G20210A Polymorphism Research Articles

Cognitive impairment viz-a-viz genetic and biochemical variations in one carbon metabolic pathway: A population-based study from North India

Disturbances in the one‑carbon metabolic pathway (OCMP) have been reported to be associated with cognitive impairment (CI). The study aimed to examine the association of MTR A2756G, MTRR A66G, and CBS 844ins68 polymorphisms present at critical steps of OCMP with CI independently and in light of vitamin B12, folate deficiencies, and hyperhomocysteinemia. The study also aimed to understand gene-gene interactions among selected markers linked with OCMP in CI using multifactor dimensionality reduction (MDR) analysis. A total of 808 individuals, aged 30–70 years of either sex, were recruited from Haryana, North India. Participants were screened for CI using MMSE. Individuals with mild CI were considered as case-1 and moderate/severe CI as case-2. Sociodemographic data were collected using an interview schedule. Biochemical and genetic analyses were performed using standard protocols. In the present study, CI was not found to be associated with MTR A2756G or CBS 844ins68 polymorphisms. AG and AA+AG genotypes of MTRR A66G polymorphism, with GG as the reference genotype, were found to pose 1.97 to 2.59-folds significantly increased risk for case-1 and case-2 CI. These associations, however, lost statistical significance for normal levels of vitamin B12 and homocysteine. In MDR analysis, two-loci models with MTHFR+MTRR for case-1 and MTR+MTRR for case-2 were found to have the highest TA% and CVC. Overall, MTRR A66G polymorphism appears to be a risk factor for CI in the studied population. Vitamin B12 seems to modulate the association of CI with MTRR A66G. MDR analysis suggests the involvement methionine cycle of OCMP in CI.

Association of CBS 844ins68, MTR A2756G and MTRR A66G gene polymorphisms with depression: A population-based study from North India

BackgroundDepression is one of the major global health problem currently affecting about 350 million people worldwide. Its cause is a multi-factorial which involves a complex mechanism of social, physiological, and biological factors. Mutations of genes in one-carbon metabolic pathway such as cystathionine-β-synthase (CBS 844ins68), methyltransferase (MTR A2756G) and methyltransferase reductase (MTRR A66G) have been implicated in various neurological disorders. ObjectiveIn the present study, we attempted to understand the association of these gene polymorphisms with depression among a North Indian population. MethodsA total of 808 participants aged between 30‐ and 70 years of either sex were recruited through door-to-door household survey. Depression status was identified by administering BDI-II. Genotyping of the selected gene polymorphisms were performed following previously reported protocols. ResultsThe result revealed that only MTR A2756G gene polymorphism was significantly associated with mild depression [OR 1.65 (95 % CI: 0.05–2.62) p = 0.03] but not with moderate and severe depression among the studied population. Since CBS, MTR and MTRR genes are found in OCMP, MTR A2756G gene polymorphism was found to be associated with mild depression but not with CBS 844in68 and MTRR A66G gene polymorphisms in the present study. ConclusionIdentification of susceptible genes involved in depressive disorder and early screening for mild depression may create better opportunity for timely intervention and further improve the quality of life.

Experimental study of A66G-single nucleotide polymorphism in the MTRR gene and acute myeloid leukemia

Acute Myeloid leukemia (AML) is the most common leukemia among adult population which begins with the bone marrow, but it frequently spreads to the blood stream as well. One of the common polymorphisms in AML is A66G in Methionine Synthase Reductase (MTRR), which converts isoleucine into methionine residue in the protein chain, the methionine/homocysteine cycle is disrupted. Limited studies were documented between A66G polymorphism in MTRR gene with AML. This study aimed to investigate the A66G polymorphism in MTRR gene with AML patients in the Saudi population. Peripheral blood was collected from 100 AML patients and 100 controls and DNA was isolated. Using A66G primers, polymerase chain reaction was performed followed by restriction fragment length polymorphism analysis. The mean age of both cases and controls was found to be an average of 39 years. Allele (G vs A: OR-3.41 [95 %CI: 1.87–11.24; p = 0.0001) and genotype analysis (GG vs AA: OR-3.43 [95 %CI: 1.45–8.11]; p = 0.0004) has shown the association. In conclusion, A66G polymorphism has a strong genetic role in the AML patients in Saudi population.

Association between OPG polymorphisms and osteoporosis risk: An updated meta-analysis.

