Genetic and epigenetic risks of intracytoplasmic sperm injection method

Pregnancies achieved by assisted reproduction technologies, particularly by intracytoplasmic sperm injection （ICSI） procedures, are susceptible to genetic risks inherent to the male population treated with ICSI and additional risks inherent to this innovative procedure. The documented, as well as the theoretical, risks are discussed in the present review study. These risks mainly represent thatconsequences of the genetic abnormalities underlying male subfertility （or infertility） and might become stimulators for the development of novel approaches and applications in the treatment of infertility. In addition, risks with a polygenic background appearing at birth as congenital anomalies and other theoretical or stochastic risks are discussed. Recent data suggest that assisted reproductive technology might also affect epigenetic characteristics of the male gamete, the female gamete, or might have an impact on early embryogenesis. It might be also associated with an increased risk for genomic imprinting abnormalities.

Stair climbing,genetic predisposition,and the risk of incident type 2 diabetes:A large population-based prospective cohort study

Background:Cross-sectional evidence and small-scale trials suggest positive effects of stair climbing on cardiometabolic disease and glucose regulation.However,few studies have examined the long-term association between stair climbing and the incidence of type 2 diabetes(T2D).We aimed to prospectively evaluate the association of stair climbing with T2D and assess modifications by genetic predisposition to T2D.Methods:We included 451,699 adults(mean age=56.3±8.1 years,mean±SD;55.2%females)without T2D at baseline in the UK Biobank and followed up to March 31,2021.Stair climbing information was collected through the touchscreen questionnaire.Genetic risk score for T2D consisted of 424 single nucleotide polymorphisms.Results:During a median follow up of 12.1 years,14,896 T2D cases were documented.Compared with participants who reported no stair climbing,those who climbed stairs regularly had a lower risk of incident T2D(10-50 steps/day:hazard ratio(HR)=0.95,95%confidence interval(95%CI):0.89-1.00;60-100 steps/day:HR=0.92,95%CI:0.87-0.98;110-150 steps/day:HR=0.86,95%CI:0.80-0.91;>150 steps/day:HR=0.93,95%CI:0.87-0.99,p for trend=0.0007).We observed a significant interaction between stair climbing and genetic risk score on the subsequent T2D risk(p for interaction=0.0004),where the risk of T2D showed a downward trend in subjects with low genetic risk and those who reported stair climbing activity of 110-150 steps/day appeared to have the lowest overall T2D risk among those with intermediate to high genetic risk.Conclusion:A higher number of stairs climbed at home was associated with lower T2D incidence risk,especially among individuals with a low genetic predisposition to T2D.These findings highlight that stair climbing,as incidental physical activity,offers a simple and low-cost complement to public health interventions for T2D prevention.

The First Pilot Epigenetic Type Improvement of Neuropsychiatric Symptoms in a Polymorphic Dopamine D2 (-DRD2/ANKK (Taq1A)), OPRM1 (A/G), DRD3 (C/T), and MAOA (4R) Compromised Preadolescence Male with Putative PANDAS/CANS: Positive Clinical Outcome with Precision-Guided DNA Testing and Pro-Dopamine Regulation (KB220) and Antibacterial Therapies

Pediatric autoimmune neuropsychiatric disorders associated with or without streptococcal and other bacterial infections (PANDAS/CANS) are emerging as a featured pediatric disorder. Although there is some controversy regarding treatment approaches, especially related to the behavioral sequelae, we have hypothesized in other published work that it is characterized by the rapid onset of Reward Deficiency Syndrome (RDS) in children. We propose utilizing a multi-systems biological approach involving the coupling of genetic addiction risk testing and pro-dopamine regulation (KB220/POLYGEN®) to help induce “dopamine homeostasis” in patients with PANDAS, especially those with known DNA-induced hypodopaminergia. This case study examines a 12-year-old Caucasian male with no prior psychiatric issues who presented with a sudden onset of severe anxiety, depression, emotional liability, and suicidal ideation. The patient underwent genotyping and the genetic addiction risk score (GARS) testing, which revealed risk polymorphisms in the dopamine D2 (-DRD2/ANKK (Taq1A), OPRM1 (A/G), DRD3 (C/T), and MAOA (4R) genes. These polymorphisms have been linked to hypodopaminergia. The patient was subsequently placed on research ID-KB220ZPBMPOLY (POLYGEN®), and albeit the possibility of bias, based upon self and parental assessment, a marked rapid improvement in psychiatric symptoms was observed. In the second phase of treatment (102 days utilizing KB220), the patient received standard antibody testing, which was positive for Lyme. Antibacterial therapy started immediately, and KB220z was discontinued to provide a wash-out period. A monotonic trend analysis was performed on each outcome measure, and a consistently decreasing trend was observed utilizing antibacterial therapy. Our recommendation, albeit only one case, is to utilize and further research a combined therapeutic approach, involving precision-guided DNA testing and pro-dopamine regulation along with antibacterial therapy, as well as glutathione to address offensive enhanced cytokines, in patients with suspected PANDAS/CANS.

