Multifactor Dimensionality Reduction Research Articles

MYLK*FLNB and DOCK1*LAMA2 gene–gene interactions associated with rheumatoid arthritis in the focal adhesion pathway

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease caused by a combination of genetic and environmental factors. Rare variants with low predicted effects in genes participating in the same biological function might be involved in developing complex diseases such as RA. From whole-exome sequencing (WES) data, we identified genes containing rare non-neutral variants with complete penetrance and no phenocopy in at least one of nine French multiplex families. Further enrichment analysis highlighted focal adhesion as the most significant pathway. We then tested if interactions between the genes participating in this function would increase or decrease the risk of developing RA disease. The model-based multifactor dimensionality reduction (MB-MDR) approach was used to detect epistasis in a discovery sample (19 RA cases and 11 healthy individuals from 9 families and 98 unrelated CEU controls from the International Genome Sample Resource). We identified 9 significant interactions involving 11 genes (MYLK, FLNB, DOCK1, LAMA2, RELN, PIP5K1C, TNC, PRKCA, VEGFB, ITGB5, and FLT1). One interaction (MYLK*FLNB) increasing RA risk and one interaction decreasing RA risk (DOCK1*LAMA2) were confirmed in a replication sample (200 unrelated RA cases and 91 GBR unrelated controls). Functional and genomic data in RA samples or relevant cell types argue the key role of these genes in RA.

The associations of IGF2, IGF2R and IGF2BP2 gene polymorphisms with gestational diabetes mellitus: A case-control study.

To investigate the associations of Insulin-like growth factor-II (IGF2) gene, Insulin-like growth factor-II receptor (IGF2R) gene and Insulin-like growth factor-II binding protein 2 (IGF2BP2) gene polymorphisms with the susceptibility to gestational diabetes mellitus (GDM) in Chinese population. A total of 1703 pregnant women (835 GDM and 868 Non-GDM) were recruited in this case-control study. All participants underwent prenatal 75 g oral glucose tolerance test (OGTT) examinations during 24-28 gestational weeks at the Maternal and Child Health Hospital of Hubei Province from January 15, 2018 to March 31, 2019. Genotyping of candidate SNPs (IGF2 rs680, IGF2R rs416572, IGF2BP2 rs4402960, rs1470579, rs1374910, rs11705701, rs6777038, rs16860234, rs7651090) was performed on Sequenom MassARRAY platform. Logistic regression analysis was conducted to investigate the associations between candidate SNPs and risk of GDM. In addition, multifactor dimensionality reduction (MDR) method was applied to explore the effects of gene-gene interactions on GDM risk. There were significant distribution differences between GDM group and non-GDM group in age, pre-pregnancy BMI, education level and family history of diabetes (P < 0.05). After adjusted for age, pre-pregnancy BMI, education level and family history of diabetes, there were no significant associations of the candidate SNPs polymorphisms and GDM risk (P > 0.05). Furthermore, there were no gene-gene interactions on the GDM risk among the candidate SNPs (P > 0.05). However, the fasting blood glucose (FBG) levels of rs6777038 CT carriers were significantly lower than TT carriers (4.69±0.69 vs. 5.03±1.57 mmol/L, P < 0.01), and the OGTT-2h levels of rs6777038 CC and CT genotype carriers were significantly lower than TT genotype carriers (8.10±1.91 and 8.08±1.87 vs. 8.99±2.90 mmol/L, P < 0.01). IGF2 rs680, IGF2R rs416572, IGF2BP2 rs4402960, rs1470579, rs11705701, rs6777038, rs16860234, rs7651090 polymorphisms were not significantly associated with GDM risk in Wuhan, China. Further lager multicenter researches are needed to confirm these results.

Early Life Stress Unravels Epistatic Genetic Associations of Cortisol Pathway Genes With Depression

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis represents one of the most consistent pathophysiological findings in depressive disorders. Cortisol signaling is affected by proteins that mediate its cellular responses or alters its availability to mineralocorticoid and glucocorticoid receptors. In our study, we evaluated candidate genes that may influence the risk for depression and suicide due to its involvement in cortisol signaling. The aim of the study was to assess whether the genotypes of these genes are associated with the risk for depression, severity of depressive symptoms, suicidal ideation, and suicide attempts. and whether there is interaction between genes and early stress. In this study, 100 healthy controls and 140 individuals with depression were included. The subjects were clinically assessed using the 21-item GRID-Hamilton questionnaires (GRID-HAMD-21), Beck Scale for Suicidal Ideation (BSI), and the Childhood Trauma Questionnaire (CTQ). A robust multifactorial dimensionality reduction analysis was used to characterize the interactions between the genes HSD11B1, NR3C1, NR3C2, and MDR1 and early-life stress. It was found a significant association of the heterozygous genotype of the MDR1 gene rs1128503 polymorphism with reduced risk of at least one suicide attempt (OR: 0.08, p=0.003*) and a reduction in the number of suicide attempts (β= -0.79, p=0.006*). Furthermore, it was found that the MDR1 rs1228503 and NR3C2 rs2070951 genes interact with CTQ resulting in a strong association with depression (p=0.001). Our findings suggest that polymorphisms in the MDR1 and NR3C2 genes and their interaction with childhood trauma may be important biomarkers for depression and suicidal behaviors.