Background: Numerous studies have demonstrated an association between osteoprotegerin (OPG) polymorphisms (A163G (rs3102735), T245G (rs3134069), T950C (rs2073617), G1181C (rs2073618)) and osteoporosis risk. However, their conclusions are inconsistent. In addition, some new studies have been updated, and more importantly, previous meta-analyses have not tested for false-positive results. In order to further explore these associations, we recently conducted a meta-analysis. Objectives: To study the relationship between OPG polymorphisms A163G, T245G, T950C, G1181C and the risk of osteoporosis. Methods: PubMed, Medline, International Statistical Institute (ISI), China National Knowledge Infrastructure (CNKI) and China Wanfang Database were used for research searches. Associations were assessed with five genetic models using odds ratios (ORs) with 95% confidence intervals (CIs). In addition, confidence in statistically significant associations was assessed using false-positive report probability (FPRP), Bayesian probability of False discovery (BFDP), and Venice criteria. Results: On the whole, the OPG A163G polymorphism was not significantly associated with risk of osteoporosis. However, in a subgroup analysis, we found that the OPG A163G polymorphism increased the risk of osteoporosis in Caucasians (AG + GG vs AA: OR = 1.35, 95% CI = 1.06-1.73; AA + GG vs AG: OR = 0.64, 95% CI = 0.49-0.82) and the female (G vs A: OR = 1.30, 95% CI = 1.03-1.64; AG + GG vs AA: OR = 1.42, 95% CI = 1.18-1.71). At the same time, the OPG G1181C polymorphism reduces the risk of osteoporosis (C vs G: OR = 0.84, 95% CI = 0.74-0.95; CC vs GG: OR = 0.75, 95% CI = 0.60-0.93; GC + CC vs GG: OR = 0.80, 95% CI = 0.67-0.95; CC vs GG + GC: OR = 0.84, 95% CI = 0.70-1.00). Moreover, a significantly decreased risk of osteoporosis was also discovered in Asian (C vs G: OR = 0.80, 95% CI = 0.66-0.98; CC vs GG: OR = 0.67, 95% CI = 0.47-0.95; GC + CC vs GG: OR = 0.74, 95% CI = 0.58-0.95) and the female (C vs G: OR = 0.85, 95% CI = 0.75-0.97; CC vs GG: OR = 0.77, 95% CI = 0.61-0.96; GC + CC vs GG: OR = 0.79, 95% CI = 0.66-0.95). Finally, we did not find a close association between OPG T245G and T950C polymorphisms and osteoporosis risk. However, when we retained only studies in the control group that was consistent with Hardy-Weinberg equilibrium (HWE) and high-quality scores, we observed that the OPG A163G polymorphism increased the risk of osteoporosis in the overall analysis (G vs A: OR = 1.40, 95% CI = 1.16-1.68; GG vs AA: OR = 1.96, 95% CI = 1.20-3.21; AG + GG vs AA: OR = 1.45, 95% CI = 1.22-1.72). Finally, after the credibility assessment, we concluded that all statistically significant association results in the meta-analysis in this study and those in the previous study were 'positive results with low confidence'. Conclusion: In conclusion, our study concluded that all meaningful results between OPG A163G and G1181C polymorphisms and osteoporosis risk were false-positive results rather than true associations.

Relationship of MTHFD1 G1958A and CBS 844ins68 polymorphism with congenital heart defects in North Indian population (Jammu and Kashmir): A case-control study

Objectives: There are many multifactorial causes for Congenital Heart Defects (CHDs) in which both genetic and non-genetic factors play role. MTHFD1 and CBS are two of the key enzymes that plays pivotal role in the metabolic pathway of homocysteine. Most of the studies revealed that genes involved in folate/homocysteine pathways are involved in the occurrence of CHDs. The present study was planned to investigate the role of common polymorphisms in MTHFD1 and CBS gene in children with CHD in Jammu region of Jammu and Kashmir UT. Material and Methods: A total of 160 (80 CHD patients and 80 controls) children were enrolled for the present case-control study. After extraction of genomic DNA genotyping of SNP MTHFD1 G1958A(rs2236225) was done by PCR-RFLP and CBS 844ins68 polymorphism was done by PCR technique. Results: Our results show that there is no significant association between MTHFD1G1958A and CBS 844ins68 polymorphism with CHD. In case of SNP MTHFD1 G1958A allele A found to be higher in both patient and control group and inCBS 844ins68 polymorphism frequency of risk allele ‘I’ found higher in cases (0.06) as compared to controls (0.04). The homozygous genotype for 844ins68 (II) was found absent in both the patients and control group. Conclusion: We conclude that both MTHFD1 G1958A and CBS 844ins68 polymorphism were not found to be genetic risk factor in the development of CHD in population of Jammu region of Jammu and Kashmir UT.

