and medical treatment, mortality after myocardial infarction (MI) remains high, which necessitates the search for predictors of poor outcome. An association between the gene CYP2C19 alleles with lower functional activity and the rates of cardiovascular events has been found. In a number of studies, negative impact of the *2 and *3 alleles of this polymorphic gene on the post-infarction course was shown. However, in most of these studies the patients were followed up from 3 months to 1 year.&#x0D; Aim: To evaluate the effect of CYP2C19 gene polymorphism (*2, *3) on the long-term prognosis in patients with a history of ST-segment elevation myocardial infarction (STEMI).&#x0D; Materials and methods: This open-label prospective two-center study included 145 patients aged 45 to 75 years with a history of STEMI. For 1 year from STEMI on, all the patients were taking medications recommended for outcome improvement, such as statins, clopidogrel as a component of dual antiplatelet therapy, beta-blockers, angiotensin converting enzyme inhibitors. The outcomes were assessed at 12 months by the endpoints of cardiovascular death and recurrent non-fatal MI, and at 5 years by the endpoints of overall mortality and recurrent non-fatal MI.&#x0D; Results: During one year of the follow up, 7 of 145 patients (4.8%) died from cardiovascular causes. Recurrent MI occurred in 8.3% (n = 12) of the patients. The carriers of *1*2 and *1*3 genotypes of the polymorphic CYP2C19 gene were 3.27-fold more likely to experience recurrent MI within 1 year, compared to the carriers of other genotypes (relative risk = 3.27 [95% confidence interval 1.03; 10.36], p = 0.03). After 5 years of the follow up, this association has disappeared. No influence of the assessed polymorphisms on overall and cardiovascular mortality was found (p 0.05). One hundred and seven (107) patients were followed up for 5 years; 14 (13.0%) of them died, other 15 patients (14.0%) had recurrent MIs.&#x0D; Conclusion: *2 and *3 alleles of the polymorphic CYP2C19 gene responsible for the metabolism of clopidogrel, are risk factors of an unfavorable 12-month outcome after STEMI. Subsequently, the influence of the CYP2C19 gene polymorphism on the outcomes evades and is not associated with a 5-year prognosis. To improve post-STEMI outcomes at 1 year, it is necessary to implement the earliest personalized approached to antiplatelet treatment based on the results of the CYP2C19 gene polymorphism analysis.

Associations of APOE Gene Variants rs429358 and rs7412 with Parameters of the Blood Lipid Profile and the Risk of Myocardial Infarction and Death in a White Population of Western Siberia.

The present study aimed to analyze possible associations of rs7412 and rs429358 of the APOE gene with lipid profile parameters, the risk of myocardial infarction, and death in the mostly white population of Western Siberia (Russia). The study population was selected from a sample surveyed within the framework of the Health, Alcohol and Psychosocial Factors In Eastern Europe (HAPIEE) study (9360 subjects, age 53.8 ± 7.0 years, males/females 50/50). PCR was conducted with fluorescence detection according to the TaqMan principle on a real-time PCR machine. The frequency of a minor allele (C) of rs429358 was 0.13, and the frequency of a minor allele (T) of rs7412 was 0.09. In our study, the woman with the rare ɛ1/ɛ4 genotype had substantial aberrations in blood lipid levels. In Kaplan–Meier curves, statistically significant differences were revealed in the prognosis of survival within the subgroup of females who had a myocardial infarction (p = 0.0006): the prognosis was worse for carriers of the ɛ2/ɛ2 genotype and for ɛ4/ɛ4 carriers. Survival analysis regarding deaths from all causes showed (p = 0.0238) that female carriers of the ɛ2/ɛ4 genotype had a worse prognosis than did carriers of other genotypes. Thus, in the population of Western Siberia (Russia), we confirmed statistically significant associations between rs7412 & rs429358 genotypes and lipid profile parameters.

The interaction between glycemic index, glycemic load, and the genetic variant ADIPOQ T45G (rs2241766) in the risk of colorectal cancer: a case-control study in a Korean population.

