Prenatal exposure to per- and polyfluoroalkyl substances, genetic factors, and autistic traits: Evidence from the Shanghai birth cohort.

The epidemiological evidence regarding prenatal PFAS exposure and its interaction with genetic factors on the autistic traits risk is unclear. This study included 1610 mother-child pairs from the Shanghai Birth Cohort (SBC). Ten PFAS were quantified in blood serum collected in the first trimester. Child autistic traits were evaluated at age 4 using a Chinese version of the social responsiveness scale-short form (SRS-SF). We calculated the polygenic risk score (PRS) to evaluate the cumulative genetic effects of autism. Additive interaction models were established to explore whether genetic susceptibility modified the effects of prenatal PFAS exposure. After adjusting for confounders, we found prenatal PFOA exposure was associated with an increased risk of autistic traits in children (OR, 3.05; 95 % CI, 1.14-7.58), and the increased risk associated with PFOA was mitigated among women who reported pre-pregnancy folic acid supplementation. Additionally, an increased risk of autistic traits was observed in children with higher levels of prenatal PFHxS exposure and a high PRS (p for interaction = 0.021). Our findings suggest prenatal PFAS exposure may increase the risk of autistic traits in children, especially in those with a high genetic risk. Further research is warranted to confirm this association and explore the underlying mechanisms.

Explore genetic susceptibility association between viral infections and Guillain-Barré syndrome risk using two-sample Mendelian randomization.

BACKGROUND: Numerous observational studies have indicated that patients with Guillain-Barré syndrome (GBS) frequently had infections with various pathogens before the onset of the disease, particularly several viral infections. Some of these infections are linked to specific clinical and immunological subgroups of GBS, suggesting a potential correlation between viral infections and the development of GBS. However, observational studies have several limitations, including the presence of confounding factors. METHOD: We explored the potential correlation between HIV, SARS-CoV-2, varicella-zoster virus, herpes simplex virus, Epstein-Barr virus, hepatitis B virus, and influenza virus with GBS using a two-sample Mendelian randomization approach. The data was derived from published summary statistics from genome-wide association studies (GWAS). After removing linkage disequilibrium, selecting strong instrumental variables and addressing confounding factors, we would conduct a two-sample Mendelian randomization analysis along with sensitivity testing and the MR-Steiger directional test. RESULT: HIV may have a causal association with GBS (IVW: p = 0.010, OR [95% CI] 1.240 [1.052-1.463]), while no such relationship exists with COVID-19 (IVW: p = 0.275, OR [95% CI] 0.831[0.596-1.159]), varicella (IVW: p = 0.543, OR [95% CI] 0.919 [0.701-1.206]), herpes zoster (IVW: p = 0.563, OR [95% CI] 0.941 [0.766-1.156]), HSV (IVW: p = 0.280, OR [95% CI] 1.244 [0.837-1.851]), EBV (IVW: p = 0.218, OR [95% CI] 0.883 [0.724-1.076]), HBV (IVW: p = 0.179, OR [95% CI] 1.072 [0.969-1.187]), or influenza virus (IVW: p = 0.917, OR [95% CI] 0.971 [0.553-1.703]). We did not find any abnormal SNPs, pleiotropy, or heterogeneity, nor is there any reverse causation. CONCLUSION: Our study results indicate a causal relationship between HIV and GBS, providing new research directions for the etiology of GBS.

A genome-wide gene-environmental interaction study identified novel loci for the relationship between ambient air pollution exposure and depression, anxiety.