Replication study identified EFEMP1 association with varicose vein predisposition among Indians

BackgroundVaricose vein is a chronic condition that affects the lower extremities of the human body. Several factors have been implicated in the development of this disease, viz age, gender, weight, height and prolonged standing. Recently, genome-wide studies have identified genetic biomarkers that are associated with varicose veins in different ethnic groups. Such genetic studies are lacking in South Asians specifically in Indians where the prevalence of varicose veins is high, and it is important to replicate these variants in the stated population. The study aimed to replicate the association of genetic variants associated with varicose veins in this target population, which were found to be associated with the other ethnic groups.MethodologyThe studied cohort is of the Indian population comprising unrelated 104 varicose veins cases and 448 non-varicose vein controls. The samples were genotyped using the Illumina Global Screening Array. Using the genomic data from UK BioBank and 23andMe studied cohorts; eight genetic variants were selected to replicate in our dataset. The allelic association was performed to identify the effective allele and risk was estimated using odds ratio and p-value as level of significance. Multifactor Dimensionality Reduction was used to estimate the cumulative effect of variants in Indians.ResultVariant rs3791679 of EFEMP1 was found to be associated with varicose veins in Indians. After observing the association of the EFEMP1 with varicose veins, we further ensued to identify all genetic variants within EFEMP1 to uncover the additional variants associated with this trait. Interestingly, we identified six new variants of EFEMP1 gene that have shown association. Moreover, the cumulative effect of all associated variations was estimated and the risk was 2.7 times higher in cases than controls whereas independently their effect ranges from 0.37–1.58.ConclusionThis study identifies EFEMP1 as a potential gene related to the risk of varicose veins in Indians. It also highlights that evaluating the maximum number of variants of a gene rather than focusing solely on replicating single variations offers a more comprehensive and nuanced understanding of the genetic factors contributing to a complex trait like varicose veins.

Variations in the Cadherin 23 Gene Associated With Noise-Induced Hearing Loss.

The relationship between CDH23 gene variants and NIHL is unclear. This study investigates the association between cadherin 23 (CDH23) gene variants and noise-induced hearing loss (NIHL). This is a case-control study. Workers who were exposed to noise from a steel factory in North China were recruited and divided into two groups: the case group (both ears' high-frequency threshold average [BHFTA] ≥40dB) and the control group (BHFTA ≤25 dB). This study used the generalised multifactor dimensionality reduction method to analyse the association among 18 single-nucleotide polymorphisms (SNPs) in CDH23 and NIHL. Logistic regression was performed to investigate the main effects of SNPs and the interactions between cumulative noise exposure (CNE) and SNPs. Furthermore, CNE was adjusted for age, gender, smoking, drinking, physical exercise and hypertension. This study recruited 1,117 participants. The results showed that for rs11592462, participants who carried the GG genotype showed an association with NIHL greater than that of those who carried the CC genotype. Accordingly, genetic variation in the CDH23 gene could play an essential role in determining individual susceptibility to NIHL. Genetic variations in the CDH23 gene may play an important role in determining individual susceptibility to NIHL. These results provide new insight into the pathogenesis and early prevention of NIHL.

Association of single nucleotide polymorphisms in ITLN1 gene with ischemic stroke risk in Xi'an population, Shaanxi province.

