Allele Model Research Articles

Association of thrombophilic genes (MTHFR, MTR and MTRR) polymorphisms and homocysteine level in relation to the increased risk of thrombosis among COVID-19 patients

BackgroundPatients with COVID-19 have an increased risk of thrombosis and coagulopathy. Homocysteine, an amino acid essential to coagulation, is thought to be involved in such conditions, as its level is mediated by the presence of some single nucleotide polymorphisms (SNPs) in certain genes including MTHFR, MTR and MTRR. AimThe current study aimed to assess the significant role of MTHFR (C677T and A1298C), MTR A2756G and MTRR A66G SNPs as risk factors for thrombosis among Egyptian COVID-19 patients and their effect on homocysteine level. Subjects and methodsThis case-control study was carried out on 90 Egyptian COVID-19 cases, divided into 45 non-complicated cases and 45 complicated cases with thrombosis, in addition to 80 healthy control individuals. DNA was isolated from blood samples of all the participants. The genotyping was performed using real-time PCR; in addition, serum homocysteine level was estimated. ResultsThe MTHFR (C677T and A1298C), MTR A2756G and MTRR A66G variants revealed a significant higher risk of thrombosis under different genetic models including the homozygous comparison of the co-dominant (20 % vs. 2.3 %, OR = 15.88, p = 0.007), the dominant (62.2 % vs. 33.3 % OR = 3.29, p = 0.006) and the allelic models (41.1 % vs. 17.8 %, OR = 3.2, p < 0.001) for MTHFR C677T and also the dominant (77.8 % vs. 51.1 %, OR = 3.3, p = 0.008) and the allelic models (52.2 % vs. 31.1 %, OR = 2.4, p = 0.004) for MTHFR A1298C. In addition, the heterozygous comparison of the co-dominant (60 vs. 11.1, OR = 12.7, p < 0.001), the dominant (62.2 % vs. 11.1 %, OR = 13.1, p < 0.001) and the allelic models (32.2 % vs. 5.6 %, OR = 8.08, p < 0.001) for MTR A2756G and the heterozygous and homozygous comparisons of the co-dominant model [(53.3 % vs. 31.1 %, OR = 3.4, p = 0.03) and (13.4 % vs. 2.2 %, OR = 12.0, p = 0.049), respectively], the dominant (66.4 % vs. 33.3 %, OR = 4.0, p = 0.001) and the allelic models (40 % vs. 17.8 %, OR = 3, p = 0.001) for MTRR A66G. Moreover, MTHFR (C677T and A1298C), MTR A2756G, and MTRR A66G variants were also associated with high levels of serum homocysteine (p = 0.045, 0.001, 0.005 and 0.039, respectively). The homocysteine level was related to the disease severity by its correlation with higher LDH (rs = 0.49, p < 0.001), CRP (rs = 0.44, p < 0.001), IL-6 (rs = 0.46, p < 0.001) and D-dimer (rs = 0.66, p < 0.001) levels. The multivariate regression analysis showed that homocysteine and the dominant models of MTHFR (C677T and A1298C), MTR A2756G and MTRR A66G were independent predictors of susceptibility to thrombosis among COVID-19 patients [(OR = 1.02, p = 0.007), (OR = 1.15, p = 0.043), (OR = 1.2, p = 0.024), (OR = 1.42, p < 0.001), (OR = 1.19, p = 0.021), respectively]. ConclusionMTHFR (C677T and A1298C), MTR A2756G, and MTRR A66G gene variants were associated with high homocysteine and D-dimer levels that carried a risk for thrombosis among COVID-19 patients and associated with the disease progression.

Association between tumor necrosis factor-α gene polymorphism and interleukin-6 level with mortality of neonatal sepsis

Sepsis is a systemic infection that significantly causes morbidity and mortality among neonates, which is associated with immature immune response. Variations in the tumor necrosis factor-alpha gene (TNF-α) -308G/A may be linked to neonatal sepsis mortality by modulating interleukins (ILs) involved in the immune response cascade, such as IL-6. The aim of this study was to investigate the association between TNF-α -308G/A gene variation and IL-6 level with mortality of neonatal sepsis. A cohort of 30 neonates diagnosed with clinical sepsis was recruited. Blood culture was performed for all patients and serum IL-6 levels were examined 24 hours after suspected sepsis. Genetic analysis of TNF-α single nucleotide polymorphisms (SNP) -308G/A was conducted using polymerase chain reaction and DNA sequencing. The association was assessed based on bivariate logistic regression. We found that 12 (40%) of 30 patients had blood culture-proven sepsis. Genotype of TNF-α -308G/A stratified of the patients was 56.7% for GA and 43.3% for GG. There were no AA variations found in this study. There was no significant association between the TNF-α -308 G/A genotype and mortality in neonatal sepsis (p=0.211). Similarly, the allelic model of TNF-α -308 gene had no association with mortality (p=0.325). Additionally, there was no association between serum IL-6 level and mortality in neonatal sepsis (p=0.253). In conclusion, SNP of TNF-α -308 gene and IL-6 level are not associated with mortality in neonatal sepsis.