The impact of leptin and its receptor polymorphisms on type 1 diabetes in a population of northwest Iran

Background Diabetes comprises a serious disease with significant growth in the number of cases in recent years. Here, we cover the gap in information between leptin (LEP) and type 1 diabetes in the Iranian population. Aim To recognise LEP G2548A and LEP receptor Q223R polymorphisms in Iranian people and their association with type 1 diabetes susceptibility. Subjects and methods Characteristics such as fasting blood sugar (FBS) were measured in 80 control non-diabetic individuals and 89 diabetic patients. Moreover, LEP G2548A and LEP receptor Q223R polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism technique. Results The frequency of the A allele was nearly three times greater in diabetes patients than in the control group. In addition, in the diabetes group, the AA genotype was five times greater than in the control group (p < 0.01). Furthermore, AA and AA + AG genotype models had higher FBS levels than the GG + AG and GG genotype models, respectively (p < 0.01). Conclusion The LEP G2548A polymorphism could be related to type 1 diabetes susceptibility, but not LEPR Q223R polymorphism in the Iranian population. Importantly, further studies are essential to examine the impact of LEP G2548A and LEPR Q223R polymorphisms in the endocrinology area.

Characterization of a Polymorphism in the Stimulatory Region of the TNF Gene in Type 2 Diabetic Patients in Iraq

The current study aims to analyze the distribution of the TNF-α gene and TNF-β polymorphism (-308G/A) in type 2 diabetes mellitus (T2DM) patients. According to world health organization the prevalence of diabetes is rising exponentially. Tumor necrosis factor alpha and beta are members of the tumor necrosis factor (TNF) super-family considered as pro inflammatory cytokine which play major role in DM pathogenesis. single nucleotide polymorphism reported to have associated with type 2 DM. Frequency of TNF-a G308A polymorphism was determine in different ethnic groups and was found variable highly. Few studies recorded appositive association between DM and TNF-α polymorphism; including meta-analysis failed to find such association. Our finding revealed that the TNF-α gene polymorphism (-308G/A) had 38 (12.50%) of G/G genotype, 44 (45.83%) of G/A genotype and 40 (41.67%) A/A genotype showed in this population. This preliminary result indicated that G/A genotype was a common in the TNF-α gene polymorphism (-308G/A) in T2DM patients while healthy control group does not exhibit AA and GA genotype.

Protein Z (rs3024735; G79A and rs3024719; G-103A) gene polymorphisms in Behçet’s disease patients

Aim of the workTo investigate protein Z (PZ) gene polymorphic variations; PZ G79A (rs3024735) and PZ G-103A (rs3024719) in Behçet's disease (BD) patients and their possible relation with disease manifestations, activity and damage. Patients and methodsThis study included 100 BD patients and 100 controls. BD current activity form (BDCAF) and the BD damage index (BDI) were assessed. Genomic DNA analysis of PZ G79A (rs3024735) and PZ G-103A (rs3024719) single nucleotide polymorphisms, was assessed by Real-time PCR-TaqMan SNP genotyping assay. ResultsThe mean age of patients was 33.4 ± 6.8 years and median disease duration was 9 years. AA and GA genotypes of PZ G79A polymorphism were significantly higher in patients than controls (p = 0.003 and p = 0.004 respectively). The frequency of A allele was significantly higher in patients than controls (p < 0.001). There was no difference between patients and controls regarding AA and GA genotypes of PZ G-103A polymorphism (p = 0.5 and p = 0.2 respectively). There was a significant association between AA and GA genotypes of PZ G79A polymorphism with retinal vascular occlusion (RVO) (p < 0.001) and deep vein thrombosis (DVT) (p = 0.003), neutrophil–lymphocyte ratio (p < 0.001) and BDI (p < 0.001). There was no association between PZ G79A genotypes and BDCAF (p = 0.8). A allele of PZ G79A polymorphism was associated with increased BD susceptibility (p < 0.001), RVO (p = 0.001) and DVT (p = 0.01). ConclusionPZ G79A (rs3024735) polymorphism A allele was associated with increased susceptibility to BD with increased risk of developing RVO, DVT and damage, while AA and GA genotypes of PZ G-103A polymorphism were not significantly increased in BD patients.