BACKGROUND: Genetic factors and environmental exposures, including air pollution, contribute to the risk of depression and anxiety. While the association between air pollution and depression and anxiety has been established in the UK Biobank, there has been limited research exploring this relationship from a genetic perspective. METHODS: Based on individual genotypic and phenotypic data from a cohort of 104,385 participants in the UK Biobank, a polygenic risk score for depression and anxiety was constructed to explore the joint effects of nitric oxide (NO), nitrogen dioxide (NO2), particulate matter (PM) with a diameter of ⩽2.5 µm (PM2.5) and 2.5-10 µm (PMcoarse) with depression and anxiety by linear and logistic regression models. Subsequently, a genome-wide gene-environmental interaction study (GWEIS) was performed using PLINK 2.0 to identify the genes interacting with air pollution for depression and anxiety. RESULTS: A substantial risk of depression and anxiety development was detected in participants exposed to the high air pollution concomitantly with high genetic risk. GWEIS identified 166, 23, 18, and 164 significant candidate loci interacting with NO, NO2, PM2.5, and PMcoarse for Patient Health Questionnaire-9 (PHQ-9) score, and detected 44, 10, 10, and 114 candidate loci associated with NO, NO2, PM2.5, and PMcoarse for General Anxiety Disorder (GAD-7) score, respectively. And some significant genes overlapped among four air pollutants, like TSN (rs184699498, PNO2 = 3.47 × 10-9; rs139212326, PPM2.5 = 1.51 × 10-8) and HSP90AB7P(rs150987455, PNO2 = 1.63 × 10-11; rs150987455, PPM2.5 = 7.64 × 10-11), which were common genes affecting PHQ-9 score for both NO2 and PM2.5. CONCLUSION: Our study identified the joint effects of air pollution with genetic susceptibility on the risk of depression and anxiety, and provided several novel candidate genes for the interaction, contributing to an understanding of the genetic architecture of depression and anxiety.

Exposure to air pollution, genetic susceptibility, and prevalence of sarcopenia in the UK.

BACKGROUND: The role of environmental factors, particularly air pollutants, in the prevalence of sarcopenia remains unclear. OBJECTIVES: This study explored the relationship between the prevalence of sarcopenia and prolonged exposure to air pollutants, and investigated potential interactions with genetic susceptibility and inflammation. METHODS: Data from 408,117 people at baseline and 35,060 participants in the longitudinal analysis in the UK Biobank were used in this prospective cohort study. Utilizing land use regression models, air pollutants (nitrogen dioxide (NO2), nitric oxides (NOx), and particulate matter with aerodynamic diameters of ≤2.5 µm (PM2.5) and ≤10 µm (PM10) were estimated and classified into quartiles. Alterations in body composition were among the secondary results. RESULTS: Lastly, 3353 people (0.8 %) developed sarcopenia. Higher levels of air pollutants were linked to an increased prevalence of sarcopenia after controlling for confounding variables (highest vs lowest quartile: NOx, OR, 1.21 [95 % CI, 1.16-1.26]; NO2, OR, 1.22 [95 % CI, 1.16-1.27]; PM2.5, OR, 1.17 [95 % CI, 1.12-1.22]; PM10, OR, 1.15 [95 % CI, 1.10-1.20]; all P<.001). Longitudinal analysis revealed that air pollutants had adverse changes in body composition, including increased muscle fat infiltration and decreased muscle mass. At baseline, the probability of sarcopenia was strongly correlated with NOx, NO2, PM2.5, and PM10, and increased with elevated PRSBMI or CRP levels in subgroup analyses. CONCLUSION: Air pollutants may contribute to accelerated muscle aging and highlight the importance of environmental factors in sarcopenia development.

Serum 25-hydroxyvitamin D, genetic susceptibility and abdominal aortic aneurysm risk.

CONTEXT: The association of serum 25-hydroxyvitamin D [25(OH)D] and genetic polymorphisms of the vitamin D receptor (VDR), and the vitamin D binding protein (VDBP) with incident abdominal aortic aneurysm (AAA) remains uncertain. OBJECTIVE: To investigate whether serum 25(OH)D, genetic polymorphisms of VDR and VDBP, genetic susceptibility to AAA, and the interactions among these factors influence the risk of incident AAA. DESIGN: Retrospective cohort study. SETTING: UK Biobank. PARTICIPANTS: 447,529 participants without a diagnosis of prevalent aortic aneurysm or aortic dissection at baseline. EXPOSURE: Serum 25(OH)D concentration. MAIN OUTCOME MEASURE: Incident AAA. RESULTS: During a median follow-up of 12.5 years, 2,042 participants developed incident AAA. A significant inverse association between serum 25(OH)D and incident AAA was observed (per SD increment, HR, 0.92; 95%CI, 0.88-0.96), which was particularly pronounced in older individuals and those without diabetes (both P for interaction <0.05). Compared to participants with serum 25(OH)D ≥ 50 nmol/L, those with serum 25(OH)D between 25 and <50 nmol/L and <25 nmol/L exhibited a significant higher risk of incident AAA. In the 371,621 participants with genetics assessment, individuals carrying AA alleles of ApaI SNP had a significant increased risk of incident AAA compared to those carrying CC alleles (HR, 1.16; 95%CI, 1.02-1.32). The inverse association between serum 25(OH)D and incident AAA was stronger in individuals with intermediate or high genetic risk for AAA (P for interaction = 0.048). CONCLUSIONS: There was a significant inverse association between serum 25(OH)D and AAA incidence, particularly among individuals with higher genetic risk for AAA, older age, and without diabetics.

