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Background: Cascade testing can offer improved surveillance and timely introduction of clinical management for the at-risk biological relatives. Data on cascade testing and costs in mitochondrial diseases are lacking. To address this gap, we performed a cross-sectional retrospective study to provide a framework for cascade testing in mitochondrial diseases, to estimate the eligibility versus real-time uptake of cascade testing and to evaluate the cost of the genetic diagnosis of index cases and the cost of predictive cascade testing. Methods: Data was collected through retrospective chart review. The variant inheritance pattern guided the identification of eligible first-degree relatives: (i) Males with mitochondrial DNA (mtDNA) single nucleotide variants (SNVs) – siblings and mothers. (ii) Females with mtDNA SNVs – siblings, mothers and offspring. (iii) Autosomal Dominant (AD) nuclear DNA (nDNA) variants – siblings, offspring and both parents. (iv) Autosomal Recessive (AR) nDNA variants – siblings. Results: We recruited 99 participants from the Adult Mitochondrial Disease Clinic in Sydney. The uptake of cascade testing was 55.2% in the mtDNA group, 55.8% in the AD nDNA group and 0% in AR nDNA group. Of the relatives in mtDNA group who underwent cascade testing, 65.4% were symptomatic, 20.5% were oligosymptomatic and 14.1% were asymptomatic. The mean cost of cascade testing for eligible first-degree relatives (mtDNA group: $694.7; AD nDNA group: $899.1) was lower than the corresponding index case (mtDNA group: $4578.4; AD nDNA group: $5715.1) (p < 0.001). Conclusion: The demand for cascade testing in mitochondrial diseases varies according to the genotype and inheritance pattern. The real-time uptake of cascade testing can be influenced by multiple factors. Early diagnosis of at-risk biological relatives of index cases through cascade testing, confirms the diagnosis in those who are symptomatic and facilitates implementation of surveillance strategies and clinical care at an early stage of the disease. [ABSTRACT FROM AUTHOR]

Background: The predictive relationship between mild-to-moderate alcohol consumption and the risk of incident atrial fibrillation (AF) remains controversial. Objective: We investigated whether the relationship between alcohol consumption and the risk of incident AF could be associated with the genetic predisposition to alcohol metabolism. Methods: A total of 399,329 subjects with genetic data from the UK Biobank database, enrolled between 2006 and 2010, were identified and followed for incident AF until 2021. Genetic predisposition to alcohol metabolism was stratified according to the polygenic risk score (PRS) tertiles. Alcohol consumption was categorized as non-drinkers, mild-to-moderate drinkers (< 30 g/day), and heavy drinkers (≥ 30 g/day). Results: During the follow-up (median 12.2 years), 19,237 cases of AF occurred. When stratified by PRS tertiles, there was a significant relationship between genetic predisposition to alcohol metabolism and actual alcohol consumption habits (P < 0.001). Mild-to-moderate drinkers showed a decreased risk of AF (HR 0.96, 95% CI 0.92–0.99), and heavy drinkers showed an increased risk of AF (HR 1.06, 95% CI 1.02–1.10) compared to non-drinkers. When stratified according to PRS tertiles for genetic predisposition to alcohol metabolism, mild-to-moderate drinkers had equivalent AF risks, and heavy drinkers showed increased AF risk in the low PRS tertile group. However, mild-to-moderate drinkers had decreased AF risks and heavy drinkers showed similar risks of AF in the middle/high PRS tertile groups. Conclusions: Differential associations between alcohol consumption habits and incident AF across genetic predisposition to alcohol metabolism were observed; individuals with genetic predisposition to low alcohol metabolism were more susceptible to AF. [ABSTRACT FROM AUTHOR]

Objectives: Human leukocyte antigen G (HLA-G) plays a crucial role in pregnancy. Pregnancy loss (PL) is caused by a variety of causes, such as fetal chromosomal abnormalities, maternal hypertension and diabetes, immune causes, spontaneous immune diseases, infections, unknown causes, etc. This study reports on the association of fetal HLA-G 3'UTR polymorphisms and diplotypes with chromosomally abnormal fetuses (CAF) or unexplained pregnancy loss (UPL)., Methods: A total of 552 specimens were collected and grouped by next-generation sequencing technology (NGS) and fetal survival: UPL (112 cases), CAF (170 cases) and control (258 cases). The polymorphisms of HLA-G 3'UTR in all samples were detected by Sanger sequencing. The