The Effects of BMI and Genetic Variation of Adipokines on Serum Concentrations of Hormones in Untreated Individuals with Breast Cancer; a Pilot Study

Background: Numerous studies have shown an association between hormones secreted by adipose tissues and cancer development. Objectives: This study aimed at investigating the effect of body mass index (BMI) and genetic variation of leptin and adiponectin on serum concentrations of leptin, adiponectin, and estradiol among untreated breast cancer. Methods: This case-control study was performed on 350 women (175 women with breast cancer and 175 healthy controls), who had not taken any medications. Serum levels of estradiol (17-beta estradiol), leptin, and adiponectin were measured, using the ELISA technique. Single-nucleotide polymorphisms of leptin gene (LepG2548A), leptin receptor (Q223, K109R, and K656N), and adiponectin gene (T45G, G276T, C11377G, and 11391A) in blood-isolated DNA were evaluated, using RFLP-PCR technique. Results: Body mass index can affect serum concentrations of hormones and is associated with breast cancer. Also, except for adiponectin C11377G polymorphism, other all genetic variations showed significant relationships with breast cancer. In both groups, BMI was significantly correlated with the mean serum concentrations of hormones, and the risk of breast cancer increased in G2548A, Q223R, K656N, and G276T polymorphisms. The effect of risk allele genotypes on serum concentration of hormones showed that changes in serum concentration of estrogen and leptin in all studied polymorphisms were associated with breast cancer in postmenopausal women. But adiponectin level was only affected by polymorphisms K109R, K656N, and G276 and G11391A. Conclusions: High BMI and genetic variation can affect cancer development by changing the serum concentrations of hormones in different genotypes. Studying various populations’ genetics and lifestyle can help definitive conclusions about genetics and obesity.

Impact of Methionine Synthase Reductase Polymorphisms in Chronic Myeloid Leukemia Patients.

Highlights What are the main findings? Our objective was to determine the relationship between the methionine synthase reductase polymorphisms (MTRR and MTR) and the risk of developing chronic myeloid leukemia (CML) in Sudanese Patients. What is the implication of the main finding? Here, we report that the heterozygous and homozygous mutant genotypes of MTRR polymorphisms were associated with a decreased risk of developing CML in the Sudanese population asa protective factor.Our findings will help to increase the understanding of MTRR A66G polymorphism and its association with CML risk in the Sudanese population. Introduction： Metabolism methionine and of folate play a vital function in cellular methylation reactions, DNA synthesis and epigenetic process.However, polymorphisms of methionine have received much attention in recent medical genetics research. Objectives: To ascertain whether the common polymorphisms of the MTRR (Methionine Synthase Reductase) A66G gene could play a role in affecting susceptibility to Chronic Myeloid Leukemia (CML) in Sudanese individuals. Methods: In a case-controlled study, we extracted and analyzed DNA from 200 CML patients and 100 healthy control subjects by the PCR-RFLP method. Results: We found no significant difference in age orgender between the patient group and controls. The MTRR A66G genotypes were distributed based on the Hardy-Weinberg equilibrium (p > 0.05). The variation of MTRR A66G was less significantly frequent in cases with CML (68.35%) than in controls (87%) (OR = 0.146, 95% CI = 0.162–0.662, p < 0.002). Additionally, AG and GG genotypes and G allele were reducing the CML risk (Odds ratio [OR] = 0.365; 95% CI [0.179–0.746]; p = 0.006; OR = 0.292; 95% CI [0.145–0.590]; p = 0.001 and OR = 0.146; 95% CI [0.162–0.662]; p = 0.002 and OR = 2.0; 95% CI [1.3853–2.817]; respectively, (p = 0.000)). Conclusions: Our data demonstrated that heterozygous and homozygous mutant genotypes of MTRR polymorphisms were associated with decreased risk of developing CML in the Sudanese population.