The association of serum level and polymorphisms of IFN-γ (rs2069705) with the susceptibility to cutaneous leishmaniasis

Leishmaniasis, a broad range of parasitic diseases, caused by Leishmania which is a flagellated intracellular protozoan parasite of the family Trypanosomatidae. The severity of leishmaniasis diseases ranges from minor cutaneous lesions to severe visceral illnesses that can be disfiguring and life-threatening. Cytokines are glycoprotein molecules produced by various cells in response to various immunological triggers. They regulate the body’s innate and adaptive immunological responses. The aim of this study was to clarify the association of serum level and polymorphisms of IFN-γ with susceptibility to cutaneous leishmaniasis (CL). The whole blood 200 samples were collected from patients and controls from Diyala Governorate/ Iraq from October 2022 to February 2023 which were used to measure IFN-γ polymorphisms using High Resolution Melting technique. Enzyme-linked immunosorbent assay was used to detect the serum level of IFN-γ. The findings of this investigation showed that the IFN-γ serum concentration elevated significantly in patients compared to controls (P < 0.01). Also, the study found that the highest mean level IFN-γ concentrations were found in adults aged 46–55 years old for patients compared with controls with significant differences (P < 0.01). While, no significant differences were observed in the rest age groups except children aged 5–15 years old. Additionally, significant differences between patients and controls were revealed by polymorphisms data in all genetic models for genotypes GA, AA, (GA + AA) and allele A with (P < 0.01) and OR > 1. However, the distribution of IFN-γ serum levels by SNP (rs2069705) demonstrated no differences between genotypes except GG genotype which has significant differences for patients comparing to the same genotype in controls. Taking together, the SNP for IFN-γ (rs2069705) could be a risk factor for susceptibility infection with CL. Also, considered the mutant allele A as a risk allele and genotype AA in codominant genetic model as more risk factor than the genotype GA.

Association between human telomerase reverse transcriptase (hTERT) MNS16A polymorphism and risk of breast cancer.

It is well known that telomerase activity is suppressed in normal human tissues and reactivated in tumors, suggesting that the human telomerase reverse transcriptase (hTERT, MIM: 187270) gene may be involved in carcinogenesis. A polymorphic tandem repeat minisatellite located downstream of exon 16 of hTERT and upstream in the putative promoter region of an antisense hTERT transcript, termed MNS16A, results in a functional polymorphism. Because the association between the MNS16A genetic polymorphism and breast cancer (BC) risk remains an open question, the present case-control study was conducted in Shiraz (Fars Province, Southern Iran). A total of 711 samples were collected, including 362 BC patients and 349 healthy individuals. Genotyping was performed by polymerase chain reaction method. Alleles were determined by classifying DNA amplicons of less than and greater than 300bp as short (S) and long (L) alleles, respectively. Different inheritance models (codominant, dominant, recessive, overdominant genotype models and the allele model) were used to evaluate the association between the MNS16A polymorphism and the risk of BC. No significant association was observed in any of the analyses. It should be noted that the statistical power of the comparisons was low. The present study did not support the association between hTERT MNS16A polymorphism and breast cancer risk. Similar studies in other populations with larger sample sizes are needed to determine the association between the hTERT MNS16A polymorphism and susceptibility to breast cancer.

Bottleneck Effect Analysis in Indigenous Poonchi Chicken Located Near International Border of India and Pakistan

Background: Poonch is the remotest district of Jammu, India located near to line of control with Pakistan. Poonchi chicken is the first native poultry breed of Jammu region which is being characterized and registered with National Bureau of Animal Genetic Resources. Present study is the first study on genetic bottleneck assessment in Poonchi chicken population using recommended microsatellite markers. This study in Poonchi chicken would be of immense use in tracing evolutionary origin and formulating effective conservation strategies for genetic diversity within breeds. Methods: Blood samples were collected randomly from Poonch and Rajouri districts of Jammu for DNA extraction and analysis. Microsatellite markers selected for the analysis were ADL0268, MCW0206, MCW0081, ADL0278, MCW0069, MCW0248, MCW0111, MCW0222, MCW0016 and LEI0094. To evaluate the Poonchi chicken for mutation drift equilibrium, Bottleneck software was used. Infinite allele model (IAM), two phase model of mutation (TPM) and stepwise mutation model (SMM) tests were done. Mode shift test was also used as another method of qualitative test for allele frequency. Result: Total number of alleles observed were 72, with the total number alleles ranged from 6 to 9. The results of all three models (IAM, TPM, SMM) in Sign test depicted the heterozygosity was more in the expected number of loci in Poonchi chicken as 5.97 (P less than 0.05), 5.93 (P less than 0.05), 5.90 (P less than 0.05) respectively. Whereas for Wilcoxon rank test the IAM, TPM and SMM revealed significant values of (P less than 0.05) deviation indicating that all the loci deviate from mutation-drift equilibrium. Mode shift test graph obtained depicted a slight shift from normal L-shaped curve indicating recent bottleneck effect in Poonchi chicken. This might have resulted in the loss of number of effective alleles which suggests a need of planning and implementing an effective breeding policy in order to preserve and promote this native breed.