Association of psychosocial state with subsequent risk of dementia: a prospective cohort study based on the UK Biobank.

BACKGROUND: Multiple psychosocial factors have been associated with dementia, while the individual or joint effects of various psychosocial states on dementia remain unrevealed due to the complex interplay between those factors. Here, the authors examined the associations of psychosocial factors and patterns with subsequent risk of dementia, and if the associations could be modified by genetic susceptibility to dementia. METHODS: UK Biobank dementia-free participants were followed from one year after recruitment (median date: 24 January, 2010) until 31 October, 2022. Psychosocial states were measured by 22 items related to five dimensions, including psychiatric history, recent stressful life events, current psychiatric symptoms, social contact, and individual socioeconomic state. We identified clusters of individuals with distinct psychosocial patterns using latent class analysis. Cox proportional hazards models were used to evaluate the association between psychosocial items, as well as psychosocial patterns, and risk of dementia. We further performed stratification analyses by apolipoprotein E (APOE) genotype, polygenic risk score (PRS) of dementia, and family history of dementia. RESULTS: Of 497,787 included participants, 54.54% were female. During a median follow-up of 12.70 years, we identified 9,858 (1.98%) patients with newly diagnosed dementia. We identified seven clusters with distinct psychosocial patterns. Compared to individuals with a pattern of 'good state', individuals with other unfavorable patterns, featured by varying degrees of poor psychological state ('fair state' and 'mildly, moderately, and extremely poor psychological state'), low social contact or socioeconomic state ('living alone' and 'short education years'), were all at an increased risk of dementia (hazard ratios [HR] between 1.29 and 2.63). The observed associations showed no significant differences across individuals with varying APOE genotypes, levels of PRS, and family histories of dementia. CONCLUSION: Unfavorable psychosocial patterns are associated with an increased risk of dementia, independent of genetic susceptibility. The findings highlight the importance of surveillance and prevention of cognitive decline among individuals with suboptimal psychosocial state.

Serum albumin, genetic susceptibility, and risk of venous thromboembolism.

Background: Previous research on the association between serum albumin (ALB) and venous thromboembolism (VTE) has produced inconclusive results. The polygenic risk score is constructed from a set of independent risk variants associated with a disorder, enabling the identification of a larger fraction of the population at comparable or greater disease risk. It is still unknown whether ALB and genetic factors jointly contribute to the incidence of VTE. Objectives: The present study aimed to explore ALB, genetic susceptibility, and the risk of VTE. Methods: The present investigation was an analysis of prospectively collected data from UK Biobank, a population-based, longitudinal cohort. Cox proportional models were used to calculate hazard ratios and 95% CIs for VTE. The Kaplan-Meier curve was utilized to visualize the cumulative risk of VTE according to different serum ALB levels, and the restricted cubic spline model was leveraged to explore the exposure-response relationship among ALB levels and VTE risk. Results: During median follow-up of 13.5 years, 11,502 cases with VTE were diagnosed among 417,113 participants in the UK Biobank. The lower ALB levels were associated with a higher risk for VTE. Individuals with both a high genetic risk and lowest ALB level had the highest risk of VTE (hazard ratio, 3.89; 95% CI, 3.41-4.43), compared with those with low genetic risk and highest ALB level. The positive joint effects of low ALB and polygenic risk score increased the risk of VTE in individuals with high genetic risk. This study excluded non-European patients and primarily focused on the European population, which may limit the generalizability of the findings. Conclusion: Low serum ALB levels were linked to an increased risk of VTE, which was in accordance with a linear dose-response relationship. There was a positive additive effect of ALB and genetic susceptibility on the risk of VTE. ALB could serve as a biomarker for predicting the risk of VTE.