LEP G2548A polymorphism is associated with increased serum leptin and insulin resistance among T2DM Malaysian patients.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic syndrome that is rapidly increasing across the world, especially in Malaysia. Leptin plays a vital role in the regulation of metabolism through its effect on peripheral tissues. G2548A polymorphism in the LEP gene promoter has been associated with insulin resistance, leptin, and type 2 diabetes mellitus across different population, but has not been inclusively reported within the Malaysian population. Thus, our study aimed to investigate the impact of G2548A polymorphism on serum leptin levels and insulin resistance among Malaysian T2DM patients. This case-control study involved 150 T2DM patients and 150 non-diabetic volunteers from ethnic Malays, Chinese and Indians. Genotyping of G2548A polymorphism was carried out using PCR-RFLP. Serum leptin and insulin levels were determined via ELISA. ANOVA and Chi-square tests were used to determine the distribution of genotypes and allelic frequencies based on serum leptin and insulin levels. Frequency of AA genotype and A allele of G2548A variant were significantly (P < 0.05) higher in T2DM patients of Malay and Indian ethnicities (4%, 35%, and 36%, 57%, respectively) as compared to the control groups (0%, 22%, and 18%, 35%, respectively). Fasting serum leptin levels were significantly (P < 0.001) higher in T2DM patients compared to non-diabetic subjects (166.78 pg/ml, 101.94 pg/ml, respectively). Additionally, elevated serum leptin, insulin levels, and BMI in diabetic patients were found to be associated with the AA genotype of this variant, compared to GG, and GA genotypes (P < 0.05). Our findings suggest a significant association between G2548A polymorphism among Malaysian T2DM subjects, particularly among Malay and Indian ethnic groups. Moreover, the A allele frequency of the G2548A variant significantly increased the risk of T2DM and is significantly associated with increased serum leptin, insulin levels, and elevated BMI.

Analysis of polymorphisms in recurrent pregnancy loss: Factor V Leiden G1691A, Factor II G20210A, MTHFR C677T and Factor V H1299R

The distribution of factor V Leiden G1691A, factor II G20210A, MTHFR C677T, and factor V H1299R polymorphisms known to predispose to thrombophilia in 215 cases and 40 controls admitted with indication of recurrent pregnancy loss (RPL) was investigated. Genotyping was performed by melting curve analysis using simultaneous PCR (RT-PCR). There was no difference between genotype and allele frequencies in the case and control groups in terms of the polymorphisms examined (p>0.05). In the genotype distribution of the Factor V gene G1691A polymorphism, 12.6% GA in the case group and 90.0% GG (wild) genotypes in the control group were found to be higher than the other genotypes. In the genotype distribution of the factor II gene G20210A polymorphism, the GG (wild) genotype was found to be higher in 94.5% and 97.5%, respectively, in the case group and control group than the other genotypes. In the genotype distribution of MTHFR gene C677T polymorphism, 43.7% CC (wild) in the case group and 40.0% CT genotype in the control group were found to be higher than the other genotypes. In the genotype distribution of the factor V gene A4070G polymorphism, 87.4% AA (wild) in the case group and 80% AA (wild) genotype in the control group were found to be higher than the other genotypes. However, the frequency of risk allele A for factor V Leiden G1691A (6.8% and 5%), the frequency of risk allele A for factor II gene G20210A (3% and 1.2%), MTHFR gene C677T were determined in the case and control groups. The frequency of the T allele (35.9% and 42.5%), which is the risk allele for A4070G, and the frequency of the G allele (6.5% and 16.6%), which is the risk allele for the factor V gene A4070G, were determined. When our study results were evaluated, no relationship was found between RPL and factor V Leiden G1691A, factor II G20210A, MTHFR C677T, and factor V A4070G polymorphisms.

MTHFR Gene-Polymorphism and Infertile Men in Indian Population: A Systematic Literature Review