Inflammatory Factor Interleukin-6 and its Correlation with Rheumatoid Arthritis: A Meta-analysis

Introduction: at present, there are inconsistent research findings regarding the precise relationship between IL-6 gene polymorphisms (GPMs) and rheumatoid arthritis (RA). This work employed meta-analysis (MA) methodology to systematically evaluate the correlation between IL-6 GPMs and susceptibility to RA. Material and Methods: this study comprehensively searched multiple databases from inception to March 31, 2024. The search utilized keywords including “IL-6,” “Interleukin-6,” “Cytokines,” “Autoimmune diseases,” “Arthritis,” “rheumatoid arthritis,” “Inflammation,” “genetic polymorphism,” and “genetic variation.” Included studies focused on patients diagnosed with rheumatoid arthritis (RA), with healthy individuals or those without RA-related diseases as controls. The study designs encompassed cohort studies and case-control studies. Genetic frequency distributions of IL-6 gene rs1800795 (G-174C), rs1800796 (G-572C), and rs1800797 (G-597A) polymorphic sites were statistically analyzed. Quality of included studies was assessed. The preliminary assessment of literature heterogeneity was conducted. Quantitative assessment of heterogeneity results was performed using the I2 statistic in RevMan5.3. Publication bias (PB) assessment was conducted. Result: the study included a total of 21 articles, comprising 9,772 participants, with 4,679 cases diagnosed with RA and 5,093 individuals in the control (CT) group. The IL-6 gene allelic model (G vs C) exhibited a notable association with RA [OR=0.66, 95%CI: 0.51∼0.87, Z=3.02, P=0.003]. In Southeast Asian populations, IL-6 gene rs1800795 (G-174C) genotype (CC) demonstrated a considerable correlation with RA [OR=15.23, 95%CI: 3.53∼65.67, P=0.00003]. IL-6 gene rs1800795 (G-174C) genotype (CG) was associated with RA [OR=1.54, 95%CI: 1.10∼2.17, Z=2.48, P=0.01], with only the Asian population showing an observable correlation [OR=6.55, 95%CI: 1.28∼33.45, P=0.02]. Additionally, IL-6 rs1800795 (G-174C) genotype (GG) was associated with RA [OR=0.66, 95%CI: 0.49∼0.91, Z=2.55, P=0.01], with notable associations observed in the Asian [OR=0.17, 95%CI: 0.03∼0.83, P=0.03] and mixed populations [OR=1.29, 95%CI: 1.011.65, P=0.04]. No correlation was found between rs1800796 (G-572C) and rs1800797 (G-597A) GPMs and RA (P>0.05). ConclusionIL-6 gene rs1800795 (G-174C) allelic model and genotypes (CC, CG, GG) were all associated with susceptibility to RA, with the G allele model being susceptible in Southeast Asian populations, and genotypes (CG and GG) being susceptible in Asian populations. However, there was neglectable correlation between rs1800796 (G-572C) and rs1800797 (G-597A) GPMs and susceptibility to RA.

The 14-bp insertion/deletion as a promising gene polymorphism to understand cancer risk: Evidence from a systematic review and comprehensive meta-analysis