The association between plasma fatty acids and risk of lung cancer: a prospective cohort study of the UK Biobank.

CONTEXT: Fatty acids (FAs) have emerged as significant contributors to tumorigenesis, yet prospective evidence regarding their specific effects on lung cancer risk remains scarce. OBJECTIVE: To investigate the association between plasma FAs and lung cancer incidence, as well as a potential modification effect of genetic susceptibility on lung cancer risk. METHODS: A cohort study was conducted involving 112,547 cancer-free participants from the UK Biobank, with measurements of plasma FAs, including saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs) at baseline (2006-2010). Cox regression models were employed to assess lung cancer risk according to plasma FA quartiles or 1-SD increment. Furthermore, interaction between plasma FAs and polygenic risk score (PRS) was evaluated using an additive model. RESULTS: Over an average 10.9-year follow-up, 1122 lung cancer cases occurred. After multivariable adjustment, MUFAs were positively associated with lung cancer risk (hazard ratio [HR] per 1-SD = 1.32, 95% confidence interval [CI]: 1.13-1.54). In contrast, PUFAs, particularly n-3 PUFAs, n-6 PUFAs, docosahexaenoic acid, and linoleic acid, were associated with a lower risk of lung cancer, with HRs ranging from 0.79 (95% CI: 0.72-0.87) to 0.89 (95% CI: 0.83-0.95). SFAs were not significantly associated with lung cancer risk. Moreover, we observed an additive interaction between plasma PUFAs and genetic risk. Individuals with a high genetic risk and the lowest quartile of plasma PUFAs had the highest risk of lung cancer (HR = 2.20, 95% CI: 1.43-3.38). CONCLUSION: Our findings suggest that plasma PUFAs may serve as protective factors, while MUFAs represent risk factors for lung cancer, offering novel insights into lung cancer carcinogenesis and prevention.

Effect of post-traumatic stress disorder on type 2 diabetes and the mediated effect of obesity: a Mendelian randomization study.

Objective: Whether the role of post-traumatic stress disorder (PTSD) on type 2 diabetes (T2D) is mediated by obesity or other mediating factors is controversial. This study was designed to assess the impact of PTSD on genetic susceptibility to T2D and mediating factors. Methods: The datasets for PTSD, T2D, obesity, hypertension, hyperlipidemia, smoking status, and alcohol consumption were obtained from genome-wide association studies. Mendelian randomization (MR) was used to assess exposure-outcome causality, and inverse variance weighted was used as the primary tool for MR analysis. MR-Egger intercept, Cochran's Q, and leave-one-out sensitivity analysis were employed to assess horizontal pleiotropy, heterogeneity, and robustness, respectively. Results: The MR analysis showed that PTSD was associated with increased genetic susceptibility to T2D (OR, 1.036; 95% CI, 1.008-1.064; p = 0.011), obesity (OR, 1.033; 95% CI, 1.016-1.050; p < 0.001), and hypertension (OR, 1.002; 95% CI, 1.000-1.003; p = 0.015), but not not with genetic susceptibility to hyperlipidemia, alcohol consumption, and smoking status (p ≥ 0.05). Mediated effect analysis showed that PTSD increased genetic susceptibility to T2D by increasing genetic susceptibility to obesity and hypertension, with obesity accounting for 9.51% and hypertension accounting for 2.09%. MR-Egger intercept showed no horizontal pleiotropy (p ≥ 0.05). Cochran's Q showed no heterogeneity (p ≥ 0.05). Leave-one-out sensitivity analysis showed that the results were robust. Conclusion: This MR analysis suggests that PTSD increases the risk of T2D and that this effect is partially mediated by obesity and hypertension. Active prevention and treatment of PTSD can help reduce the risk of T2D.

Toll-Like Receptor Genes and Risk of Latent Tuberculosis Infection in People Infected with HIV-1.