Single nucleotide polymorphisms (SNPs) in the genetic makeup of the methylenetetrahydrofolate reductase gene (MTHFR C677-T, A1298-C, and G1793-A) alongside environmental and lifestyle component has shown some links as a potential factor responsible for male infertility across the globe posing huge genetic vulnerability to the gender. However, SNPs in the MTHFR gene implicated in male infertility are not without their own controversial results even within the same population. The goal of this study was to provide comprehensive insights into the controversial nature of MTHFR gene polymorphism on male infertility across all Indian populations as well as other ethnicities. The electronic PubMed database was utilized to conduct and select eligible studies for this systematic review (update to December 2021). Only high-quality studies with a link between MTHFR polymorphisms and male infertility were included based on our exclusion and inclusion criteria. The connection between the MTHFR gene polymorphism and male infertility in Indian population studies was evaluated using odds ratios (ORs) with a 95% confidence interval (CI). A total of five studies presenting 1,237 cases and 1,044 controls were assessed for this study. The collective results revealed that MTHFR C667-T and A1298-C gene polymorphism were significantly linked with an increased chance of male infertility both in south India and north India, however, with some conflicting results. Interestingly, no study has been carried out to investigate the impact of G1793-A polymorphism on infertile males in the Indian population at the time of our report. Results generated from the few case-control evaluated on MTHFR gene polymorphism in the Indian population are found to conflict with some extrinsic factors (such as nutritional status-folate metabolism, lifestyle, varying recruitment procedures, and epigenetic elements) identified to have played some critical roles. Therefore, broader studies across all regions in India addressing the grave impact of MTHFR gene polymorphism on male infertility are of utmost importance.

Association between MTR A2756G polymorphism and susceptibility to congenital heart disease: A meta-analysis.

The association between methionine synthase (MTR) A2756G (rs1805087) polymorphism and the susceptibility to congenital heart disease (CHD) has not been fully determined. A meta-analysis of case-control studies was performed to systematically evaluate the above association. Studies were identified by searching the PubMed, Embase, Web of Science, China National Knowledge Infrastructure, and WanFang databases from inception to June 20, 2021. Two authors independently performed literature search, data extraction, and quality assessment. Predefined subgroup analyses were carried out to evaluate the impact of the population ethnicity, source of healthy controls (community or hospital-based), and methods used for genotyping on the outcomes. A random-effects model was used to combine the results, and 12 studies were included. Results showed that MTR A2756G polymorphism was not associated with CHD susceptibility under the allele model (odds ratio [OR]: 0.96, 95% confidence interval [CI]: 0.86 to 1.07, P = 0.43, I2 = 4%), heterozygote model (OR: 0.95, 95% CI: 0.84 to 1.07, P = 0.41, I2 = 0%), homozygote model (OR: 1.00, 95% CI: 0.64 to 1.55, P = 0.99, I2 = 17%), dominant genetic model (OR: 0.95, 95% CI: 0.84 to 1.07, P = 0.41, I2 = 0%), or recessive genetic model (OR: 0.94, 95% CI: 0.62 to 1.43, P = 0.32, I2 = 13%). Consistent results were found in subgroup analyses between Asian and Caucasian populations in studies with community and hospital-derived controls as well as in studies with PCR-RFLP and direct sequencing (all P values for subgroup differences > 0.05). In conclusion, current evidence does not support an association between MTR A2756G polymorphism and CHD susceptibility.

Evaluation of the g473a polymorphism in the lysyl oxidase gene as a risk factor related to the occurrence of breast cancer in brazilian women

Introduction: breast cancer is the most diagnosed type of cancer and the leading cause of death among women worldwide. Approximately 1.67 million new cases of breast cancer were diagnosed in 2012, leading to more than half a million deaths. Breast cancer accounted for 11.6% of newly diagnosed cancers (2,089 million) and 9.2% (787,000) of cancer-related deaths for both sexes and at all ages worldwide in 2018. Objective: breast cancer, as the most diagnosed carcinoma in the world and the leading cause of death among women, is a morbidity of outstanding importance, and the object of this study is to evaluate the association between the LOX gene G473A (rs1800449) polymorphism and breast cancer occurrence, potentially establishing a new finding in the identification of risks, prevention, and care for a specific group of women. Methods:in this retrospective cohort study, LOX G473A polymorphism frequency was assessed in 148 women with breast cancer and 245 women without breast cancer. All patients completed a questionnaire to identify possible risk factors and subsequently underwent peripheral blood collection to study the LOX gene. DNA was extracted followed by gene amplification via PCR, and the polymorphism was studied by specific fragment electrophoresis after digestion of the samples with the restriction endonuclease Pstl. Results: this study identified the use of oral contraceptives and family history of breast cancer as risk factors for breast cancer; the G473A polymorphism in LOX was not identified as a risk factor. Conclusion: a relationship was not observed between the LOX G473A polymorphism and the occurrence of breast cancer.

Evaluating the Association Between Genetic Polymorphisms Related to Homocysteine Metabolism and Unexplained Recurrent Pregnancy Loss in Women.