BackgroundHLA-G is associated with cancer cell escape. The 3’UTR polymorphism is involved in the regulation of membrane-bound HLA-G and soluble HLA-G proteins. The aim of our study was to assess the association of the HLA-G 14-bp insertion (I)/deletion (D) polymorphism with cancer susceptibility and its interaction with clinicopathological features and environmental factors. MethodsA meta-analysis was performed to investigate the association between the HLA-G 14-bp I/ D polymorphism and different types of cancers according to the Prisma guidelines. ResultsThirty-nine publications that studied the 14-bp I/D polymorphism in cancers met our inclusion criteria. The findings of the meta-analysis showed a significant association between the 14-bp I/D polymorphism and cancer risk under the allelic contrast model D vs. I (OR=1.112, 95% CI= 1.009-1.227, P = 0.033) suggesting that the D allele was a risk factor for cancer susceptibility. Stratification by cancer type demonstrated a significant association of the 14-bp I/D polymorphism with breast cancer under the D vs. I contrast allele model (OR=1.267, 95% CI= 1.028-1.563, P=0.027). No significant association was found for digestive, cervical, haematological and thyroid cancers. A comparison of groups stratified by ethnicity showed a significant association for Caucasians under the D vs. I model (OR=1.147, 95% CI= 1.002-1.313, P=0.047); and for mixed ethnicities under the DD+DI vs. II (OR=1.388, 95% CI= 1.083-1.780, P=0.010) and DI vs. II (OR= 1.402, 95% CI=1.077-1.824, P=0.012) models. A comparison of cancer risks associated with the 14-bp I/D polymorphism according to geographic location revealed significant risks for the D allele and DD genotype in North Africa, the Middle East and South America. However, no significant susceptibility to cancer associated with the 14-bp I/D polymorphism was shown for Europe and North Asia. The findings of a meta-analysis of subgroups by disease stage showed a significant association in both early and advanced stages, with the 14-bp deletion variant being a risk factor. Similarly, a significant cancer risk was shown for the 14-bp deletion variant in both low- and high-grade cancers. Finally, the risk associated with the 14-bp I/D polymorphism was higher in cancers with concomitant viral infection with human papillomavirus (HPV), hepatitis B virus (HBV) or hepatitis C virus (HCV). ConclusionThe findings of the overall meta-analysis showed a significant association between the HLA-G 14-bp I/D polymorphism and cancer susceptibility. The findings stratified analysis and subgroup comparisons showed that the 14-bp I/D deletion variant was associated with an increased risk of breast cancer. The HLA-G 14-bp I/D polymorphism may interact with individual and clinicopathological factors to alter cancer risk. These promising findings for cancer risk provide the basis for further studies that explore 14bp I/D polymorphism in cancer screening and immunotherapeutic approach.

Association of HOTAIR rs7958904 Polymorphism with Cervical Cancer Risk.

Cervical cancer (CC) has been the prominent cause of cancer-associated fatalities among women in developing countries. In terms of occurrence and mortality, it is ranked second in Bangladesh. Although different genetic polymorphisms linked with this cancer have been investigated over time, the association between the HOTAIR rs7958904 variant and cervical cancer is being reported for the first time in Bangladeshi women. RT-PCR-based TaqMan assay was employed to perform this case-control study on 200 cervical cancer patients and 148 healthy volunteers. Both cases and controls had average ages of 57.5 and 52.5years, respectively. According to Hardy-Weinberg equilibrium, the rs7958904 allele of HOTAIR gene pretended no deviation for both cases and control groups. The genotyping results showed that rs7958904 has a significant correlation to the development of cervical cancer in different genetic association models, such as co-dominant 1 (CC vs. GG: OR = 1.67, p = 0.0435), co-dominant 2 (CC vs. GG: OR = 3.13, p = 0.0006), co-dominant 3 (CC vs. CG: OR = 1.88, p = 0.0384), dominant (CG + CC vs. GG: OR = 1.98, p = 0.004), recessive (CC vs. GG + CG: OR = 2.25, p = 0.005), and allele model (C vs. G: OR = 1.70, p = 0.0006). In conclusion, the HOTAIR rs7958904 variant has a substantial role in cervical cancer development in Bangladeshi women. Further functional studies with a larger population size are required to support our findings.

The rs3918188 and rs1799983 loci of eNOS gene are associated with susceptibility in patients with systemic lupus erythematosus in Northeast China

To investigate the association between single nucleotide polymorphism (SNP) at the rs3918188, rs1799983 and rs1007311 loci of the endothelial nitric oxide synthase (eNOS) gene and genetic susceptibility to systemic lupus erythematosus (SLE) in northeastern China. The base distribution of eNOS gene rs3918188, rs1799983 and rs1007311 in 1712 human peripheral blood samples from Northeast China was detected by SNaPshot sequencing technology. The correlation between genotype, allele and gene model of these loci of the eNOS gene and the genetic susceptibility to SLE was investigated by logistic regression analysis. The results of the differences in the frequency distribution of their gene models were visualised using R 4.3.2 software. Finally, HaploView 4.2 software was used to analyse the relationship between the haplotypes of the three loci mentioned above and the genetic susceptibility to SLE. A multifactor dimensionality reduction (MDR) analysis was used to determine the best SNP-SNP interaction model. The CC genotype and C allele at the rs3918188 locus may be a risk factor for SLE (CC vs AA: OR = 1.827, P < 0.05; C vs A: OR = 1.558, P < 0.001), and this locus increased the risk of SLE in the dominant model and the recessive model (AC + CC vs AA: OR = 1.542, P < 0.05; CC vs AA + AC: OR = 1.707, P < 0.001), while the risk of SLE was reduced in the overdominant model (AC vs AA + CC: OR = 0.628, P < 0.001). The GT genotype and T allele at locus rs1799983 may be a protective factor for SLE (GT vs GG: OR = 0.328, P < 0.001; T vs G: OR = 0.438, P < 0.001) and this locus reduced the risk of SLE in the overdominant model (GT vs GG + TT: OR = 0.385, P < 0.001). There is a strong linkage disequilibrium between the rs1007311 and rs1799983 loci of the eNOS gene. Among them, the formed haplotype AG increased the risk of SLE compared to GG. AT and GT decreased the risk of SLE compared to GG. In this study, the eNOS gene rs3918188 and rs1799983 loci were found to be associated with susceptibility to SLE. This helps to deeply explore the mechanism of eNOS gene and genetic susceptibility to SLE. It provides a certain research basis for the subsequent exploration of the molecular mechanism of these loci and SLE, as well as the early diagnosis, treatment and prognosis of SLE.