Ischemic stroke (IS) is the main cause of death and adult disability. However, the pathogenesis of this complicated disease is unknown. The present study aimed to assess the relationship between ITLN1 single nucleotide polymorphisms (SNPs) and the susceptibility to IS in Xi'an population, Shaanxi province. In this study, we designed polymerase chain reaction (PCR) primers located at -3,308 bp upstream of the transcription initiation site within promoter region of the ITLN1 gene. The target fragment was amplified by PCR and identified by agarose gel electrophoresis. Sanger sequencing was then performed in the samples extracted from a cohort comprising 1,272 participants (636 controls and 636 cases), and the obtained sequences were compared with the reference sequences available on the National Center for Biotechnology Information (NCBI) website to detect SNPs in the ITLN1 gene promoter region. Logistic regression analysis was employed to assess the relationship between ITLN1 polymorphisms and IS risk, with adjustments for age and gender. Significant positive results were tested by false-positive report probability (FPRP) and false discovery rate (FDR). The interaction among noteworthy SNPs and their predictive relationship with IS risk were explored using the Multi-Factor Dimensionality Reduction (MDR) software. The results of Sanger sequencing were compared with the reference sequences on the NCBI website, and we found 14 SNPs in ITLN1 gene promoter satisfied Hardy-Weinberg equilibrium (HWE). Logistic regression analysis showed that ITLN1 was associated with a decreased risk of IS (rs6427553: Homozygous C/C: adjusted OR: 0.69, 95% CI [0.48-0.97]; Log-additive: adjusted OR: 0.83, 95% CI [0.70-0.98]; rs7411035: Homozygous G/G: adjusted OR: 0.66, 95% CI [0.47-0.94]; Dominant G/T-G/G: adjusted OR: 0.78, 95% CI [0.62-0.98]; Log-additive: adjusted OR: 0.81, 95% CI [0.69-0.96]; rs4656958: Heterozygous G/A: adjusted OR: 0.74, 95% CI [0.59-0.94]; Homozygous A/A: adjusted OR: 0.51, 95% CI [0.31-0.84]; Dominant G/A-A/A: adjusted OR: 0.71, 95% CI [0.57-0.89]; Recessive A/A: adjusted OR: 0.59, 95% CI [0.36-0.96]; Log-additive: adjusted OR: 0.73, 95% CI [0.61-0.88]), especially in people aged less than 60 years and males. In short, our study revealed a correlation between ITLN1 variants (rs6427553, rs7411035 and rs4656958) and IS risk in Xi'an population, Shaanxi province, laying a foundation for ITLN1 gene as a potential biomarker for predicting susceptibility to IS.

The relationship between long non-coding gene CASC21 polymorphisms and cervical cancer

ABSTRACT Background CASC21 was reported to be a hotspot gene in cervical cancer. The relationship between CASC21 genetic polymorphisms and cervical cancer has not been reported. Genetic factors influence the occurrence of cervical cancer. Thus, we explored the correlation between CASC21 polymorphisms and cervical cancer. Methods A total of 973 participants within 494 cervical cancer cases and 479 healthy controls were recruited. Five single nucleotide polymorphisms (SNPs) in the CASC21 gene were genotyped using the Agena MassARRAY platform. Chi-squared test, logistic regression analysis, odds ratio (OR), multifactor dimensionality reduction (MDR), and 95% confidence interval (95%CI) were used for data analysis. Results In the overall analysis, rs16902094 (p = .014, OR = 1.86, 95% CI = 1.12–3.08) and rs16902104 (p = .014, OR = 1.86, 95% CI = 1.12–3.09) had the risk-increasing correlation with the occurrence of cervical cancer. Stratification analysis showed that rs16902094 and rs16902104 were still associated with cervical cancer risk in the subgroups with age > 51, BMI < 24 kg/m2, smokers, and patients with cervical squamous cell carcinoma. MDR analysis displayed that rs16902094 (.49%) and rs16902104 (.52%) were the main influential attribution factor for cervical cancer risk. Conclusion Our finding firstly determined that two CASC21 SNPs (rs16902094, rs16902104) were associated with an increased risk of cervical cancer, which adds to our knowledge regarding the effect of CASC21 on cervical carcinogenesis.

Novel polymorphisms in CYP4A22 associated with susceptibility to coronary heart disease

BackgroundCoronary heart disease (CHD) has become a worldwide public health problem. Genetic factors are considered important risk factors for CHD. The aim of this study was to explore the correlation between CYP4A22 gene polymorphism and CHD susceptibility in the Chinese Han population.MethodsWe used SNPStats online software to complete the association analysis among 962 volunteers. False-positive report probability analysis was used to confirm whether a positive result is noteworthy. Haploview software and SNPStats were used for haplotype analysis and linkage disequilibrium. Multi-factor dimensionality reduction was applied to evaluate the interaction between candidate SNPs.ResultsIn overall and some stratified analyses (male, age ≤ 60 years or CHD patients complicated with hypertension), CYP4A22-rs12564525 (overall, OR = 0.83, p-value is 0.042) and CYP4A22-rs2056900 (overall, OR = 1.22, p-value is 0.032) were associated with the risk of CHD. CYP4A22-4926581 was associated with increased CHD risk only in some stratified analyses. FPRP indicated that all positive results in our study are noteworthy findings. In addition, MDR showed that the single-locus model composed of rs2056900 is the best model for predicting susceptibility to CHD.ConclusionThere are significant associations between susceptibility to CHD and CYP4A22 rs12564525, and rs2056900.