The glycemic index (GI), glycemic load (GL), and adiponectin level contribute to glycemic response and insulin sensitivity in the body. Studies have shown that tumor development is related to glycemic disorders; however, the results are contradictory. We aimed to investigate the association of GI and GL with colorectal cancer (CRC) risk in a Korean population and their possible interactions with the genetic variant ADIPOQ T45G. A case-control study including 2096 participants with 695 CRC cases was conducted. The results showed that diets with high GI or GL were significantly associated with an increased risk of CRC [odds ratio (OR) = 5.44, 95% confidence interval (CI) 3.85-7.68; OR = 4.43, 95% CI 3.18-6.15, respectively; all p-trends < 0.001]. Moreover, even with a low-GI and low-GL diet, G/G genotype carriers may have 2.93-fold and 3.77-fold higher risk of rectal cancer compared to carriers of other genotypes (T/T + T/G), (OR = 2.93, 95% CI 1.01-8.59, p-interaction = 0.011 for GI; OR = 3.77, 95% CI 1.46-9.77, p-interaction = 0.025 for GL). Overall, our study suggests positive associations of GI and GL with CRC risk. Moreover, the associations of GI and GL with rectal cancer risk could be modified by ADIPOQ T45G in a Korean population. Further studies with larger sample sizes are needed to confirm our findings.

Встречаемость мутаций и потери гетерозиготности в гене ТР53 в зависимости от генотипа rs1042522 при диффузной В-крупноклеточной лимфоме

Introduction. Recent studies have shown that in tumor cells of various types of malignant neoplasms, in carriers of the heterozygous variant rs1042522 of the TP53 gene, most of the point mutations are detected in the G allele of the gene, while the C allele was lacking as a result of loss heterozygosity (LH). At the same time, the association of the G allele of the rs1042522 gene with a decrease in the effectiveness of therapy in patients with malignant neoplasms was described. Previously, the study of rs1042522 on samples of patients with lymphomas was carried out only in healthy tissues; in the tumor tissue of diffuse large B-cell lymphoma (DLBCL), this single nucleotide polymorphism was not studied. Given the propensity of B-lymphocytes to p53-mediated apoptosis, the study of the rs1042522 genotype in combination with somatic aberrations, such as mutations or LH of the TP53 gene in the tumor tissue of DLBCL is of particular interest. Aim. To describe the frequency of occurrence of somatic mutations and LH in the TP53 gene depending on the rs1042522 genotype in the tumor tissue of patients with DLBCL. Materials and methods. The study included 150 patients with a diagnosis of DLBCL confirmed histologically and immunohistochemically. DNA was isolated from paraffinized blocks of tumor lymph nodes and extranodal lesions by phenol-chloroform extraction using guanidine. Genotyping according to rs1042522 and detection of cases of loss of heterozygosity in the TР53 gene was carried out by PCR with the analysis of polymorphism of the lengths of restriction fragments. Confirmation of LH and the search for mutations in the TP53 gene were carried out by direct Sanger sequencing. Results. In the study group, almost a third (28.6%) of patients with DLBCL at the stage of tumor diagnosis had genetic anomalies in the structure of the TР53 gene (LH and mutations). The combination of LH and the mutant status of this gene in patients with heterozygous Arg/Pro genotype of the tested polymorphism in the tumor tissue was not revealed. At the same time, it was noted that in a subgroup of 73 samples with a homozygous G/G genotype, mutations were detected in 20 cases (27.3%). In the subgroups of C/C homozygous and G/C heterozygous samples, the mutation was detected only in 1/13 (7.7%) and 4/64 (6.25%) cases, respectively. The significance of differences in the frequency of detection of mutations between G/G homozygous patients and other patients with DLBCL (genotypes C/C+G/C) was p &lt; 0.001, and the probability of detecting mutations in the TР53 gene in carriers of the G/G genotype was more than 5.4 times higher than that in carriers of other genotypes (odds ratio – 5.4, 95% confidence interval – 1.9; 15.4). Conclusion. In order to increase the probability of identifying of combined detection of LH and mutations in TP53 with different rs1042522 genotypes, it is possible to increase the number of lymphoma samples, as well as the use of high-performance sequencing and methods for searching for allelic imbalance, which will allow registering the loss of heterozygosity in homozygous samples as well. A possible direction for further research may also be the analysis of the clinical significance of the combined detection of the homozygous genotype G/G of the marker and LH or/and somatic mutations in the TP53 gene in the tumor tissue of patients with lymphoma.