ObjectiveTo investigate the relationship between unexplained recurrent pregnancy loss (URPL) and polymorphisms of homocysteine metabolism-related genes in women.Materials and MethodsA case–control study included 90 women with two or more consecutive unexplained pregnancy losses and 92 controlled women without miscarriage history; the female participants were in the age category of 18–35 years. The high-resolution melting technique was used to detect the single-nucleotide variants related to homocysteine metabolism disorder, namely MTHFR C677T, MTHFR A1298C, MTR A2756G, and MTRR A66G polymorphism.ResultsThe MTHFR C677T polymorphism had significantly correlation with URPL. Indeed, the frequency of the677T allele and genotypes (677CT, 677TT) in the URPL group was significantly higher than that in the control group (p < 0.05). However, the allele, as well as genotype distribution of MTHFR A1298C, MTR A2756G, and MTRR A66G polymorphisms showed no significant difference (p > 0.05). MTHFR 677CT-1298AC genotype combination led to a 9.0-fold increased risk of URPL (OR 9.0; 95% CI, 2.25–35.99; p = 0.001), while the risk increased 10.0-fold (OR 10.0; 95% CI, 1.8–55.53; p = 0.008) when participants had more than the 3 variant loci.ConclusionThe MTHFR C677T polymorphism was a risk factor for URPL, and determining the MTHFR C677T polymorphism had a potential prediction of URPL risk. Moreover, the MTHFR C677T and MTHFR A1298C joint mutants might have a synergistic effect on URPL. Conversely, there is a lack of evidence suggesting the URPL risk of MTHFR A1298C, MTR A2756G, and MTRR A66G polymorphisms.

0296 Vigilant Attention Performance Advantage Conferred by TNFα G308A Polymorphism is Associated with Diminished Delta and Theta Power in the Non-REM Sleep EEG

Abstract Introduction Carriers of the A allele of a single nucleotide polymorphism of the TNFα gene (G308A, rs1800629) are relatively resilient to vigilant attention performance impairment from total sleep deprivation (TSD), as compared to G/G homozygotes, and even exhibit a small performance advantage at baseline. The mechanism underlying this effect remains unclear. As TNFα is a sleep regulatory substance, we investigated whether TNFα G308A genotype is associated with systematic differences in markers of sleep homeostasis. Methods N=168 healthy young adults (ages 27.4±5.4y; 86 women) participated in one of seven in-laboratory TSD studies. During TSD, performance was assessed every 2–3h using a psychomotor vigilance test (PVT). The TSD period was preceded and followed by nocturnal sleep opportunities (baseline and recovery, respectively), which were recorded polysomnographically and scored according to AASM criteria. The EEG (C3-M2 derivation) of stages N2 and N3 non-REM sleep was investigated using spectral analysis. Results The genotype distribution of the sample was 0.6% A/A, 26.8% A/G, 72.6% G/G, in Hardy-Weinberg equilibrium (P=0.14). As documented previously, A allele carriers, compared to G/G homozygotes, had fewer PVT lapses (RTs&amp;gt;500ms) at baseline and during TSD, indicating greater resilience to sleep deprivation. During both baseline and recovery sleep, A allele carriers, compared to G/G homozygotes, displayed reduced power in the delta (0.8–4.0Hz; P=0.017) and theta (4.2–8.0Hz; P=0.004) bands of the non-REM sleep EEG. Conclusion The performance advantage of the A allele carriers brings to mind the “banking sleep” phenomenon previously observed in sleep deprivation studies with prior sleep extension, suggesting that the A allele carriers gained this advantage by essentially being able to bank sleep. If this interpretation is correct, then the diminished power in the delta and theta bands of the non-REM sleep EEG in the A allele carriers, which suggests reduced homeostatic sleep pressure during both baseline and recovery sleep, may imply that the A allele carriers operate at a lower homeostatic setpoint due to an underlying advantage in the recuperative efficiency of sleep. Support (If Any) NIH R01HL070154, R21CA167691, R01HL105768; ONR N00014-13-C-0063, N00014-13-1-0302, FAA DTFAAC-11-A-00003, CDMRP W81XWH-16-1-0319, USAMRDC W81XWH-05-1-0099, and an SRS Elliot D. Weitzman, M.D. Research Grant.