Polymorphic markers of several immune regulatory genes modulate the susceptibility for eczema and related phenotypes in children.

Eczema is associated with multiple genes regulating epidermal barrier functions and immunological pathways. However, their epistatic interactions are not well studied. This cross-sectional study investigated the relationship between childhood eczema phenotypes and single-nucleotide polymorphisms (SNPs) of immune regulatory genes. One thousand three hundred and twenty-nine Chinese eczematous children and 1,179 non-allergic controls were recruited. Nine SNPs of immune regulatory genes signal transducer and activator of transcription 3 (STAT3), interleukin-10 (IL10), transforming growth factor-beta 1 (TGFB1), and IL-6 receptor (IL6R) were genotyped by TaqMan genotyping assays. Logistic regression was used to analyze the associations between SNPs and eczema phenotypes. Generalized multifactor dimensionality reduction (GMDR) was used to examine epistatic interactions among these SNPs as well as those reported by our group [filaggrin (FLG) and 11q13] for eczema phenotypes. TGFB1_rs1800469 was found to be associated with eczema [odds ratio (OR), 0.82; 95% confidence interval (CI): 0.73-0.92; P=0.001], atopic eczema (OR, 0.83; 95% CI: 0.72-0.95; P=0.009) and allergic rhinitis (OR, 0.84; 95% CI: 0.74-0.95; P=0.005). We also found a trend between IL10_rs1800872 and increased total immunoglobulin E (IgE) levels (P=0.009). Epistatic interaction among IL10_rs3021094, TGFB1_rs1800469, IL6R_rs2228145, and STAT3_rs4796793 were found for total IgE [testing accuracy (TA), 0.551; cross-validation consistency (CVC), 10; P=0.014]. Mean log-transformed total IgE (logIgE) levels in high-risk cases, low-risk cases, high-risk controls, and low-risk controls were 2.75, 2.60, 1.90, and 1.81 respectively (P=0.019 for trend). Functional TGFB1 polymorphism is associated with both eczema and allergic rhinitis, suggesting the role of TGF-β1 in allergy susceptibility. IL10 may be associated with increased total IgE levels. Interaction among immune regulatory genes modulates total IgE levels.

Functional polymorphisms of NOS3 and GUCY1A3 affect both nitric oxide formation and association with hypertensive disorders of pregnancy.

Impaired nitric oxide (NO) formation may be associated with endothelial dysfunction and increased cardiovascular disease risk in preeclampsia (PE). Functional single-nucleotide polymorphisms (SNPs) of nitric oxide synthase 3 (NOS3) (rs3918226) and guanylate cyclase 1, soluble, alpha 3 (GUCY1A3) (rs7692387) increase susceptibility to the adverse consequences due to inadequate generation of NO by the endothelium. However, no previous study has examined whether these SNPs affect NO formation in healthy pregnancy and in gestational hypertension (GH) and PE. Here, we compared the alleles and genotypes of NOS3 (rs3918226) and GUCY1A3 (rs7692387) SNPs in normotensive pregnant women (NP, n = 153), in GH (n = 96) and PE (n = 163), and examined whether these SNPs affect plasma nitrite concentrations (a marker of NO formation) in these groups. We further examined whether the interaction among SNP genotypes is associated with GH and PE. Genotypes were determined using TaqMan allele discrimination assays, and plasma nitrite concentrations were determined by an ozone-based chemiluminescence assay. Multifactor dimensionality reduction was used to examine the interactions among SNP genotypes. Regarding NOS3 rs3918226, the CT genotype (p = 0.046) and T allele (p = 0.020) were more frequent in NP than in GH, and GH patients carrying the CT+TT genotypes showed lower nitrite concentrations than NP carrying the CT+TT genotypes (p < 0.05). Regarding GUCY1A3 rs7692387, the GA genotype (p = 0.013) and A allele (p = 0.016) were more frequent in PE than in NP, and NP women carrying the GG genotype showed higher nitrite concentrations than GH or PE patients carrying the GG genotype (p < 0.05). However, we found no significant interactions among genotypes for these functional SNPs to be associated with GH or PE. Our novel findings suggest that NOS3 rs3918226 and GUCY1A3 rs7692387 may affect NO formation and association with hypertensive disorders of pregnancy.