Association of alcohol withdrawal severity with MTNR1A (rs34532313) and MTNR1B (rs10830963) genes polymorphisms

Alcohol withdrawal is the most threatening condition encountered in patients with alcohol use disorder. Our study aimed to investigate the association of alcohol withdrawal severity with polymorphic variants in melatonin receptor genes. Methods. The clinical study was carried out on the basis of the Republican Narcological Dispensary №1 in Ufa and the Republican Narcological Dispensary №2 in Sterlitamak. Genetic analysis was performed at the Department of Personalised Psychiatry and Neurology at the V.M. Bekhterev Research Centre, Saint Petersburg. The final sample consisted of 307 subjects. Results. Carriers of the TT genotype of the MTNR1A gene (rs34532313) were found to have less hypertension during alcohol withdrawal than carriers of the other genotypes. In comparison, carriers of the GG genotype of the MTNR1B gene (rs10830963) experienced more symptoms than other genotypes: paroxysmal sweating, visual hallucinations, anxiety, and overall CIWA-Ar score. Conclusions. Thus, it can be concluded that the TT genotype of MTNR1A gene (rs34532313) is associated with a lower risk of hypertension during alcohol withdrawal compared to carriers of other gene genotypes. The GG genotype of MTNR1B gene (rs10830963) is associated with severe withdrawal. In general, it can be concluded that melatonin receptors are involved in the pathogenesis of alcohol withdrawal and the severe of some of its symptoms.

Stromal Derived Factor-1 Gene Polymorphism in Pediatric Immune Thrombocytopenia.

Immune thrombocytopenia (ITP) is a multifactorial disease in which both environmental and genetic factors have been implicated. The study aimed to investigate a possible association of single nucleotide polymorphisms (SNPs rs266085 and rs2839693) in the stromal derived factor-1 (SDF-1) gene and its association to ITP and effect on ITP severity and response to treatment. Genomic DNA was extracted from peripheral blood and polymorphism in SDF-1 gene rs266085 and rs2839693 was analyzed using PCR-restriction fragment length polymorphism technique in DNA extracted from 60 children with ITP together with 90 healthy controls. On analysis of SDF-1 rs266085 polymorphism, there was a high frequency of CC genotype in cases than controls and that difference was significant at codominant, overdominant, and dominant models (P<0.05). Furthermore, carriers of the CC genotype were more susceptible to severe ITP at onset, steroid dependency, and chronicity than carriers of other genotypes (P<0.05). Otherwise, no significant differences between ITP patients and controls as regard SDF-1 rs2839693 genotypes and alleles, and we did not find a relation between this polymorphism and ITP severity, steroid dependency, or duration. SDF-1 gene rs266085 SNP C allele is associated with susceptibility to develop ITP as well as increases the risk for severe ITP at onset, chronic ITP and steroid dependency.

Pharmacogenetics of therapy effectiveness for anthracycline-induced cardiotoxicity