\u201cAssociation of MTHFR and MS/MTR gene polymorphisms with congenital heart defects in North Indian population (Jammu and Kashmir): a case\u2013control study encompassing meta-analysis and trial sequential analysis\u201d

BackgroundThe risk of Congenital Heart Defects (CHD) is greatly influenced by variants within the genes involved in folate-homocysteine metabolism. Polymorphism in MTHFR (C677T and G1793A) and MS/MTR (A2756G) genes increases the risk of developing CHD risk, but results are controversial. Therefore, we conducted a case–control association pilot study followed by an up-dated meta-analysis with trial sequential analysis (TSA) to obtain more precise estimate of the associations of these two gene variants with the CHD risk.MethodsFor case–control study, we enrolled 50 CHD patients and 100 unrelated healthy controls. Genotyping was done by PCR–RFLP method and meta-analysis was performed by MetaGenyo online Statistical Analysis System software. For meta-analysis total number of individuals was as follows: for MTHFR C677T 3450 CHD patients and 4447 controls whereas for MS A2756G 697 CHD patients and 777 controls.ResultsResults of the original pilot study suggested lack of association for MTHFR C677T and MS A2756G polymorphism with risk of CHD whereas MTHFR G1793A was significantly associated with the disease. On performing meta-analysis, a significant association was observed with MTHFR C677T polymorphism but not with MS A2756G. Trial sequential Analysis also confirmed the sufficient sample size requirement for findings of meta-analysis.ConclusionsThe results of the meta-analysis suggested a significant role of MTHFR in increased risk of CHD.

G870A Polymorphic Variants of CCND1 Gene and Cyclin D1 Protein Expression as Prognostic Markers in Laryngeal Lesions.

CCND1 gene encodes Cyclin D1 protein, the alternations and overexpression of which are commonly observed in human cancers. Cyclin D1 controls G1-S transition in the cell cycle. The aim of the study was to assess utility of the genotyping and protein expression in predicting the susceptibility of transformation from normal tissue to precancerous laryngeal lesions (PLLs) and finally to laryngeal cancer (LC). Four hundred and thirty-five patients (101 with LC, 100 with PLLs and 234 healthy volunteers) were enrolled in the study. Cyclin D1 expression was examined by immunohistochemistry and G870A polymorphism of gene CCND1 by PCR-RFLP technique. We confirmed association between the A allele and risk of developing LC from healthy mucosa (p = 0.006). Significantly higher expression of Cyclin D1 was observed in LC compering with PLLs (p < 0.0001) and we found that it could be a predictive marker of shorter survival time. To sum up, in the study population CCND1 gene polymorphism A870G and Cyclin D1 expression have a significant impact on the risk of developing PLLs and LC, and, therefore, Cyclin D1 could be a useful marker for the prediction of survival time in LC, whereas CCND1 gene polymorphism does not have a direct impact on patients’ outcome.

Clinical Implication of Toll-Like Receptors (TLR2 and TLR4) Polymorphisms in Adult Patients with Acute B-cell Lymphoblastic Leukemia.

Backgrounds:Neutropenia after intensive chemotherapy of acute lymphoblastic leukemia (ALL) could lead to infectious complications that affect outcome of acute leukemia patients. Many single-nucleotide polymorphisms (SNPs) of Toll-like receptors (TLRs) can affect the genetic susceptibility to infections. We investigated the impact of different SNPs on the incidence of developing sepsis and pneumonia in patients with newly diagnosed B-ALL following induction chemotherapy. Subjects and methods:We analyzed three SNPs in the TLR2 (Arg753Gln) and TLR4 (Asp299Gly& Thr399Ile) genes using polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) in a case control study of 40 precursor B-ALL patients and 50 control subjects. The risk of developing sepsis and pneumonia were assessed by multiple logistic regression analyses. Results:The presence of the TLR-2 AG polymorphism was significantly associated with pneumonia in B-ALL patients. Furthermore, TLR4 Thr399Ile AG was a risk factor for sepsis in B-ALL patients. Moreover; Significant association between TLR-2 AA, TLR-4 CC and TL-4 AA genotypes and longer OS were detected in studied B-ALL patients. Conclusion:We concluded that TLR-4 (AG and CT) genotypes are associated with high susceptibility to sepsis and pneumonia respectively; while, TLR-2, TLR-4 AA and TLR-4 CC genotypes could predict good B-ALL patients outcome.