The purpose of this study was to determine the contribution of genetic factors, i.e., the level of expression and polymorphisms of Toll-like receptors (TLR), to the susceptibility of latent tuberculosis infection in a Russian cohort of individuals infected with HIV. The patients (n = 317) with confirmed HIV infection were divided into two groups according to the results of the STANDARD E TB-Feron test: 63 cases with a latent TB infection and 274 controls without LTBI. Total DNA and RNA were isolated from whole-blood samples. SNP genotyping and expression levels of five TLR genes (TLR1, TLR2, TLR4, TLR6, and TLR8) were determined by means of real-time PCR. There were no significant differences in the expression levels of the TLRs between the case and control groups. In addition, we did not observe any significant association between the analyzed SNPs and the susceptibility of Latent tuberculosis infection (LTBI) in patients with HIV. However, patients from an entire cohort with the rs4986790-GG (TLR4) and rs5743708-GG (TLR2) genotypes were characterized by lower CD4 T-cell counts compared to carriers of alternative alleles. Moreover, we found a significant risk of a hazardous drop in the CD4 T-cell count below 350 cells/mm3 associated with the rs4986790-G (TLR4) allele. Latent tuberculosis infection in individuals infected with HIV does not significantly modify the level of TLR gene expression.

Insights into the genetic theory of infectious diseases.

Over the past century, classical approaches from microbiology and immunology have produced spectacular results in the control of infectious diseases. However, the recent SARS-COV-2 pandemic has highlighted our continued failure to control some infections. Other microorganisms still pose a threat to humanity such as HIV, Ebola, and influenza viruses. It seems that conventional approaches are not able to solve all the current problems caused by infectious diseases. Human genetics has shown that infections have a strong genetic determinism that can lead to a predisposition or resistance to infections. This explains much of the clinical variability observed in individuals infected with the same pathogen. The identification of the genetic etiology allows a better understanding of the pathogenesis of infectious diseases and, consequently, the consideration of appropriate preventive and therapeutic strategies. This review provides insights into the genetic theory and the concrete evidence to support it. We highlight the role of primary immunodeficiencies in the discovery of Mendelian and monogenic susceptibility to infections, then we show how genetic and phenotypic heterogeneity, redundancy, and resistance to infection manifest in the context of this genetic determinism. To effectively combat the constant threat of microbes, it is essential to integrate human genetics with microbiology to examine the interactions between pathogens and our immune system.

Genetics, epigenetics and autoimmunity constitute a Bermuda triangle for the pathogenesis of rheumatoid arthritis.

Rheumatoid arthritis (RA), a multigene disorder with a heritability rate of 60 %, is characterized by persistent pain, synovial hyperplasia, and cartilage and bone destruction, ultimately causing irreversible joint deformity. The etiology and pathogenesis of rheumatoid arthritis (RA) are primarily influenced by specific genetic variants, particularly HLA alleles such as HLA-DRB1*01 and DRB1*04. However, other HLA alleles such as HLA-DRB1*10 and DPB*1 have also been found to contribute to increased susceptibility to RA. However, non-HLA genes also confer a comparatively high risk of RA disease manifestation. The most relevant single nucleotide polymorphisms (SNPs) associated with non-HLA genes are PTPN22, TRAF1, CXCL-12, TBX-5, STAT4, FCGR, PADI4, and MTHFR. In conjunction with genetic susceptibility, epigenetic alterations orchestrate paramount involvement in regulating RA pathogenesis. Increasing evidence implicates DNA methylation and histone protein modifications, including acetylation and methylation, as the primary epigenetic mechanisms that drive the pathogenesis and clinical progression of the disease. In addition to genetic and epigenetic changes, autoimmune inflammation also determines the pathological progression of the synovial membrane in joints with RA. Glycosylation changes, such as sialylation and fucosylation, in immune cells have been shown to be relevant to disease progression. Genetic heterogeneity, epigenetic factors, and changes in glycosylation do not fully explain the features of RA. Therefore, investigating the interplay between genetics, epigenetics, and autoimmunity is crucial. This review highlights the significance and interaction of these elements in RA pathophysiology, suggesting their diagnostic potential and opening new avenues for novel therapeutic approaches.