genotypes, haplotypes and diplotypes of HLA-G 3'UTR were analyzed. The classification and regression tree (CART) analysis was used to evaluate the role of HLA-G diplotypes in predicting fetal outcomes. The correlations between CAF or UPL and maternal age, paternal age, times of miscarrage, times of delivery were analyzed by logistic regression., Results: The frequencies of HLA-G + 2960del/del and + 3035CC genotypes were remarkablly increased in CAF than those in control group. The frequencies of HLA-G + 2960ins/del, + 3010CC, + 3035TC, + 3142GG, + 3187AA in CAF were significantly lower than those in normal fetuses. Through genetic models and logistic regression analysis, the dominant model of HLA-G 3'UTR genotypes [such as + 2960 (OR = 1.27, 95% CI = 1.05-1.54, p = 0.016), + 3010 (OR = 0.78, 95% CI = 0.63-0.97, p = 0.026), + 3035 (OR = 1.22, 95% CI = 1.00-1.49, p = 0.047), + 3142 (OR = 0.76, 95% CI = 0.62-0.95, p = 0.014) and + 3187 (OR = 0.80, 95% CI = 0.65-0.99, p = 0.041)] were dramatically associated with CAF. However, the frequencies of HLA-G + 3010GC, + 3142GC and + 3187AG in fetuses with UPL were memorably decreased than those in normal fetuses. No significant difference was found in the frequencies of HLA-G haplotypes in all groups. However, the frequency of UTR-1 positive specimens in CAF was significantly higher than that in UPL and control group. At the same time, the frequency of UTR-1/UTR-3 diplotypes in CAF was observably higher than that in UPL and control group, while the UTR-1/UTR-7 frequency in UPL was signally lower than that in control group. Multivariate logistic regression analysis indicated that positive HLA-G UTR-1 (OR = 1.8, 95% CI = 1.16-2.81, p = 0.009), times of abortion (OR = 1.23, 95% CI = 1.02-1.50, p = 0.035), and times of delivery (OR = 0.31, 95% CI = 0.20-0.48, p < 0.001) were correlated with CAF., Conclusions: This study suggests that HLA-G 3'UTR polymorphisms and diplotypes play an important role in the process of successful pregnancy of the embryos with abnormal chromosomes after fertilization. At the same time, Different alleles or diplotypes also affect the development of embryos with UPL., Competing Interests: Declarations Ethics approval and consent to participate This study was approved by the Medical Ethics Review Committee of Taizhou Hospital (approval #K20231035), and written informed consent from all study participants was obtained before enrolment. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Observational epidemiological studies suggested that immunological dysregulation and inflammation play a significant role in the placental and renal dysfunction that leads to maternal hypertension. The immunophenotypes' possible causalities with hypertensive disease of pregnancy remain ambiguous. We performed two-sample Mendelian randomization (MR) analyses to comprehensively investigate the causal effect of immunophenotypes on hypertensive disorder of pregnancy (HDP)., Methods: The large-scale genome-wide association studies (GWASs) data on immunological traits was taken from public catalog for 731 immunophenotypes. The summarized GWAS data in 4 types of HDP were retrieved from FinnGen database, including 811,605 Finnish individuals. The primary analysis was the inverse variance weighted (IVW) method, supplemented by conducting sensitivity analysis. To confirm whether cardiovascular proteins mediated the causal effect of immune cells on HDP, we additionally executed a mediation MR study., Results: After looking into genetically predicted immunophenotype biomarkers, we discovered 14 highly correlative immunophenotypes and 104 suggestive possible factors. The IVW analysis indicated that HLA DR on myeloid DC, HLA DR on plasmacytoid DC, and HLA DR on DC had a significant association with pre-eclampsia/eclampsia (PE), whereas CD4 + CD8 dim AC and CD4 + CD8 dim % leukocyte were protective against gestational hypertension (GH). All of HDP in our study had no statistically significant impact on immune cells, according to reverse MR analysis. The mediating role of LOX-1between HLA DR on plasmacytoid DC and chronic hypertension prior to pregnancy was validated., Conclusion: This study showed that many immunophenotypes are implicated in HDP. Furthermore, the level of LOX-1 mediated the pathophysiology relationship between HLA DR on plasmacytoid dendritic cells and chronic hypertension prior to pregnancy., Competing Interests: Declarations Ethics approval and consent to participate The GWAS summary statistics for 731 immune traits are publicly available from the GWAS Catalog (accession numbers from GCST90001391 to GCST90002121). All participants signed informed consent to study protocols approved by the Sardinian Regional Ethics Committee (protocol no. 2171/CE). FinnGen research project is based on samples from Finnish biobanks and data from national health registers and applies the permissions to utilise the register data for research purposes from national authorities. All studies were conducted in accordance with the Declarationof Helsinki. All the GWAS statistics used in this study have been published and the ethics committee at each institutional review board has acquired the written informed consent of all participants. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: The NLRP3 inflammasome, a pivotal mechanism regulating inflammatory responses and featuring the pyrin domain containing 3 (NLRP3) within the NOD-like receptor family, is widely recognized as a central pathogenic factor in cardiovascular diseases. The present study endeavors to delve into the correlation and potential interplay between the rs10754558 polymorphism of NLRP3 and the predisposition to hypertension among the Chinese adult population., Methods: All the participants who came from a community in Bengbu, China were investigated by being interviewed with a questionnaire. Overall, 354 paired case-control participants were analyzed. Genomic DNA was extracted from 5ml venous blood using the Tiangen DNA extraction kit. The rs10754558 polymorphism of the NLRP3 gene was genotyped by TaqMan allelic discrimination real-time PCR.The association between the rs10754558 polymorphism and hypertension risk was investigated by a logistic regression analysis. Furthermore, an additive interaction analysis was conducted using related indicators, including the relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (SI)., Results: Participants carrying the GG genotype were more likely to develop hypertension than participants carrying the CC genotype (adjusted odds ratio [OR]: 2.16, 95% confidence interval [CI]: 1.33-3.52). A significant additive interaction between the NLRP3 polymorphism and obesity status concerning the risk of hypertension was observed, as estimated by all indicators: RERI (1.12, 95% CI: 0.70-1.5), AP (0.34, 95% CI: 0.14-0.53), and SI (1.92, 95% CI: 1.03-3.59). The values of RERI (1.74, 95% CI: 0.37-3.11), AP (0.46, 95% CI: 0.21-0.70), and SI (2.62, 95% CI: 1.18-5.83) showed that a significant interaction between the rs10754558 polymorphism and a family history of hypertension., Conclusions: Our findings indicate a significant association between the NLRP3 rs10754558 polymorphism and the risk of hypertension in Chinese adults. Moreover, a notable additive interaction emerges between NLRP3 polymorphisms and obesity status, further amplifying the risk of hypertension., Competing Interests: Declarations Ethics approval and consent to participate This study was approved by the Ethics Committee of Bengbu Medical College (No. 202201). Written informed consent was obtained from all participants. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Current effective breast cancer treatment options have severe side effects, highlighting a need for new therapies. Drug repurposing can accelerate improvements to care, as FDA-approved drugs have known safety and pharmacological profiles. Some drugs for other conditions, such as metformin, an antidiabetic, have been tested in clinical trials for repurposing for breast cancer. Here, we exploit the genetics of breast cancer and linked predisposing diseases to propose novel drug repurposing opportunities. We hypothesize that if a predisposing disease contributes to breast cancer pathology, identifying the pleiotropic genes related to the risk of cancer could prioritize drugs, among all drugs treating a predisposing disease. We aim to develop a method to not only prioritize drugs for repurposing, but also to highlight shared etiology explaining repurposing., Methods: We compile breast cancer's predisposing diseases from literature. For each predisposing disease, we use GWAS summary statistics data to identify genes in loci showing genetic correlation with breast cancer. Then, we use a network approach to link these shared genes to canonical pathways. Similarly, for all drugs treating the predisposing disease, we link their targets to pathways. In this manner, we are able to prioritize a list of drugs based on each predisposing disease, with each drug linked to a set of implicating pathways. Finally, we evaluate our recommendations against drugs currently under investigation for breast cancer., Results: We identify 84 loci harboring mutations with positively correlated effects between breast cancer and its predisposing diseases; these contain 194 