Genetic variants involved in gallstone formation and capsaicin metabolism,and the risk of gallbladder cancer in Chilean women

AIM:To determine the effects of genetic variants associated with gallstone formation and capsaicin (a pungent component of chili pepper) metabolism on the risk of gallbladder cancer (GBC).METHODS: A total of 57 patients with GBC, 119 patients with gallstones, and 70 controls were enrolled in this study. DNA was extracted from their blood or paraffi n block sample using standard commercial kits. The statuses of the genetic variants were assayed using Taqman SNP Genotyping Assays or Custom Taqman SNP Genotyping Assays.RESULTS:The non-ancestral T/T genotype of apolipoprotein B rs693 polymorphism was associated with a decreased risk of GBC (OR:0.14,95% CI:0.03-0.63). The T/T genotype of cholesteryl ester transfer protein (CETP) rs708272 polymorphism was associated with an increased risk of GBC (OR:5.04,95% CI:1.43-17.8).CONCLUSION: Genetic variants involved in gallstone formation such as the apolipoprotein B rs693 and CETP rs 708272 polymorphisms may be related to the risk of developing GBC in Chilean women.

CYP4F2 polymorphism as a genetic risk factor for major hemorrhagic complications in Chinese patients on warfarin therapy

Warfarin is a commonly used anticoagulant with a narrow therapeutic range and risk of hemorrhagic complications. After CYP2C9 and VKORC1, CYP4F2 was confirmed as the third principle genetic determinant of warfarin dose variability.

Genetic and phenotypic heterogeneity in tropical calcific pancreatitis

Tropical calcific pancreatitis(TCP)is a form of chronic non-alcoholic pancreatitis initially reported in the developing parts of the tropical world.The clinical phenotype of TCP has undergone marked changes since its first description in 1968.The disease is now seen in relatively older people with less severe symptoms.In addition,there are varying reports on the proportion of cases presenting with imaging abnormalities like calcification,ductal dilation,and glandular atrophy.Significant progress has also been made in understanding the etiopathology of TCP.The role of malnutrition and cassava toxicity in its pathogenesis is disproven and few studies have focused on the role of micronutrient deficiency and oxidative stress in the etiopathogenesis of TCP.Emerging evidence support an important role for genetic risk factors in TCP.Several studies have shown that,rather than mutations in trypsinogens,variants in serine protease inhibitor kazal type 1,cathepsin B,chymotrypsin C,cystic fibrosis transmembrane regulator,and carboxypeptidase A1,predict risk of TCP.These studies also provided evidence of mutational heterogeneity between TCP and chronic pancreatitis in Western populations.The current review summarizes recent advances that have implications in the understanding of the pathophysiology and thus,heterogeneity in genotype-phenotype correlations in TCP.

Single-nucleotide polymorphisms based genetic risk score in the prediction of pancreatic cancer risk

BACKGROUND Disease-related single nucleotide polymorphisms(SNPs)based genetic risk score(GRS)has been proven to provide independent inherited risk other than family history in multiple cancer types.AIM To evaluate the potential of GRS in the prediction of pancreatic cancer risk.METHODS In this case-control study(254 cases and 1200 controls),we aimed to evaluate the association between GRS and pancreatic ductal adenocarcinoma(PDAC)risk in the Chinese population.The GRS was calculated based on the genotype information of 18 PDAC-related SNPs for each study subject(personal genotyping information of the SNPs)and was weighted by external odd ratios(ORs).RESULTS GRS was significantly different in cases and controls(1.96±3.84 in PDACs vs 1.09±0.94 in controls,P<0.0001).Logistic regression revealed GRS to be associated with PDAC risk[OR=1.23,95%confidence interval(CI):1.13-1.34,P<0.0001].GRS remained significantly associated with PDAC(OR=1.36,95%CI:1.06-1.74,P=0.015)after adjusting for age and sex.Further analysis revealed an association of increased risk for PDAC with higher GRS.Compared with low GRS(<1.0),subjects with high GRS(2.0)were 99%more likely to have PDAC(OR:1.99,95%CI:1.30-3.04,P=0.002).Participants with intermediate GRS(1.0-1.9)were 39%more likely to have PDAC(OR:1.39,95%CI:1.03-1.84,P=0.031).A positive trend was observed(P trend=0.0006).CONCLUSION GRS based on PDAC-associated SNPs could provide independent information on PDAC risk and may be used to predict a high risk PDAC population.