Abstract Objective To evaluate role of genetic factors (polymorphisms of ADRB1 gene (Arg389Gly, rs1801253) and ACE gene (I/D, rs4343) for effectiveness assessment of β-blocker (carvedilol) and angiotensin-converting enzyme inhibitor (enalapril) therapy in women with anthracycline- induced cardiotoxicity during 12-month follow-up period. Methods A total of 82 women, median age of 45.0 (42.0; 50.0) years with anthracycline-induced cardiotoxicity and without prior cardiovascular diseases were enrolled in the study. All patients received chemotherapy for the treatment of breast cancer included a combination of doxorubicin and cyclophosphamide, or combination of doxorubicin, cyclophosphamide and docetaxel. The cumulative dose of doxorubicin was 300–360 mg/m2. Criteria for the development of cardiotoxicity were a decrease in the left ventricle ejection fraction (LVEF) at the 12 months after chemotherapy completion by &amp;gt;10%, the development of heart failure (HF) with symptoms and clinical signs, and NT-proBNP levels ≥125 pg/mL. Echocardiography and serum levels of NT-proBNP were performed at baseline and at 12 months after enrollment. Average up-titrated dosage of carvedilol was 50 (25; 50) mg per day and enalapril was 10 (10; 20) mg per day. Evaluation of gene polymorphisms of ADRB1 gene and ACE gene were carried out by polymerase chain reaction at baseline before treatment initiation. Results The baseline LVEF, end-systolic and end-diastolic dimension indexes, NT-proBNP levels, 6-minute walk test distance did not differ among patients with different genotypes of ADRB1 and ACE genes. However, carriers of T/T genotype of ADRB1 gene had a significant increasing in LVEF (&amp;lt;0.001) by 11% from 50.0 (48.0; 51.0) to 56.0 (53.0; 57.0)% and decreasing in end-systolic dimension index (p&amp;lt;0.001) by 27.7% and end-systolic dimension index (p&amp;lt;0.001) by 6% within 12 months of follow-up period. The levels of NT-proBNP decreased (p=0.001) by 34.2% from 327.5 (260.1; 381.8) to 213.5 (195.3; 256.7) pg/mL and 6-minute walk test distance increased (0.008) by 10%. Carriers of G/G genotype of ACE gene had the same benefits from this therapy: LVEF (&amp;lt;0.001) increased by 6.5% from 50.5 (47.0; 51.0) to 54.0 (50.0; 57.0)%, end-systolic dimension index (p&amp;lt;0.001) decreased by 5.3% and end-systolic dimension index (p&amp;lt;0.001) by 3% within 12 months of follow-up period. The levels of NT-proBNP decreased (p=0.005) by 20.3 from 314.1 (279.6; 372.9) to 249.9 (197.3; 267.8) pg/mL and 6-minute walk test distance increased (0.008) by 5%. Carriers of other genotypes had decreasing in LVEF, increasing in LV dimensions and NT-proBNP, and further progression of HF. Conclusion Our data suggest that evaluation of gene polymorphisms of ADRB1 (Arg389Gly, rs1801253) and ACE gene (I/D, rs4343) can be recommended before treatment initiation of anthracycline- induced cardiotoxicity in women without prior cardiovascular diseases to determine who will benefit of carvedilol and enalapril therapy. Funding Acknowledgement Type of funding sources: None.

Why PRP works only on certain patients with tennis elbow? Is PDGFB gene a key for PRP therapy effectiveness? A prospective cohort study

BackgroundThere is variability in individual response to platelet-rich plasma (PRP) therapy in tennis elbow treatment. Genetic variation, especially within genes encoding growth factors may influence the observed inter-individual differences. The purpose of this study was to identify polymorphic variants of the platelet-derived growth factor beta polypeptide gene (PDGFB) that determine an improved individual response to PRP therapy in tennis elbow patients.MethodsThis prospective cohort study was designed in accordance with STROBE and MIBO guidelines. A cohort of 107 patients (132 elbows, 25 bilateral) was studied, including 65 females (77 elbows) and 42 males (55 elbows), aged 24–64 years (median 46.00 ± 5.50), with lateral elbow tendinopathy treated with autologous PRP injection. The effectiveness of PRP therapy was recorded in all subjects at 2, 4, 8, 12, 24 and 52 weeks after PRP injection using the Visual Analog Scale (VAS), quick version of Disabilities of the Arm, Shoulder and Hand score (QDASH) and Patient-Rated Tennis Elbow Evaluation (PRTEE). In order to determine the PDGFB variants with the best response to PRP therapy, patient reported outcome measures were compared between individual genotypes within studied polymorphic variants (rs2285099, rs2285097, rs2247128, rs5757572, rs1800817 and rs7289325). The influence of single nucleotide polymorphisms on blood and PRP parameters, including the concentration of PDGF-AB and PDGF-BB proteins was also analyzed.ResultsOur analysis identified genetic variants of the PDGFB gene that lead to a better response to PRP therapy. The TT (rs2285099) and CC (rs2285097) homozygotes had higher concentration of platelets in whole blood than carriers of other genotypes (p = 0.018) and showed significantly (p < 0.05) lower values of VAS (weeks 2–12), QDASH and PRTEE (weeks 2–24). The rs2285099 and rs2285097 variants formed strong haplotype block (r2 = 98, D’=100). The AA homozygotes (rs2247128) had significantly lower values of VAS (weeks 4–52), QDASH and PRTEE (weeks 8, 12).ConclusionsPDGFB gene’s polymorphisms increase the effectiveness of PRP therapy in tennis elbow treatment. Genotyping two polymorphisms of the PDGFB gene, namely rs2285099 (or rs2285097) and rs2247128 may be a helpful diagnostic tool while assessing patients for PRP therapy and modifying the therapy to improve its effectiveness.

PPARA Polymorphism Influences the Cardiovascular Benefit of Fenofibrate in Type 2 Diabetes: Findings From ACCORD-Lipid.