identified shared genes. Out of the 112 drugs indicated for the predisposing diseases, 74 drugs can be linked to shared genes via pathways (candidate drugs for repurposing). Fifteen out of these candidate drugs are already in advanced clinical trial phases or approved for breast cancer (OR = 9.28, p = 7.99e-03, one-sided Fisher's exact test), highlighting the ability of our approach to identify likely successful candidate drugs for repurposing., Conclusions: Our novel approach accelerates drug repurposing for breast cancer by leveraging shared genetics with its known predisposing diseases. The result provides 59 novel candidate drugs alongside biological insights supporting each recommendation., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Objectives: This study aimed to provide insight into the effect of genetically predicted linoleic acid (LA) levels on osteoarthritis (OA)., Methods: The LA dataset was obtained from the UK Biobank (UKBB) consortium and contained 114,999 samples. The OA discovery dataset was derived from MRC-IEU consortium and included 38,472 cases and 424,461 controls. The OA validation set was derived from a summary-level genome-wide association study (GWAS) and included 39,427 cases and 378,169 controls. Genetic variants strongly associated with LA (p < 5 × 10 - 8 ) were extracted as instrumental variables (IVs). The inverse variance weighted (IVW) approach was adopted as the primary analysis method in this study. In addition, multiple sensitivity analysis methods were used to assess the reliability of our results., Results: The IVW approach showed that circulating LA levels were negatively associated with OA risk in the discovery set (odds ratio (OR) = 0.993, 95% confidence interval (95% CI): 0.988-0.998, p = 0.011). A consistent result was obtained in the validation set (OR = 0.904, 95%CI: 0.845-0.967, p = 0.003). These results were validated by sensitivity analysis., Conclusion: This study provides new evidence for the causal relationship between LA and OA, which provides new insights for the treatment of OA., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Clinical trial number Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Numerous observational studies consistently highlight a strong association between serum uric acid (sUA) levels and atrial fibrillation (AF). However, the causal relationship and the direction of this association remain elusive, despite extensive research efforts., Objective: This study aimed to investigate the bidirectional causal relationships between sUA, gout, and the risk of AF using the two-sample Mendelian randomization (MR) approach., Methods: We conducted a comprehensive analysis utilizing publicly available genome-wide association studies (GWAS) summary statistics, employing stringent criteria to meticulously select genetic variants associated with sUA, gout, and AF. Our primary analytical approach was the inverse-variance weighted (IVW) method, complemented by some sensitivity analyses, including MR-Egger, weighted median, simple mode, and weighted mode, to estimate the causal effects. To identify potential violations, we conducted Egger regression and leave-one-SNP-out analyses. We assessed the strength of instrumental variables using F values to evaluate weak instruments. Additionally, we referenced the Phenoscanner database to exclude single nucleotide polymorphisms (SNPs) associated with confounding factors or outcomes., Results: Our forward Mendelian randomization analysis suggests that there is no causal relationship between UA levels/gout from different populations and the risk of AF [IVW OR 1.03, 95% CI: 0.97-1.08; p = 0.335; IVW OR 0.99, 95% CI: 0.97-1.02; p = 0.583; and IVW OR 1.07, 95% CI: 0.84-1.37; p = 0.575], respectively. We did not detect significant heterogeneity or potential pleiotropy, and we also excluded the possibility of weak instrumental variables. Furthermore, we did not find any reverse causal effects of AF on sUA levels and gout risk., Conclusion: Our findings challenge the widely held belief that lowering urate levels is uniformly effective in reducing the risk of atrial fibrillation (AF). Our study fails to substantiate the existence of a causal link between uric acid (UA) levels or gout and the development of AF, regardless of direction., Competing Interests: Declarations Ethics approval and consent to participate Ethical approval from patients were obtained in the original studies and no further ethical approval is required for this study. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Declaration of competing interest All authors declare no competing interests., (© 2024. The Author(s).)