IL-10 A-Allele as a Biomarker for Periodontitis Severity in Bulgarian Patients.

BACKGROUND: Periodontitis is a complex disease, and bacterial factors play a crucial role in its initiation. The contributions of genetic and epigenetic factors to the pathogenesis of periodontal disease are increasingly recognized. Single-nucleotide polymorphisms (SNPs) in various molecules, including cytokines, are of particular interest due to their established involvement in numerous diseases. This study investigates the influence of SNPs in the IL-10 gene at positions -592 (rs1800872) C>A and -1082 (rs1800896) T>C (also referred to as 1082A>G) on the severity of periodontitis in a cohort of Bulgarian patients. METHODS: In the recent study, both clinical and paraclinical methodologies were employed to comprehensively assess the periodontal status of the participants. The genotypic characterization of IL-10 polymorphisms was performed by PCR RFLP analysis. Statistical analyses, including principal component analysis (PCA), were executed utilizing IBM SPSS Statistics Version 21. RESULTS: We have established a statistically significant association between the presence of at least one A-allele in the patients' genotype and the incidence of severe periodontitis (p = 0.047). CONCLUSIONS: IL-10 single-nucleotide polymorphisms (SNPs) could be effectively considered as biomarkers for the severity of periodontitis.

Genetic susceptibility and clinical features of CYP2D6 associated with systemic lupus erythematosus in a Chinese population.

OBJECTIVE: This study aims to explore possible susceptibility genes and clinical features for systemic lupus erythematosus (SLE) patients in a Chinese population. METHODS: Expanding on the results of a prior single-center observational study involving 60 systemic lupus erythematosus patients, a subsequent single-center prospective observational study was conducted on SLE patients undergoing treatment at Nanfang Hospital Affiliated to Southern Medical University from 2021 to 2023. The identification process for drug-related target genes entailed an extensive search across PharmGKB (https://www.pharmgkb.org/), the Clinical Pharmacogenetics Implementation Consortium (CPIC),and PubMed literature databases, to pinpoint common drugs and target single nucleotide polymorphisms(SNPs)for SLE. Blood samples were individually collected and genotyped using MassARRAY® high-throughput nucleic acid mass spectrometry. Genotype frequency differences were assessed through Chi-square tests against both the larger East Asian population as well as kidney transplant recipients. Data collection relied on electronic medical records, encompassing demographic details(age, gender),medication regimens(hormones, NSAIDs, hydroxychloroquine, DMARDs, biologic agents, stomach medications, calcitriol, etc.),laboratory indicators(RF, Anti-CCP antibody, ESR, CRP, anti-ANA antibodies, dsDNA antibodies, anti-SM antibodies, S m. RNP antibodies, A LT, ALB, CR, UA, WBC, PLT, HGB, Ca, K, Glu, CHOL, TG, LDL-C, HDL-C) and lupus activity scores(SLEDAI-2K). Possible disease susceptibility genes were categorized, and SPSS26 software facilitated statistical analyses. RESULTS: The research encompassed a total of 137 SLE patients along with 50 SNPs. After conducting statistical analyses, it emerged that there existed significant disparities in CYP2D6 gene (rs1065852) distribution when compared against allele mutation rates within both East Asian populations (p < .05) and kidney transplant patients(p < .05). Wild-type gene (GG) constituted 14% of cases while mutant gene (GA + AA) constituted 86%. Allele mutation rate (A63.6%) was significantly higher among SLE patients (RR = 0.802; p = .0355). Furthermore, the variant rs1065852 genotype (GA + AA) demonstrated significant associations with lower CRP levels, higher HGB levels, and higher HDL-C levels (p < 0 0.05). CONCLUSION: The metabolic enzyme CYP2D6 may be used as susceptibility gene for predicting systemic lupus erythematosus and are correlated with CRP and other indicators.

Polymorphisms in miRNA Genes Targeting the AMPK Signaling Pathway are Associated with Cervical Cancer Susceptibility in a Han Chinese Population.