Association of TLR4 polymorphisms (Asp299Gly and Thr399Ile) with sepsis: a meta-analysis and trial sequence analysis.

Several investigations have been carried out to explore the genetic association of TLR4 codon variants, specifically Asp299Gly and Thr399Ile, and susceptibility to sepsis, but the results have been contradictory. The present study aimed to conduct a meta-analysis to draw a definitive conclusion regarding the role of TLR4 genetic variants (Asp299Gly and Thr399Ile) in sepsis. A thorough literature search was conducted using the PubMed, Scopus, and Science Direct databases. The inclusion and exclusion criteria were established to ensure the accuracy of the data. The Comprehensive Meta-Analysis Software v4 was utilized to perform the meta-analysis and related analyses. A total of 13 studies were analyzed, including 2328 sepsis cases and 2495 healthy controls for the TLR4 Asp299Gly variant. Eight studies provided genotype data for the rs4986791 polymorphism. The Asp299Gly variant showed a marginal protective effect in the allele (p = 0.08, odds ratio = 0.71) and dominant (p = 0.09, odds ratio = 0.71) genetic models, although it was not statistically significant. The trial sequential analysis indicated that further case-control studies are necessary to draw definitive conclusions about the TLR4 polymorphisms in sepsis. The TLR4 Asp299Gly variant may have a protective effect against sepsis. However, additional research with larger sample sizes across diverse populations is required to validate this finding.

An association between fat mass and obesity-associated (FTO) (rs9939609) and kisspeptin-1 (KISS-1) (rs4889, rs372790354) gene polymorphisms with polycystic ovary syndrome: an updated meta-analysis and power analysis.

The present meta-analysis aimed to investigate FTO rs9939609 and KISS1 rs4889, rs372790354 gene polymorphisms and its association with PCOS in Asian population. The studies included in this article were obtained by using online databases. We searched databases such as Scopus, PubMed, Embase, and Web of Science for case-control articles related to FTO and KISS1 gene polymorphism with PCOS. Metagenyo software was used to determine the 95% confidence interval (CI) and odds ratio (OR). A total of 13 articles was included in this meta-analysis for FTO (rs9939609) and KISS1 (rs4889; rs372790354) gene polymorphisms related with PCOS in the Asian population. According to the findings of this study, people with FTO rs9939609 show an association with PCOS risk in dominant model. On contradictory, KISS1 gene polymorphism specifically, rs4889 show an association with PCOS risk in allelic, recessive, and dominant models whereas rs372790354 show an association with PCOS risk in allelic and dominant models. Power analysis was performed and PPI is > 0.04. The sting analysis network for FTO and KISS1 gene estimated 12 nodes and 23 edges. The FTO rs9939609 variant exhibits an association with an increased risk of PCOS in the dominant model. KISS1 gene polymorphism, particularly rs4889, shows a significant association with PCOS risk in allelic, recessive, and dominant models. Similarly, KISS1 rs372790354 gene is associated with PCOS risk in both allelic and dominant models. Researches were focused only on the Asian population so; it is imperative to conduct further research across diverse populations.

Association of telomerase reverse transcriptase gene rs10069690 variant with cancer risk: an updated meta-analysis

ObjectiveExisting evidence suggests telomerase activation is a crucial step in tumorigenesis. The telomerase reverse transcriptase (TERT), encoded by the human TERT gene, is critical for telomerase expression. The TERT rs10069690 (C > T) variant was identified to be associated with the risk of cancer, however, there have been inconsistent results. Therefore, we performed a comprehensive meta-analysis aiming to clarify the association between this variant and cancer susceptibility.MethodsWe conducted literature search in PubMed, EMbase, MEDLINE and Cochrane Library up to April 30, 2024. Overall, there are 55 studies involving 334,196 patients with cancer and 741,187 controls included in the present study. All statistical analyses were performed by STATA software (version 11.0).ResultsThe pooled results showed a significant association between rs10069690 and an increased risk of cancer under allele model (OR = 1.10, 95% CI: 1.07–1.13, P < 0.001), especially in European and Asian populations. When stratified by cancer types, this variant was associated with elevated risk of breast cancer (OR = 1.11, 95% CI: 1.07–1.15, P < 0.001), ovarian cancer (OR = 1.14, 95% CI: 1.10–1.19, P < 0.001), lung cancer (OR = 1.20, 95% CI: 1.07–1.35, P = 0.003), thyroid cancer (OR = 1.23, 95% CI: 1.15–1.32, P < 0.001), gastric cancer (OR = 1.31, 95% CI: 1.19–1.45, P < 0.001), and renal cell carcinoma (OR = 1.29, 95% CI: 1.07–1.55, P = 0.007), while decreased risk was found for hepatocellular carcinoma, prostate cancer and pancreatic cancer. Our results also indicated that this variant was significantly associated with solid cancer (OR = 1.11, 95% CI: 1.07–1.14, P < 0.001), but not with hematological tumor.ConclusionThis systematic meta-analysis demonstrated that the TERT rs10069690 variant was a risk factor for cancer. However, the effects of this variant may vary in different types of cancer and differ across ethnic populations.