Association of maternal phthalates exposure and metabolic gene polymorphisms with congenital heart diseases: a multicenter case-control study

BackgroundThe majority of congenital heart diseases (CHDs) are thought to result from the interactions of genetics and the environment factors. This study aimed to assess the association of maternal non-occupational phthalates exposure, metabolic gene polymorphisms and their interactions with risk of CHDs in offspring.MethodsA multicenter case-control study of 245 mothers with CHDs infants and 268 control mothers of health infant was conducted from six hospitals. Maternal urinary concentrations of eight phthalate metabolites were measured by ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). Twenty single nucleotide polymorphisms (SNPs) in cytochrome P450 family 2 subfamily C member 9 (CYP2C9) and 19 (CYP2C19), uridine diphosphate (UDP) glucuronosyl transferase family 1 member A7 (UGT1A7), family 2 member B7 (UGT2B7) and B15(UGT2B15) genes were genotyped. The multivariate logistic regressions were used to estimate the association between maternal phthalates exposure or gene polymorphisms and risk of CHDs. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the gene–gene and gene–phthalates exposure interactions.ResultsThere was no significant difference in phthalate metabolites concentrations between the cases and controls. No significant positive associations were observed between maternal exposure to phthalates and CHDs. The SNPs of UGT1A7 gene at rs4124874 (under three models, log-additive: aOR = 1.74, 95% CI:1.28–2.37; dominant: aOR = 1.86, 95% CI:1.25–2.78; recessive: aOR = 2.50, 95% CI: 1.26–4.94) and rs887829 (under the recessive model: aOR = 13.66, 95% CI: 1.54–121) were significantly associated with an increased risk of CHDs. Furthermore, the associations between rs4124874 (under log-additive and dominant models) of UGT1A7 were statistically significant after the false discovery rate correction. No significant gene-gene or gene-phthalate metabolites interactions were observed.ConclusionsThe polymorphisms of maternal UGT1A7 gene at rs4124874 and rs887829 were significantly associated with an increased risk of CHDs. More large-scale studies or prospective study designs are needed to confirm or refute our findings in the future.

Maternal Age at Menarche Genes Determines Fetal Growth Restriction Risk.

We aimed to explore the potential link of maternal age at menarche (mAAM) gene polymorphisms with risk of the fetal growth restriction (FGR). This case (FGR)-control (FGR free) study included 904 women (273 FGR and 631 control) in the third trimester of gestation examined/treated in the Departments of Obstetrics. For single nucleotide polymorphism (SNP) multiplex genotyping, 50 candidate loci of mAAM were chosen. The relationship of mAAM SNPs and FGR was appreciated by regression procedures (logistic/model-based multifactor dimensionality reduction [MB-MDR]) with subsequent in silico assessment of the assumed functionality pithy of FGR-related loci. Three mAAM-appertain loci were FGR-linked to genes such as KISS1 (rs7538038) (effect allele G-odds ratio (OR)allelic = 0.63/pperm = 0.0003; ORadditive = 0.61/pperm = 0.001; ORdominant = 0.56/pperm = 0.001), NKX2-1 (rs999460) (effect allele A-ORallelic = 1.37/pperm = 0.003; ORadditive = 1.45/pperm = 0.002; ORrecessive = 2.41/pperm = 0.0002), GPRC5B (rs12444979) (effect allele T-ORallelic = 1.67/pperm = 0.0003; ORdominant = 1.59/pperm = 0.011; ORadditive = 1.56/pperm = 0.009). The haplotype ACA FSHB gene (rs555621*rs11031010*rs1782507) was FRG-correlated (OR = 0.71/pperm = 0.05). Ten FGR-implicated interworking models were founded for 13 SNPs (pperm ≤ 0.001). The rs999460 NKX2-1 and rs12444979 GPRC5B interplays significantly influenced the FGR risk (these SNPs were present in 50% of models). FGR-related mAAM-appertain 15 polymorphic variants and 350 linked SNPs were functionally momentous in relation to 39 genes participating in the regulation of hormone levels, the ovulation cycle process, male gonad development and vitamin D metabolism. Thus, this study showed, for the first time, that the mAAM-appertain genes determine FGR risk.

Association between Gene Polymorphisms and SNP-SNP Interactions of the Matrix Metalloproteinase 2 Signaling Pathway and the Risk of Vascular Senescence*