Purpose: Cervical cancer (CC) poses a significant threat to women's health worldwide, and multiple signaling pathways have been confirmed to be involved in its development. The AMPK signaling pathway plays a central role in maintaining energy homeostasis, and its dysregulation is closely associated with the occurrence of CC. Changes in microRNA (miRNA) expression levels might be related to the AMPK signaling pathway. Single nucleotide polymorphisms (SNPs) can affect the function of miRNA and result in the development of CC. To investigate the association between the SNPs of AMPK pathway-associated miRNAs and CC in a Han Chinese population, we selected eight miRNA genes located in the AMPK pathway and analyzed nine SNP loci within these genes to explore whether they are associated with genetic susceptibility to cervical intraepithelial neoplasia (CIN) and CC. Methods: A total of 2,220 subjects were included in this study, including 928 healthy controls, 421 CIN patients, and 871 CC patients. Nine candidate SNPs (rs895819 in miR-27a, rs10061133 in miR-449b, rs41291179 in miR-216a, rs76481776 in miR-182, rs10406069 in miR-5196, rs12803915 and rs550894 in miR-612, rs66683138 in miR-3622b, and rs2620381 in miR-627) were genotyped using the TaqMan method. Results: The results showed significant differences in the allele distribution of rs41291179 and rs12803915 between the control group and the CIN group, as well as between the control group and the CC group (all P values < 0.005). The A allele of rs41291179 and the G allele of rs12803915 were associated with decreased risk of CIN (OR = 0.05, 95% CI: 0.01-0.39; OR = 0.61, 95% CI: 0.49-0.76) and CC (OR = 0.08, 95% CI: 0.01-0.66; OR = 0.71, 95% CI: 0.59-0.86), respectively. Conclusion: Our results suggest that polymorphisms in miRNA genes of the AMPK signaling pathway are associated with the development of CC.

Harmonisation of the HLA tests for the diagnosis of coeliac disease: experiences from the Czech external proficiency testing program.

Coeliac disease (CD) is an autoimmune disorder caused by the ingestion of gluten-containing grains. One of the prerequisites for the development of the disease is the presence of specific combinations of HLA alleles at the DQA1 and DQB1 loci. The HLA test is a supportive diagnostic test. In the Czech Republic, approximately 3,500 HLA tests for CD diagnosis are performed annually in almost three dozen laboratories. The HLA Department of the Institute of Haematology and Blood Transfusion in Prague has been offering the EPT "Detection of HLA Alleles Associated with Diseases" for more than 10 years. The results are evaluated in terms of the correct determination of predisposing alleles/allelic groups and clinical interpretation. Every year, we notice some problems with the detection of CD-associated alleles and the interpretation of results. Annual workshops are part of this EPT, and they also include recommendations for the interpretation of results. This interpretation is evolving based on the current knowledge in the field. The current recommendation for interpretation was adopted in 2023, dividing HLA-DQA1/DQB1 genotypes into three categories: 1) detected HLA genotype is associated with predisposition to coeliac disease; 2) coeliac disease could not be excluded based on the detected HLA genotype; 3) coeliac disease could be excluded with high probability based on the detected HLA genotype. The quality of examination is increasing but still needs improvement. Correct results and accurate interpretation can inform clinicians' decisions about the diagnosis of coeliac disease in appropriate patients.

Multi-step gene set analysis identified HTR3 family genes involving childhood acute lymphoblastic leukemia susceptibility.

In our previous conventional genome-wide association study (GWAS), WWOX was a susceptibility gene associated with acute lymphoblastic leukemia (ALL) development. Nowadays, advancements in genetic association analyses promote an in-depth exploration of ALL genomics. We conducted a two-step enrichment analysis at both gene and pathway levels based on ALL GWAS data including 269 cases and 1039 controls of Chinese descent. The following functional prediction and experiments were used to evaluate the genetic biology of candidate variants and genes. The serotonin-activated cation-selective channel complex gene-set was a potential biological pathway involved in ALL occurrence. Of which, individuals carrying the T allele of rs33940208 exhibited a prominent reduced risk of ALL [odds ratio (OR) = 0.71, 95% confidence interval (CI) = 0.53 to 0.96, P = 2.81 × 10-2], whereas those with the A allele of rs6779545 demonstrated an increased risk (OR = 1.23, 95% CI = 1.01 to 1.51, P = 4.11 × 10-2). Notably, the two variants displayed a better prediction capability when combined, that the risk of developing childhood ALL increased by 131% in subjects with 2-4 risk alleles compared to those with 0-1 risk alleles (Ptrend = 2.05 × 10-3). In addition, the T allele of rs33940208 could reduce HTR3A mRNA level, while the A allele of rs6779545 increased HTR3D mRNA expression. In this study, we identified HTR3A rs33940208 and HTR3D rs6779545 as potential susceptibility loci for ALL in Chinese children. Future validation and functional research will elucidate the underlying molecular processes, refining preventive strategies for this disease.