The cardiovascular benefits of fibrates have been shown to be heterogeneous and to depend on the presence of atherogenic dyslipidemia. We investigated whether genetic variability in the PPARA gene, coding for the pharmacological target of fibrates (PPAR-α), could be used to improve the selection of patients with type 2 diabetes who may derive cardiovascular benefit from addition of this treatment to statins. We identified a common variant at the PPARA locus (rs6008845, C/T) displaying a study-wide significant influence on the effect of fenofibrate on major cardiovascular events (MACE) among 3,065 self-reported white subjects treated with simvastatin and randomized to fenofibrate or placebo in the ACCORD-Lipid trial. T/T homozygotes (36% of participants) experienced a 51% MACE reduction in response to fenofibrate (hazard ratio 0.49; 95% CI 0.34–0.72), whereas no benefit was observed for other genotypes (Pinteraction = 3.7 × 10−4). The rs6008845-by-fenofibrate interaction on MACE was replicated in African Americans from ACCORD (N = 585, P = 0.02) and in external cohorts (ACCORD-BP, ORIGIN, and TRIUMPH, total N = 3059, P = 0.005). Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia. Among these individuals, but not among carriers of other genotypes, fenofibrate treatment was associated with lower circulating levels of CCL11—a proinflammatory and atherogenic chemokine also known as eotaxin (P for rs6008845-by-fenofibrate interaction = 0.003). The GTEx data set revealed regulatory functions of rs6008845 on PPARA expression in many tissues. In summary, we have found a common PPARA regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify patients with type 2 diabetes who would derive benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia.

NEUROPROTECTIVE EFFECT OF APOE2: EVIDENCE AND IMPLICATION FOR COGNITIVE AGING

Apolipoprotein E is a glycoprotein mediator and regulator of lipid transport and uptake. The APOE4 allele has been associated with higher risk of Alzheimer’s disease and of mortality, but the protective effect of the less prevalent APOE2 allele is less well established. This symposium will bring together experts in epidemiology, molecular biology, neurology and systems biology to clarify the role of APOE2 in longevity and cognitive health, to describe molecular targets of APOE alleles, and to suggest mechanisms of protection conferred by APOE2 using IPSc derived systems. Dr Seshadri will show the strong association between APOE2 and human longevity using data of 38,537 individuals of European ancestry. Mr Sweigart will examine longitudinal trajectories of cognitive function in participants of the Long Life Family Study and the New England Centenarian Study and show that carriers of the homozygote genotype of APOE2 have a significant slower rate of decline of their cognitive function compared to carriers of other genotypes. Dr Monti will present an association analysis of APOE genotype data with 4137 human proteins in serum of 222 New England Centenarian Study participants. The analysis discovered a signature of 16 proteins that associated with different APOE genotypes, and replicated in 3 independent studies. Dr. Ellerby will summarize her recent analyses that used transcription analysis of isogenic iPSCs with APOE2 and APOE4 homozygote genotypes differentiated into inhibitory GABAergic neurons to show that E2 inhibitory GABAergic neurons regulate genes involved in nuclear division, DNA integrity and DNA damage checkpoint.

SU65 - ASSOCIATION OF POLYMORPHISM RS934945 GENE PER2 WITH SLEEP DISODERS IN THE MALE POPULATION 25–44 YEARS IN NOVOSIBIRSK

Background To study the prevalence and associations of gene PER2 with sleep disorders. Methods A random representative sample of the male population aged 25–44 years who were residents of one of Novosibirsk district was examined in 2014–2016. Results The most common genotype of rs934945 PER2 gene was genotype G / G - 65,36%. A/G was in 30.17% and genotype A/A was in 4,47% of men. Those carriers with the A/A genotype has an increasing tendency of anxious dreams during sleep compared to carriers of other genotypes. Carriers of genotype A / A often wake up during the night. Sleep was the strongest in men with A / G and G / G genotype. Lack of sleep (5 hours or less) is also more common in persons who had genotype with homozygous allele A was presented in. Discussion The gene PER2 (rs934945) in our population has a relationship with various chronotype that plays an important role in understanding the basics of sleep disorders.