Association of sleep quality with myopia based on different genetic risk levels

AIM: To analyse the association of sleep quality with myopia under different genetic risk(GR) levels.METHODS: A cross-sectional survey of students aged 9-14 y in Wenzhou, China, was conducted. Refraction without cycloplegia and ocular parameters were measured. Sleep quality was assessed with the Pittsburgh Sleep Quality Index(PSQI). Seventeen single nucleotide polymorphisms(SNPs) were replicated by association analysis and used to compute the GR score(GRS). Possible confounders were assessed by a questionnaire that collected information about the children and their parents. Generalized linear models were used to analyse the sleep quality, the GR, and their interaction effects on the risk of myopia.RESULTS: Out of 1354 children included in this study, 353(26.07%) had sleep disturbances. The GRS ranged from 4.49 to 12.89 with a mean of 7.74±1.23, and the participants were divided into a low GR group, a moderate GR group and a high GR group according to the GRS quartile. In the generalized linear model, the children with sleep disturbances and high GR had a higher risk of myopia than those without sleep disturbances and with low GR(OR=1.59, 95%CI: 1.12-2.25;OR=1.88, 95%CI: 1.23-2.88, respectively). Compared to those with low GR and SDs, children with high GR with or without SDs had a higher risk of myopia(OR=4.88, 95%CI: 2.03-11.71;OR=1.70, 95%CI: 1.06-2.72, respectively).CONCLUSION: The prevalence of sleep disturbances in elementary school students in Wenzhou was 26.07%. There is a significant interaction between sleep disturbances and a high GR of myopia, suggesting that a high GR of myopia may increase children’s sensitivity to sleep disturbances. This study indicates that children with a high GR of myopia need to achieve adequate sleep duration and excellent sleep quality.

Multi-locus genetic risk score predicts risk for Crohn's disease in Slovenian population

AIM: To develop a risk model for Crohn&#x02019;s disease (CD) based on homogeneous population.METHODS: In our study were included 160 CD patients and 209 healthy individuals from Slovenia. The association study was performed for 112 single nucleotide polymorphisms (SNPs). We generated genetic risk scores (GRS) based on the number of risk alleles using weighted additive model. Discriminatory accuracy was measured by area under ROC curve (AUC). For risk evaluation, we divided individuals according to positive and negative likelihood ratios (LR) of a test, with LR &#x0003e; 5 for high risk group and LR &#x0003c; 0.20 for low risk group.RESULTS: The highest accuracy, AUC of 0.78 was achieved with GRS combining 33 SNPs with optimal sensitivity and specificity of 75.0% and 72.7%, respectively. Individuals with the highest risk (GRS &#x0003e; 5.54) showed significantly increased odds of developing CD (OR = 26.65, 95%CI: 11.25-63.15) compared to the individuals with the lowest risk (GRS &#x0003c; 4.57) which is a considerably greater risk captured than in one SNP with the highest effect size (OR = 3.24). When more than 33 SNPs were included in GRS, discriminatory ability was not improved significantly; AUC of all 74 SNPs was 0.76.CONCLUSION: The authors proved the possibility of building accurate genetic risk score based on 33 risk variants on Slovenian CD patients which may serve as a screening tool in the targeted population.