Genetic insights and emerging therapeutics in diabetic retinopathy: from molecular pathways to personalized medicine.

Diabetic retinopathy (DR) is a major complication of diabetes worldwide, significantly causing vision loss and blindness in working-age adults, and imposing a substantial socioeconomic burden globally. This review examines the crucial role of genetic factors in the development of DR and highlights the shift toward personalized treatment approaches. Advances in genetic research have identified specific genes and variations involved in angiogenesis, inflammation, and oxidative stress that increase DR susceptibility. Understanding these genetic markers enables early identification of at-risk individuals and the creation of personalized treatment plans. Incorporating these genetic insights, healthcare providers can develop early intervention strategies and tailored treatment plans to improve patient outcomes and minimize side effects. This review emphasizes the transformative potential of integrating genetic information into clinical practice, marking a paradigm shift in DR management and advancing toward a more personalized and effective healthcare model.

Gene-environment interaction in functional hypothalamic amenorrhea.

Functional hypothalamic amenorrhea (FHA) is a common cause of amenorrhea and chronic anovulation in adolescent girls and young women, diagnosed after excluding other organic causes. It is commonly associated with calorie restriction, excessive physical exercise, and psychosocial stress. These stressors alter the pulsatile secretion of gonadotropin-releasing hormone, leading to a chronic condition of hypoestrogenism and significant health consequences. Recent evidence has highlighted a genetic predisposition to FHA that could explain interindividual variability in stress response. Indeed, not all women experience FHA in response to stress. Rare variants in genes associated with idiopathic hypogonadotropic hypogonadism have been identified in women with FHA, suggesting that these mutations may contribute to an increased susceptibility of women to the trigger of stress exposure. FHA appears today as a complex disease resulting from the combination of genetic predisposition, environmental factors, and epigenetic changes. Furthermore, the genetic background of FHA allows for the hypothesis of a male counterpart. Despite the paucity of data, preliminary findings indicate that an equivalent condition of FHA exists in men, warranting further investigation. This narrative review aims to summarize the recent genetic evidence contributing to the pathophysiology of FHA and to raise awareness on a possible male counterpart.

NQO1 polymorphism and susceptibility to ischemic stroke in a Chinese population.

BACKGROUND: Ischemic stroke (IS) is a major cause of death and disability worldwide. Genetic factors are important risk factors for the development of IS. The quinone oxidoreductase 1 gene (NQO1) has antioxidant, anti-inflammatory, and cytoprotective properties. Thus, in this study, we investigated the relationship between NQO1 gene polymorphism and the risk of IS. METHODS: Peripheral blood was collected from 143 patients with IS and 124 the control groups in Yunnan, China, and NQO1 rs2917673, rs689455, and rs1800566 were genotyped. Logistic regression was used to analyze the relationship between the three NQO1 loci and IS susceptibility. The difference in the expression levels of NQO1 between the control groups and IS groups was verified using public databases and enzyme-linked immunosorbent assay. RESULTS: The rs2917673 locus increased the risk of IS by 2.375 times in TT genotype carriers under the co-dominance model compared with CC carriers and was statistically associated with the risk of IS (OR = 2.375, 95% CI = 1.017-5.546, P = 0.046). In the recessive model, TT genotype carriers increased IS risk by 2.407 times compared with CC/CT carriers and were statistically associated with the risk of IS (OR = 2.407, 95% CI = 1.073-5.396, P = 0.033). CONCLUSIONS: NQO1 rs2917673 polymorphism is significantly associated with IS. Mutant TT carriers are risk factors for IS.