Association and causal impact of TERT genetic variants on peripheral blood leukocyte telomere length and cerebral small vessel disease risk in a Chinese Han population: a mendelian randomization analysis

BackgroundPrevious observational studies have highlighted potential relationships between the telomerase reverse transcriptase (TERT) gene, short leukocyte telomere length (LTL), and cerebrovascular disease. However, it remains to be established as to whether TERT gene variants are associated with an elevated risk of cerebral small vessel disease (CSVD), and whether there is a causal relationship between LTL and CSVD.MethodsFive TERT single nucleotide polymorphisms (SNPs) were analyzed in 307 CSVD patients and 320 healthy controls in whom LTL values were quantified. Allele models and four genetic models were used to explore the relationship between these SNP genotypes and CSVD risk. A Mendelian randomization analysis of CSVD risk was then performed using LTL-related SNPs and the polygenic risk score (PRS) constructed from these SNPs as genetic instrumental variables to predict the causal relationship between LTL and CSVD risk.ResultsModel association analyses identified two SNPs that were significantly associated with CSVD risk. LTL was significantly correlated with age (P < 0.001), and the MR analysis revealed an association between short LTL and an elevated risk of CSVD. PRS-based genetic prediction of short LTLs was also significantly related to an elevated CSVD risk.ConclusionMultiple genetic models and MR results indicate that TERT gene SNPs may be related to an elevated risk of CSVD, and that shorter LTL may be causally linked to such CSVD risk.

Association of FOXO3 (rs17069665) gene polymorphism and childhood acute lymphoblastic leukemia in Egypt

BackgroundAcute lymphoblastic leukemia (ALL) is the most common malignancy in children. Genetic variations, particularly gene polymorphisms, have been closely linked to increased susceptibility to ALL. One of those genes is Forkhead box O3 (FOXO3), which is considered a potential tumor suppressor gene. AimThis study intended to examine the potential significance of the FOXO3 (rs17069665) single nucleotide polymorphism (SNP) as a risk factor for childhood ALL, in addition to its effect on the laboratory results, clinical manifestations and the clinical outcome after induction of chemotherapy. Subjects and methodsSixty-six newly diagnosed ALL children and 70 healthy children of matched age and sex as controls were recruited. FOXO3 (rs17069665) polymorphism was detected using TaqMan real time PCR. ResultsHigher frequencies of the (AG) genotype and G-allele of FOXO3 (rs17069665) variant were present in ALL patients in comparing with the controls (16.7 % vs. 4.3 %, p = 0.017 and 11.4 % vs. 2.1 %, p = 0.003, respectively). The frequencies of the FOXO3 (rs17069665) SNP reflected a noticeably higher risk of ALL under diverse genetic models, including the co-dominant model (AG vs. AA, OR = 2.55), dominant (AG + GG vs. AA, OR = 2.81), and allelic (G-allele vs. A-allele, OR = 2.9) models. The single case of c-MYC mutation was observed with the (GG) genotype. No significant association between FOXO3 (rs17069665) SNP polymorphism and response to chemotherapy was found. ConclusionOur findings showed that the FOXO3 (rs17069665) polymorphism was associated with a greater incidence of ALL in Egyptian children, which might be a potential biomarker for ALL susceptibility.

Association between vitamin D receptor gene polymorphisms and susceptibility to tuberculosis: a systematic review and meta-analysis.