Progress and challenges in genome-wide studies to understand the genetics of diabetic retinopathy

There are many advantages to understanding the genetics of human disease.Genetic markers can be used to calculate the risk of developing a disease,and elucidation of genetic risk factors can pinpoint the molecular aetiology of disease,which can facilitate the development of targeted therapies.Diabetic retinopathy(DR)is a common complication of diabetes that has a significant impact on quality of life.It has a clear genetic component,but determination of the genetic risk factors has proven difficult.To date,genome-wide studies for DR have been conducted on relatively small patient cohorts compared to other complex eye diseases and replication of genetic findings has been limited.The disease is highly heterogeneous,confounding attempts to classify patients into appropriate groups for genetic analysis and making direct comparisons between studies challenging.Future studies to determine the genetic causes of DR will need to focus on larger sample sizes,detailed phenotyping and appropriate classification of patients.Global co-operation and meta-analyses combining data from multiple studies will be critical to the discovery of genetic risk loci for DR.

A Genetic Susceptibility Study of Lung Cancer Risk Potentially Associated with Polycyclic Aromatic Hydrocarbon Inhalation Exposure

For lifetime non-smokers, lung cancer risk is mainly associated with inhalation exposure to air pollution. For the Chinese population, indoor air pollution due to solid fuel combustion has been the primary source of inhalation exposure for decades. Polycyclic aromatic hydrocarbons （PAHs） are the by-products of incomplete combustion.

The power of a healthy lifestyle for cancer prevention:the example of colorectal cancer

Objective:We aimed to directly compare the estimated effects of adherence to a healthy lifestyle with those of risk predisposition according to known genetic variants affecting colorectal cancer(CRC)risk,to support effective risk communication for cancer prevention.Methods:A healthy lifestyle score(HLS)was derived from 5 lifestyle factors:smoking,alcohol consumption,diet,physical activity,and body adiposity.The association of lifestyle and polygenic risk score(PRS)(based on 140 CRC-associated risk loci)with CRC risk was assessed with multiple logistic regression and compared through the genetic risk equivalent(GRE),a novel approach providing an estimate of the effects of adherence to a healthy lifestyle in terms of percentile differences in PRS.Results:A higher HLS was associated with lower CRC risk(4,844 cases,3,964 controls).Those adhering to all 5 healthy lifestyle factors had a 62%(95%CI 54%-68%)lower CRC risk than those adhering to≤2 healthy lifestyle factors.The estimated effect of adherence to all 5 compared with≤2 healthy lifestyle factors was as strong as the effect of having a 79 percentile(GRE 79,95%CI 61-97)lower PRS.The association between a healthy lifestyle and CRC risk was independent of PRS level but was particularly pronounced among those with a family history of CRC in≥1 first-degree relative(P-interaction=0.0013).Conclusions:A healthy lifestyle was strongly inversely associated with CRC risk.The large GRE indicated that CRC risk determined by polygenic risk may be offset to a substantial extent by adherence to a healthy lifestyle.

A common variant in the precursor miR-146a sequence does not predispose to cholangiocarcinoma in a large European cohort

BACKGROUND:Micro-RNAs(miRNAs) are small,non-coding RNA species considered to fine-tune basic cellular functions by modulating target gene translation and/or mRNA stability.A common G/C polymorphism(rs2910164) in the precursor(pre-) miR-146a gene engaged in NF-κB signaling and apoptosis pathways has been reported to modulate the genetic risk of hepatocellular carcinoma by increased G-allelic production of mature miR-146a.We investigated rs2910164 in a large Europeanbased cholangiocarcinoma(CCA) cohort.METHODS:We recruited 182 CCA patients and 350 controls in three academic medical centers.Genotyping for rs2910164 was performed by PCR-based assays with 5’-nuclease and fluorescence detection.Genotype frequencies were tested for consistency with the Hardy-Weinberg equilibrium using an exact test;allelic and genotypic differences between the patients and controls were assessed by the Chi-square test and Armitage’s trend test.Exploratory subgroup analyses included gender,tumor localization(extra-versus intrahepatic CCA) and early-onset CCA.RESULTS:Genotype distributions were consistent with the Hardy-Weinberg equilibrium.No significant differences in either allele or genotype distributions were detected between the CCA and control groups or the respective subgroups investigated.However,there was a trend for a protective effect of the heterozygous single-nucleotide polymorphism state GC,as indicated by an underrepresentation in the CCA group in general(29% vs 35%;P=0.18) and,in particular,for extrahepatic tumor sites(26% vs 35%;OR=0.67;95% CI,0.43-1.02;P=0.065).CONCLUSIONS:Our data do not support a prominent contribution of the pre-miR-146a sequence variant in the genetic predisposition to CCA.However,current studies functionally characterizing rs2910164 have proposed that distinct repertoires of target genes are addressed by genotype-specific mature miR146a species.Given the detected trend towards a potentially protective role of GC heterozygosity,a subtle modulation of genetic CCA risk by the pre-miR-146a GC genotype may exist and should be evaluated further.