ObjectiveThis study aimed to explore the association of single nucleotide polymorphisms (SNP) in the matrix metalloproteinase 2 (MMP-2) signaling pathway and the risk of vascular senescence (VS). MethodsIn this cross-sectional study, between May and November 2022, peripheral venous blood of 151 VS patients (case group) and 233 volunteers (control group) were collected. Fourteen SNPs were identified in five genes encoding the components of the MMP-2 signaling pathway, assessed through carotid-femoral pulse wave velocity (cfPWV), and analyzed using multivariate logistic regression. The multigene influence on the risk of VS was assessed using multifactor dimensionality reduction (MDR) and generalized multifactor dimensionality regression (GMDR) modeling. ResultsWithin the multivariate logistic regression models, four SNPs were screened to have significant associations with VS: chemokine (C-C motif) ligand 2 (CCL2) rs4586, MMP2 rs14070, MMP2 rs7201, and MMP2 rs1053605. Carriers of the T/C genotype of MMP2 rs14070 had a 2.17-fold increased risk of developing VS compared with those of the C/C genotype, and those of the T/T genotype had a 19.375-fold increased risk. CCL2 rs4586 and MMP-2 rs14070 exhibited the most significant interactions. ConclusionCCL2 rs4586, MMP-2 rs14070, MMP-2 rs7201, and MMP-2 rs1053605 polymorphisms were significantly associated with the risk of VS.

Interplay between polygenic variants related immune response and lifestyle factors mitigate the chances of stroke in a genome-wide association study.

We aimed to investigate the intricate interplay between genetic predisposition and lifestyle factors on stroke. We conducted a comprehensive genome-wide association study to identify the genetic variants linked to stroke in the participants who experienced a stroke event (cases; n 672) and those with no stroke history (non-stroke; n 58029) in a large hospital-based cohort. Using generalised multifactor dimensionality reduction, we identified genetic variants with interactive effects and constructed polygenic risk scores (PRS) by summing up the risk alleles from the genetic variants. Food intake was measured with a validated semi-quantitative FFQ. No significant differences in stroke incidence were seen in demographic variables between the two groups. Among the metabolic indicators, only serum TAG levels were higher in males with stroke than those without stroke. The daily nutrient intake, dietary inflammation index, glycaemic index, dietary patterns, alcohol consumption, exercise and smoking did not display associations with the OR for stroke. The stroke-linked genetic variants were related to the IL-18 pathway. After accounting for covariates, the PRS derived from the 5-, 6- and 7-SNP models were positively associated with stroke chance with 2·5-, 2·9- and 2·8-fold. Furthermore, interactions between genetic predisposition and dietary components, including energy, carbohydrates, n-3 fatty acids and branched-chain amino acids (BCAA), that affected OR for stroke were observed. A high intake of energy, carbohydrates and BCAA and a low intake of n-3 fatty acids were positively associated with the chances of stroke occurrence. In conclusion, understanding the interaction between genetic variants and lifestyle factors can assist in developing stroke prevention and management strategies.

Interaction between XRCC2 gene polymorphism and abdominal obesity on risk of endometrial carcinoma

Aims The aim of this study was to investigate the impact of three single nucleotide polymorphisms (SNPs) within X-Ray Repair Cross Complementary Group 2 (XRCC2) gene and additional gene- abdominal obesity (AO) interaction with endometrial carcinoma (EC) risk. Methods Hardy–Weinberg equilibrium was tested for all participants by using SNPstats (online software: http://bioinfo.iconcologia.net/SNPstats). The best SNP–SNP and gene–AO interaction combination among three SNPs within XRCC2 gene and AO was screened using generalized multifactor dimensionality reduction (GMDR). Results We employed the logistic regression analysis showed that rs718282-T allele is associated with increased EC risk, adjusted ORs (95%CI) were 1.67 (1.23–2.04). However, we did not find statistical association between rs3218536, and rs3218384 and EC susceptibility. GMDR analysis was used for SNP-SNP- and gene-abdominal obesity analysis. The cross-validation consistency and the testing accuracy for the interaction were calculated. The two-locus model between rs718282 and AO had a testing accuracy of 60.11%, which was significant at the p < .001 level, and this two- locus model was considered as the best model. It provided statistical evidence for rs718282 gene–AO interaction effects. The results indicated that AO influenced the EC risk depending on the rs718282 genotypes. Compared with non- AO subjects with rs718282–CC genotype, AO subjects with rs718282-CT or TT genotype had the highest EC risk, OR (95%CI) was 2.83 (1.67 − 4.02), after covariates adjustment. Conclusions Both the rs718282- T allele, and its interaction with AO were associated with increased EC risk.

COMT and SCN9A gene variants do not contribute to chronic low back pain in Mexican-Mestizo patients.