Leptin gene polymorphisms are associated with weight gain during lithium augmentation in patients with major depression

Weight gain is a common adverse effect of lithium augmentation. Previous studies indicate an impact of genetic variants at the leptin gene on weight gain as a consequence of psychopharmacological treatment. The primary aim of our study was to identify variants at the leptin locus that might predict lithium-induced weight gain. The secondary aim was to investigate if these variants modulate leptin levels. In 180 patients with acute major depressive disorder, body mass index was measured before and after 4 weeks of lithium augmentation, in a subsample also after 4 and/or 7 months. In a subsample of 89 patients, leptin serum concentrations were measured before and during lithium augmentation. We used linear mixed model analyzes to investigate the effects of 2 polymorphisms at the leptin locus (rs4731426 and rs7799039, employing the respective proxy SNPs rs2278815 and rs10487506) on changes in body mass index and leptin levels. For both polymorphisms, which are in high linkage disequilibrium, body mass index was significantly lower in homozygous A-allele carriers than in carriers of other genotypes at baseline. Over the follow-up period, body mass index increased less in homozygous A-allele carriers of rs4731426 than in carriers of other genotypes. This was not the case for rs7799039. Neither polymorphism modulated leptin protein expression. Our study strongly supports the hypothesis that genetic variability at the leptin locus is involved in lithium augmentation-associated weight gain in major depressive disorder. Furthermore, Genotype-Tissue Expression data provide strong evidence that rs4731426 influences the expression of leptin messenger ribonucleic acid in fibroblasts.

IL6R Gene Polymorphic Variant rs2228145(C >A) as a Marker of Genetic Liability to Nonalcoholic Steatohepatitis in the Russian Population of Karelia.

Association of IL6R gene polymorphic variant rs2228145(C>A) with the development of nonalcoholic steatohepatitis in Karelia residents is detected. The risk of nonalcoholic steatohepatitis is more than 2-fold higher in carriers of CC genotype by rs2228145 polymorphic marker than in carriers of other genotypes. Plasma levels of IL-6 and the content of IL6R gene transcripts in the peripheral blood leukocytes are higher in patients with nonalcoholic steatohepatitis than in normal subjects. No relationships between rs2228145 polymorphism and the level of IL-6 and content of IL6 and IL6R mRNA were detected. Gene IL6R polymorphic variant rs2228145(C>A) seems to be involved in genetic predisposition of the population of Karelia to nonalcoholic steatohepatitis. However, biochemical and molecular mechanisms underlying the relationship of rs2228145 with the development of nonalcoholic steatohepatitis are not yet studied.

TCF7L2 Genetic Variation Augments Incretin Resistance and Influences Response to a Sulfonylurea and Metformin: The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH).

OBJECTIVEThe rs7903146 T allele in transcription factor 7 like 2 (TCF7L2) is strongly associated with type 2 diabetes (T2D), but the mechanisms for increased risk remain unclear. We evaluated the physiologic and hormonal effects of TCF7L2 genotype before and after interventions that influence glucose physiology.RESEARCH DESIGN AND METHODSWe genotyped rs7903146 in 608 individuals without diabetes and recorded biochemical data before and after 1) one dose of glipizide (5 mg) on visit 1 and 2) a 75-g oral glucose tolerance test (OGTT) performed after administration of metformin 500 mg twice daily over 2 days. Incretin levels were measured in 150 of the 608 participants.RESULTSTT risk-allele homozygotes had 1.6 mg/dL higher baseline fasting glucose levels and 2.5 pg/mL lower glucagon levels per T allele than carriers of other genotypes at baseline. In a subset of participants, the T allele was associated with higher basal glucagon-like peptide 1 (GLP-1) levels at visit 1 (β = 1.52, P = 0.02 and β = 0.96, P = 0.002 for total and active GLP-1, respectively), and across all points of the OGTT after metformin administration. Regarding drug response, the T allele was associated with a shorter time (β = −7.00, P = 0.03) and a steeper slope (β = 0.23, P = 0.04) to trough glucose levels after glipizide administration, and lower visit 2 fasting glucose level adjusted for visit 1 fasting glucose level (β = −1.02, P = 0.04) and a greater decline in glucose level between visits (β = −1.61, P = 0.047) after metformin administration.CONCLUSIONSOur findings demonstrate that common variation at TCF7L2 influences acute responses to both glipizide and metformin in people without diabetes and highlight altered incretin signaling as a potential mechanism by which TCF7L2 variation increases T2D risk.