Diabetes Mellitus Type 2 Prevalence, Risk Factors and Complications in the Region of Kardzhali, Bulgaria

The present study was conducted within the CINDI program and covers 1,600 individuals, divided into four age groups. The aim of this study is to investigate the key biomedical and lifestyle factors for the development of type 2 diabetes as well as the cardiovascular diabetes complications in the population aged 25-64 from Kardzhali region, Bulgaria. The results of the study show the existence of behavioral and biological risk factors of health, as well as family history in the studied individuals who suffer from diabetes. The connection between diabetes and certain cardiovascular diseases such as ischemic heart disease, myocardial infarction and cardiovascular disease is confirmed. This requires the development and implementation of intervention activities among the population of Kardzhali, aimed at reducing the level of diabetes risk factors, early identification of risk groups and timely treatment of the diseased.

Pancreatic cancer risk variant ABO rs505922 in patients with cholangiocarcinoma

The aim of this study was to investigate an association between the development of cholangiocarcinoma(CCA)and the ABO variant rs505922(known to increase pan-creatic cancer risk)in a large cohort of European individuals with CCA.In total,180 individuals with CCA and 350 CCA-free controls were included.The ABO variant rs505922 was genotyped using a polymerase chain reaction-based assay.Association between this single nucleotide polymorphism(SNP)and CCA was tested in contingency tables.Neither allele distributions nor association tests and regression analysis provided evidence for an increased risk of CCA among carriers of the ABO variant(all P > 0.05).Nevertheless,we documented a deviation from Hardy-Weinberg equilibrium in the entire CCA cohort(P = 0.028)and for patients with intrahe-patic(P = 0.037)but not extrahepatic tumor localization(P > 0.05).The association tests did not provide evidence for a prominent role of the investigated SNP in the genetic risk of CCA.However,Hardy-Weinberg disequilibrium in the entire cohort and the intrahepatic CCA subgroup warrants future studies investigating a potential CCA risk modulation by individual blood groups.

Structural brain volume differences between cognitively intact ApoE4 carriers and non-carriers across the lifespan

Apolipoprotein E4（ApoE4） is a prominent genetic risk factor for Alzheimer＇s disease. The purpose of this review is to explore differences in structural brain volume detected by magnetic resonance imaging between cognitively intact ApoE4 carriers and non-carriers across the lifespan（i.e., older adults, middle-aged adults, young adults, children and adolescents, and neonates）. Consistent findings are found throughout various developmental stages. This area of research may elucidate the mechanisms by which ApoE4 influences risk of developing Alzheimer＇s disease. It could also inform potential treatment strategies and interventions for carriers of the ApoE4 allele.

inMTSCCA:An Integrated Multi-task Sparse Canonical Correlation Analysis for Multi-omic Brain Imaging Genetics

Identifying genetic risk factors for Alzheimer's disease(AD)is an important research topic.To date,different endophenotypes,such as imaging-derived endophenotypes and proteomic expression-derived endophenotypes,have shown the great value in uncovering risk genes compared to case-control studies.Biologically,a co-varying pattern of different omics-derived endophenotypes could result from the shared genetic basis.However,existing methods mainly focus on the effect of endophenotypes alone;the effect of cross-endophenotype(CEP)associations remains largely unexploited.In this study,we used both endophenotypes and their CEP associations of multi-omic data to identify genetic risk factors,and proposed two integrated multi-task sparse canonical correlation analysis(inMTSCCA)methods,i.e.,pairwise endophenotype correlationguided MTSCCA(pcMTSCCA)and high-order endophenotype correlation-guided MTSCCA(hocMTSCCA).pcMTSCCA employed pairwise correlations between magnetic resonance imaging(MRI)-derived,plasma-derived,and cerebrospinal fluid(CSF)-derived endophenotypes as an additional penalty.hocMTSCCA used high-order correlations among these multi-omic data for regularization.To figure out genetic risk factors at individual and group levels,as well as altered endophenotypic markers,we introduced sparsity-inducing penalties for both models.We compared pcMTSCCA and hocMTSCCA with three related methods on both simulation and real(consisting of neuroimaging data,proteomic analytes,and genetic data)datasets.The results showed that our methods obtained better or comparable canonical correlation coefficients(CCCs)and better feature subsets than benchmarks.Most importantly,the identified genetic loci and heterogeneous endophenotypic markers showed high relevance.Therefore,jointly using multi-omic endophenotypes and their CEP associations is promising to reveal genetic risk factors.