Chronic low back pain (CLBP) is a complex condition in which genetic factors play a role in its susceptibility. Catechol-O-methyltransferase (COMT) and sodium channel NaV1.7 (SCN9A) genes are implicated in pain perception. The aim is to analyze the association of COMT andSCN9A with CLBP and their interaction, in a Mexican-Mestizo population. A case-control study was conducted. Cases corresponded to adults of both sexes with CLBP. Controls were adults with no CLBP. Variants of SCN9A and COMT were genotyped. Allelic and genotypic frequencies and Hardy-Weinberg equilibrium (HWE) were calculated. Association was tested under codominant, dominant, and recessive models. Multifactor dimensionality reduction was developed to detect epistasis. Gene variants were in HWE, and there was no association under different inheritance models in the whole sample. In women, in codominant and dominant models, a trend to a high risk was observed for AA of rs4680 ofCOMT (OR = 1.7 [0.5-5.3] and 1.6 [0.7-3.4]) and for TT of rs4633 (OR = 1.6 [0.7-3.7] and 1.6 [0.7-3.4]). In men, a trend to low risk was observed for AG genotype of rs4680 in the same models (OR = 0.6 [0.2-1.7] and 0.7 [0.3-1.7]), and for TC genotype of rs4633 in the codominant model (OR = 0.6 [0.2-1.7]). In the interaction analysis, a model of the SCN9A and COMT variants showed a CVC of 10/10; however, the TA was 0.4141. COMT and SCN9A variants are not associated with CLBP in the analyzed Mexican-Mestizo population.

Antioxidant Genes Variants and Their Association with Sperm DNA Fragmentation.

Semen possesses a variety of antioxidant defense mechanisms which protect sperm DNA from the damaging effects of oxidative stress. Correlation between antioxidant genes variants and sperm DNA fragmentation (SDF) level is not sufficiently studied. Therefore, we investigated the association between several single nucleotide polymorphisms (SNPs): CYP1A1 (rs1048943A > G), CYP4F2 (rs2108622G > A), NRF2 (rs6721961C > A), PON1 (rs662A > G), NOS3 (rs1799983G > T), GSTM1 (null), CAT (rs1001179C > T), SOD2 (rs4880A > G), GSTP1 (rs1695A > G), PON2 (rs7493G > C), EPHX2 (rs1042064T > C), and AHR (rs2066853G > A) and elevated SDF. The study employed a case-control design where, the allele and genotype frequencies of the selected SNPs were compared between 75 semen samples with abnormal SDF (the cases) and 75 samples with normal SDF (the controls). DNA was extracted from the semen samples and allele-specific PCR (AS-PCR) was used for genotyping the SNPs. Relevant data were collected from the patients' records et al.-Basma Fertility Center. Suitable statistical tests and multifactorial dimensionality reduction (MDR) test were used to anticipate SNP-SNP interactions. Comparison of semen parameters revealed significant differences between cases and controls in terms of liquefaction time, sperm total motility, and normal form. Genotype frequencies of NOS3 G > T (GT), SOD2 A > G (AA and AG), EPHX2 T > C (CC and CT), and AHR G > A (GA and GG) were significantly different between cases and controls. Allele frequencies of SOD2 (G-allele), and EPHX2 (T-allele) also significantly varied between cases and controls. MDR analysis revealed that the NOS3, SOD2, and EPHX2 SNPs combination has the highest impact on SDF. The study findings suggest that genetic variations in genes involved antioxidant defenses contribute to abnormal SDF.

The interaction of RELN-DNMT genes involving in neurotrophin signaling pathway contributes to schizophrenia susceptibility.

Schizophrenia belongs to a severe mental illness with complicated clinical presentations, an ill-defined pathogenesis, and no known cause. Many genetic studies imply that polygenic interaction is important in the development of schizophrenia. The main mechanism of the RELN-BDNF-CREB-DNMT signaling pathway in neurodevelopment involves RELN, brain-derived neurotrophic factor (BDNF), transcription factor cyclic adenosine monophosphate response element binding protein (CREB), DNA methyltransferase 1 (DNMT1), as well as DNA methyltransferase 3B (DNMT3B). An early case-control research on 15 polymorphisms in the RELN, CREB, BDNF, DNMT1, and DNMT3B genes was done. A single gene variation has little effect on the pathogenesis of schizophrenia, but the combination of intergenic variation loci has a bigger impact because schizophrenia is a complex polygenic disorder. The objective of the current study sought to explore the impact of genetic interactions between RELN, BDNF, CREB, DNMT1, and DNMT3B on schizophrenia in order to further highlight the genetic factors influencing the risk of schizophrenia. Taking the case-control study design, with the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) to be the evaluation norm, 134 individuals suffering from schizophrenia hospitalized in the Third People's Hospital of Zhongshan City within January 2018 to April 2020 (case group) were selected, and 64 healthy individuals (control group) from the same geographical area had been chosen as well. MassArray identified DNMT1 gene single nucleotide polymorphisms (rs2114724 and rs2228611) and DNMT3B gene SNPs (rs2424932, rs1569686, rs6119954, and rs2424908). Using the generalized multifactor dimensionality reduction (GMDR), the RELN-BDNF-CREB-DNMT pathway's gene interactions were examined for their impact on schizophrenia. GMDR analysis showed that the three-order interaction model RELN (rs2073559, rs2229864)-DNMT3B (rs2424908) was the optimal model (p = 0.001), with the consistency of cross-validation of 10/10 and the test accuracy of 0.8711. The interaction between the RELN (rs2073559, rs2229864)-DNMT3B (rs2424908) may be related to schizophrenia, and large sample sizes should be verified in different population.