Tuberculosis (TB) is the leading cause of mortality worldwide. Previous studies have reported that TB susceptibility can be caused by vitamin D deficiency, which is affected by polymorphisms in the vitamin D receptor (VDR) gene. However, these results have been inconsistent. Therefore, we performed a meta-analysis to investigate the association between VDR polymorphisms and TB susceptibility. We systematically searched for relevant literature in PubMed, Embase, and Medline databases through December 31st, 2022. Inclusion and exclusion criteria were made to ensure that HIV-negative population is the targeted subjects. The pooled odds ratio (OR) and 95% confidence interval (CI) were then used to assess the strength of the association, and the quality of the included articles was evaluated using the Newcastle-Ottawa Scale. Potential sources of heterogeneity were evaluated based on subgroup and meta-regression analyses. In our meta-analysis, we found that the FokI polymorphism in the VDR gene was associated with increased TB susceptibility in the allele and recessive genotype models (OR f vs. F = 1.235, 95%CI: 1.035-1.475; OR ff vs. Ff + FF = 1.317, 95%CI: 1.005-1.727. Further subgroup analysis based on ethnicity demonstrated the association with the risk of TB in all genotype models of the FokI polymorphism for Han population. Meta-regression analysis also indicated that ethnicity could be a potential source of heterogeneity in the FokI and BsmI polymorphisms in the VDR gene. However, publication year was another source of heterogeneity for the TaqI polymorphism. In summary, the FokI polymorphism in the VDR gene was found to increase the risk of TB in the HIV-negative population, both overall and in Asian populations. The findings presented in this paper could provide clues for preventing TB from the perspective of vitamin D supplementation, which is a controversial topic in the field of medicine and health.

Association of rare single nucleotide variant MUC5B rs35705950 with interstitial lung disease in Japanese rheumatoid arthritis.

Rheumatoid arthritis (RA) is sometimes complicated by interstitial lung disease (ILD) with a poor prognosis. A single nucleotide variant (SNV) in MUC5B was associated with ILD in European RA patients. However, associations of this SNV were not found in Japanese RA patients, because its frequency in Japanese populations is very low. We investigated the associations of candidate SNVs including the MUC5B variant with ILD in Japanese RA. Genotyping of MUC5B rs35705950, MUC2 rs7934606, MAD1L1 rs12699415, and PPFIBP2 rs6578890 in Japanese RA patients was conducted for association analyses. MUC5B rs35705950 was associated with usual interstitial pneumonia (UIP) (p = 0.0039, Pc = 0.0156, odds ratio [OR] 10.66, 95% confidence interval [CI] 2.05-55.37) or ILD (p = 0.0071, Pc = 0.0284, OR 7.33, 95%CI 1.52-35.44) in Japanese RA under the allele model. MUC2 rs7934606 was associated with UIP (p = 0.0072, Pc = 0.0288, OR 29.55, 95%CI 1.52-574.57) or ILD (p = 0.0037, Pc = 0.0148, OR 22.95, 95%CI 1.27-416.13) in RA. Haplotype analyses suggested the primary association of MUC5B rs35705950 with UIP in Japanese RA. No significant association of MAD1L1 rs12699415 or PPFIBP2 rs6578890 with UIP, nonspecific interstitial pneumonia, or ILD in RA was observed. MUC5B rs35705950 is associated with, and might be involved in the pathogenesis of ILD, especially UIP, in Japanese RA.

Unraveling the molecular significance of CYP1A2 (rs762551; c.-9–154 C>A) genetic variant on breast carcinoma susceptibility: Insights from case-control study and meta-analysis

BackgroundThe human cytochrome P450 (CYP) superfamily encompasses different categories of isoenzymes that contribute to multiple metabolic processes involving drug detoxification, cellular signaling, and the proliferation of malignant tissues. Using genetic technology, customized bioinformatic analysis, and meta-analysis design, the main goal of this study was to identify the association between the CYP1A2*rs762551 variant and the susceptibility to breast carcinoma (BRCA). MethodsThe case-control study was conducted based on 104 BRCA women and 102 healthy controls. Using the TaqMan allelic discrimination assay, the CYP1A2 (rs762551; c.–9–154 C>A) variant was genotyped. Bioinformatic frameworks and logistic regression analysis were used to assess the involvement of this genetic variant in BRCA development. A meta-analysis design was accomplished based on our case-control study and other previously published records. Publication bias, heterogeneity between studies, and trial sequential analysis (TSA) were analyzed. ResultsThe CYP1A2*rs762551 variant conferred protection against BRCA development under allelic (OR = 0.48, p-value < 0.001), dominant (OR = 0.34, p-value < 0.001), and recessive (OR = 0.44, p-value = 0.011) models. However, this intronic variant was correlated with a decreased risk of BRCA among late-onset menopause women compared to other cases. Bioinformatic analysis confirmed that this genetic variant has a functional impact on the progression of tumorgenesis. Moreover, this meta-analysis design included 12922 BRCA women and 15603 healthy controls. Our findings disclosed the contribution of the CYP1A2*rs762551 variant with protection against cancer development among Caucasian females under allelic (OR = 0.75, p-value = 0.025), and dominant (OR = 0.58, p-value = 0.015) models. ConclusionsThis case-control study confirmed the contribution of the CYP1A2*rs762551 variant with decreased risk of BRCA development among Egyptian subjects. Moreover, BRCA women with late-onset menopause conferred protection against cancer progression compared to other subjects. Our findings identified that this meta-analysis design achieved protection against BRCA development among Caucasian women compared to other ethnicities.

Comprehensive identification of genomic and environmental determinants of phenotypic plasticity in maize.