Polymorphism in cardiovascular diseases(CVD)susceptibility loci in the azores islands(Portugal)

Background: Atherosclerosis and thrombosis are the major manifestations underlying cardiovascular diseases (CVD), which are the leading cause of mortality and morbidity worldwide. Both result from an interaction between genetic and environmental risk factors. The goal of our study was to evaluate several polymorphisms identified as predisposing factors to atherosclerosis and thrombosis. Material and Methods: A series of 155 healthy unrelated individuals of Azorean origin were analyzed using the CVD StripAssay (ViennaLab Diagnostics, Austria) for the most established polymorphisms involved in blood coagulation (F2, F5, F13A1, FGB), fibrinolitic system (SERPINE1), platelet adhesion (ITGB3), homocysteine metabolism (MTHFR), reninangio-tensin system (ACE) and lipid metabolism (APOE). Results: No significant differences were observed in allelic frequencies when comparing our data to mainland Portugal. Group stratification according to the number of “increased” risk alleles, demonstrated that 116/155 (75%) individuals belong to the moderate risk group (5 - 10 risk alleles). Conclusions: Although acknowledging the fact that the allelic states at the analysed loci lack predictive value, the fact that a high frequency of individuals presents at least 5 risk alleles (124/155;80%) is important for the establishment of the appropriate preventive measures in the Azorean population.

Machine learning modeling identifies hypertrophic cardiomyopathy subtypes with genetic signature

Previous studies have revealed that patients with hypertrophic cardiomyopathy(HCM)exhibit differences in symptom severity and prognosis,indicating potential HCM subtypes among these patients.Here,793 patients with HCM were recruited at an average follow-up of 32.78±27.58 months to identify potential HCM subtypes by performing consensus clustering on the basis of their echocardiography features.Furthermore,we proposed a systematic method for illustrating the relationship between the phenotype and genotype of each HCM subtype by using machine learning modeling and interactome network detection techniques based on whole-exome sequencing data.Another independent cohort that consisted of 414 patients with HCM was recruited to replicate the findings.Consequently,two subtypes characterized by different clinical outcomes were identified in HCM.Patients with subtype 2 presented asymmetric septal hypertrophy associated with a stable course,while those with subtype 1 displayed left ventricular systolic dysfunction and aggressive progression.Machine learning modeling based on personal whole-exome data identified 46 genes with mutation burden that could accurately predict subtype propensities.Furthermore,the patients in another cohort predicted as subtype 1 by the 46-gene model presented increased left ventricular end-diastolic diameter and reduced left ventricular ejection fraction.By employing echocardiography and genetic screening for the 46 genes,HCM can be classified into two subtypes with distinct clinical outcomes.

Association between MTHFR c.677C>T variant and erectile dysfunction among males attending fertility clinic

Genetic risk factors have been shown to contribute to the development of sexual dysfunction.However,the role of methylenetetrahydrofolate reductase(MTHFR)gene variants in the risk of erectile dysfunction(ED)remains unclear.In this study,we recruited 1254 participants who underwent ED assessed by the International Index of Erectile Function-5.The MTHFR c.677C>T variant was also measured by fluorescence polymerase chain reaction(PCR).No significant difference in the genotypic frequency of the MTHFR C677T polymorphism(CC,CT,and TT)was observed between men from the ED and non-ED groups.In addition,on binary logistic regression analysis,both crude and adjusted models showed that the risk of ED was not significantly associated with the C677T polymorphism.Interestingly,a significantly higher frequency of the 677TT polymorphism was found in severe and moderate ED(P=O.02).The positive correlation between the MTHFR 677TT polymorphism and severe ED was confirmed by logistic regression analysis,even after adjusting for potential confounders(odds ratio[OR]=2.46,95%confidence interval[CI]:1.15-5.50,P=0.02).These findings suggest a positive correlation between the MTHFR 677TT polymorphism and the risk of severe ED.Identification of MTHFR gene polymorphisms may provide complementary information for ED patients during routineclinicaldiagnosis.