Potential Interaction between WNT16 and Vitamin D on Bone Qualities in Adolescent Idiopathic Scoliosis Patients and Healthy Controls.

Adolescent idiopathic scoliosis (AIS) is a three-dimensional spinal deformity that is associated with low bone mineral density (BMD). Vitamin D (Vit-D) supplementation has been suggested to improve BMD in AIS, and its outcomes may be related to genetic factors. The present study aimed to (a) investigate the synergistic effect between a low BMD-related gene (wingless-related integration site 16, WNT16) and two important Vit-D pathway genes (Vit-D receptor, VDR, and Vit-D binding protein, VDBP) on serum Vit-D and bone qualities in Chinese AIS patients and healthy adolescents, and (b) to further investigate the effect of ablating Wnt16 on the cortical bone quality and whether diets with different dosages of Vit-D would further influence bone quality during the rapid growth phase in mice in the absence of Wnt16. A total of 519 girls (318 AIS vs. 201 controls) were recruited, and three selected single-nucleotide polymorphisms (SNPs) (WNT16 rs3801387, VDBP rs2282679, and VDR rs2228570) were genotyped. The serum 25(OH)Vit-D level was significantly associated with VDBP rs2282679 alleles (OR = -4.844; 95% CI, -7.521 to -2.167, p < 0.001). Significant multi-locus models were identified by generalized multifactor dimensionality reduction (GMDR) analyses on the serum 25(OH)Vit-D level (p = 0.006) and trabecular area (p = 0.044). In the gene-edited animal study, Wnt16 global knockout (KO) and wildtype (WT) male mice were provided with different Vit-D diets (control chow (1000 IU/Kg) vs. Vit-D-deficient chow (Nil in Vit-D) vs. high-dose Vit-D chow (20,000 IU/Kg)) from 4 weeks to 10 weeks old. Wnt16 global KO mice had significantly lower serum 25(OH)Vit-D levels and higher liver Vdbp mRNA expression levels than WT mice. In addition, Wnt16 global KO mice showed a decrease in bone density, cortical thickness and cortical area compared with WT mice. Interestingly, high-dose Vit-D chow led to lower bone density, cortical thickness, and cortical area in WT mice, which were less obvious in Wnt16 global KO mice. In conclusion, WNT16 may regulate the serum 25(OH)Vit-D level and bone qualities, which might be associated with VDBP expression. Further investigations with a larger sample size and wider spectrum of scoliosis severity are required to validate our findings regarding the interaction between WNT16 and Vit-D status in patients with AIS.

Genetic association study of TERT gene variants with chronic kidney disease susceptibility in the Chinese population

The incidence and mortality of chronic kidney disease (CKD) are increasing globally. Studies have demonstrated the significance of genetic risk factors in the progression of CKD. Telomerase reverse transcriptase (TERT) may be implicated in the development of CKD. This study aimed to investigate the correlation between TERT gene variants and susceptibility to CKD in the Chinese population. A total of 507 patients with CKD and 510 healthy controls were recruited for this case-control study. Four candidate loci were identified using the MassARRAY platform. Logistic regression analysis was employed to assess the association between TERT gene variants and the risk of CKD. The false positive reporting probability (FPRP) method was utilized to evaluate the validity of statistically significant associations. The multifactorial dimensionality reduction (MDR) method was used to evaluate the interaction between SNPs and the risk of CKD. Furthermore, discrepancies in the clinical features of subjects with diverse genotypes were evaluated using one-way analysis of variance (ANOVA). Our findings revealed a correlation between rs2735940 and rs4635969 and an increased risk of CKD. Stratification analysis indicated that rs4635969 was related to an increased risk of CKD in different subgroups (age ≤ 50 years and male). MDR analysis indicated that the two-site model (rs2735940 and rs4635969) was the best prediction model. Furthermore, the rs2735940 GG genotype was found to be linked to an increased level of microalbuminuria (MAU) in patients with CKD. Our study is the first to reveal a connection between TERT gene variants and susceptibility to CKD, providing new insights into the field of nephrology.