Maize phenotypes are plastic, determined by the complex interplay of genetics and environmental variables. Uncovering the genes responsible and understanding how their effects change across a large geographic region are challenging. In this study, we conducted systematic analysis to identify environmental indices that strongly influence 19 traits (including flowering time, plant architecture, and yield component traits) measured in the maize nested association mapping (NAM) population grown in 11 environments. Identified environmental indices based on day length, temperature, moisture, and combinations of these are biologically meaningful. Next, we leveraged a total of more than 20 million SNP and SV markers derived from recent de novo sequencing of the NAM founders for trait prediction and dissection. When combined with identified environmental indices, genomic prediction enables accurate performance predictions. Genome-wide association studies (GWASs) detected genetic loci associated with the plastic response to the identified environmental indices for all examined traits. By systematically uncovering the major environmental and genomic factors underlying phenotypic plasticity in a wide variety of traits and depositing our results as a track on the MaizeGDB genome browser, we provide a community resource as well as a comprehensive analytical framework to facilitate continuing complex trait dissection and prediction in maize and other crops. Our findings also provide a conceptual framework for the genetic architecture of phenotypic plasticity by accommodating two alternative models, regulatory gene model and allelic sensitivity model, as special cases of a continuum.

Role of MTHFR, IRF6, PAX7 and TP63 SNPs in susceptibility to non-syndromic orofacial cleft, a candidate gene study in a Portuguese population.

Non-syndromic orofacial cleft (NSOC) is a complex phenotype, involving multiple genetic and environmental factors. Association studies exploring the genetic susceptibility to this prevalent oral malformation show variability of results in different populations. Using a candidate gene approach, we aimed to verify the role of four single-nucleotide polymorphisms (SNPs) in the susceptibility to NSOC in Portuguese patients. A total of 254 non-consanguineous individuals of Portuguese were recruited, including 120 patients with NSOC and 134 controls. About 92% of these patients had non-syndromic cleft lip with or without cleft palate (NSCL/P) and 8% had only non-syndromic cleft palate (NSCP). SNPs in the MTHFR (rs1801133), IRF6 (rs642961), PAX7 (rs742071) and TP63 (rs9332461) genes were studied, using a real-time approach with TaqMan probes. Allelic, genotypic, dominant, recessive and over-dominant models were explored using a chi-squared test. Adjusted p-value was calculated for multiple comparisons using the Benjamini-Hochberg false discovery rate (FDR). All SNPs were in Hardy-Weinberg equilibrium. For MTHFR, IRF6, and PAX7 SNPs, no statistically significant difference was highlighted for any of the evaluated models. For TP63 SNP, data fitted an over-dominant model, with a protective effect for heterozygotes (OR 1.897; CI 95% [1.144-3.147]; p < .016, when comparing controls vs. cases), but significance was lost when applying adjusted p-value for multiple comparisons (4 × 5 tests). In this Portuguese population, there was no evidence of an association between the evaluated SNPs and NSOC. For TP63 SNP, the possibility of a protective effect of heterozygotes should be further investigated.

Association of PLCE1 (rs7922612) and COL4A3 (rs375290088) Genetic Variants with the Risk of Nephrotic Syndrome in Egyptian Pediatric Patients.

Nephrotic syndrome is one of the most prevalent pediatric kidney illnesses seen in pediatric nephrology clinics. Steroid resistance in children with nephrotic syndrome is a primary cause of renal failure and is characterized by nephrotic range proteinuria that does not respond to conventional steroid therapy. The current work was intended to investigate the possible role of the Phospholipase C epsilon 1 (rs7922612) and collagen4 alpha 3 (rs375290088) single nucleotide polymorphisms as risk factors for developing nephrotic syndrome among Egyptian children. The study was conducted on 100 children with nephrotic syndrome and 100 age- and sex-matched healthy individuals. Geno typing was performed by two methods of polymerase chain reaction for the analysis of PLCE1 (rs7922612) and COL4A3 (rs375290088) variants. We observed a higher percentage of the heterozygous and homozygous variant genotypes of PLCE1 (rs7922612) SNP in NS patients in comparison with the controls (P < 0.001 for both). The frequencies of the PLCE1 (rs7922612) variant showed a statistically significant elevated risk of NS using several genetic models, including the dominant (OR = 9.12), recessive (OR = 2.31), and allelic (OR = 1.62) models (P < 0.001 for each). In addition, the PLCE1 (rs7922612) genotypes and alleles frequencies did not differ significantly between SRNS compared to SSNS cases. Furthermore, there was no significant difference regarding COL4A3 (rs375290088) polymorphism, neither between the NS and control groups nor between SDNS and SRNS. PLCE1 (rs7922612) is considered an independent risk factor for nephrotic syndrome in Egyptian pediatrics.COL4A3 (rs375290088) polymorphism is not correlated to Egyptian NS patients.