Background: Ischemic stroke (IS) is a commonly seen cerebrovascular disease which seriously endangers the health of middle age and old people. However, its etiology and pathogenesis have not yet fully comprehended. miR-30 gene is a novel gene which may be involved in IS. However, no studies have investigated the relationship between IS and the single-nucleotide polymorphisms (SNPs) of miR-30. Therefore, this study examined the relationship between miR-30 polymorphisms (rs2222722, rs1192037, rs10095483 and rs16827546) and the risk of IS., Methods: Totally 248 IS patients and 230 age-, sex- and race-matched controls were involved in this study. Based on SNPscan technique, four polymorphisms (rs2222722, rs1192037, rs10095483 and rs16827546) were genotyped., Results: There exists a significant association between rs2222722 polymorphism and the risk of IS according to analyses of genotypes, models and alleles (GA vs. GG: adjusted OR = 1.616, 95% CI: 0.943-2.768, P = 0. 081); (AA vs. GG: adjusted OR = 2.447, 95% CI: 1.233-4.858, P = 0.011); dominant model: adjusted (OR = 1.806, 95% CI, 1.082-3.016, P = 0.024); (G vs. A: adjusted OR = 1.492, 95% CI: 1.148-1.939, P = 0.003). Besides, miR-30a expression was significantly higher in patients undergoing IS relative to that in controls (P < 0.05)., Conclusions: To conclude, the rs2222722 polymorphism of the miR-30 gene shows a significant relationship to elevate the risk of IS in Chinese population., Competing Interests: Declarations Ethics approval and consent to participate The study protocol was approved by the Review Board of the People’s Hospital of Guangxi Zhuang Autonomous Region, (2024KY-ZC-2024-207). All the subjects signed informed consent to participate in this work. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: A common genetic variant at the glutamate-ammonia ligase (GLUL) locus has been previously associated with an increased risk of coronary artery disease (CAD) as well as alterations of glutamic acid metabolism and the γ-glutamyl cycle in individuals with type 2 diabetes (T2D). Here we investigated whether less frequent variants in GLUL and 15 additional genes in these pathways are associated with differences in CAD risk in T2D., Methods: Coding sequences and regulatory elements of these genes were sequenced in 2,394 individuals with T2D from three CAD case/control sets., Results: Ninety-six variants with minor allele frequency [MAF]< 0.05 were identified as being nominally associated with CAD status. One of these variants (rs62447457, MAF 0.025), placed in a non-coding region flanking the γ-glutamylcyclotransferase (GGCT) gene, showed nominal evidence of replication in two other cases-control sets (n = 1,132), with summary OR of 0.54 (p = 2.5 × 10 -4 ). Another variant (rs145322388, MAF = 0.039), flanking the dipeptidase 2 (DPEP2) gene, showed association with CAD status across discovery and replications sets (summary OR 0.61, p = 2.5 × 10 -4 ). A third variant (rs1238275622, MAF 0.004), flanking the GLUL gene, was associated with increased risk of CAD (summary OR 1.84, p-value 2.1 × 10 -3 ). Based on their Regulome scores (2b, 2a, and 3a, respectively), all three variants are very likely to have regulatory functions., Conclusions: In summary, we have identified low-frequency variants associated with CAD in T2D at two loci involved in glutamic acid metabolism and the γ-glutamyl cycle. These findings provide further evidence for a role of these pathways in the link between T2D and CAD., Competing Interests: Declarations Ethics approval and consent to participate The study protocols of the JHS, JKS1, and JKS2 were approved by the Joslin Committee on Human Studies. The study protocols of the NHS and HPFS were approved by the Institutional Review Boards of the Brigham and Women's Hospital and the Harvard T.H. Chan School of Public Health. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: The association between recurrent aphthous stomatitis (RAS) and neoplasms of the mouth and pharynx (NOMAP) has been reported in some previous observational studies. However, causality is still confused. Our research aims to explore the relationship between RAS and NOMAP through a Mendelian randomization (MR) analysis and to explore whether RAS can serve as a risk factor for NOMAP to provide a reference for the clinical strategy., Methods: An exposure dataset for RAS were collected from a published study based on the UK Biobank (UKB). Outcome datasets included Genome-wide association studies (GWAS) summary statistics of NOMAP from the FinnGen datasets. The core method was inverse variance weighting (IVW). The Bonferroni correction, MR-Egger, weighted median, weighted mode, Cochcan's Q test, MR-PRESSO, and leave-one-out methods served as complementary methods., Results: We found no significant evidence of causal relationships between RAS and NOMAP. After applying the Bonferroni correction, the corrected P was equal to 0.00625 (0.05/1/8). The IVW method provided the sole evidence for RAS on Benign neoplasm of floor of mouth (BNFM) (OR = 2.509, 95% CI: 1.296-4.857, P = 0.006), but the subsequent MR-Egger regression method showed that this result may be due to horizontal pleiotropy (P = 0.035). The Cochran Q-test, MR-Egger regression, and MR-PRESSO did not reveal any heterogeneity or directional pleiotropy for the other outcomes., Conclusions: In conclusion, this is the first MR analysis to investigate the relationship between RAS and NOMAP. Our research confirmed at the genetic level that no causal association has been identified between RAS and NOMAP, therefore facilitating a logical therapeutic perspective and the development of clinical therapies for them., (© 2024. The Author(s).)

Background: Observational studies and experimental evidence have shown that chemokines play important roles in lung cancer development, progression, and treatment. However, few studies have examined the causal association between them., Methods: Summary data of chemokines and lung cancer were obtained from genome-wide association studies. Mendelian randomization (MR) analyses were performed by five methods, Inverse variance weighted (IVW), Weighted median estimation, MR-Egger, Simple mode and Weighted, with IVW as the primary analysis method. Sensitivity analysis was used to assess the reliability of the MR results. Multivariate Mendelian randomization studies were used to infer whether causality was influenced by potential mediators. The expression levels of CCL21 were analyzed by quantitative real-time PCR., Results: We found that CCL21 was negatively associated with lung adenocarcinoma risk. CCL25 was positively associated with lung squamous cell carcinoma risk. CCL5 was negatively associated with small cell lung cancer risk. CCL21, CCL24, CCL27, and CCL28 was positively associated with small cell lung cancer risk. After multivariate Mendelian randomization adjustment for smoking behavior, it was found that the effect of CCL25 on lung squamous cell cancer disappeared, and the effect of CCL21 on small cell lung cancer was quite opposite to the univariate. The receiver operating characteristic curve indicated that chemokines had high accuracy in the diagnosis of lung cancer. CCL21 expression levels showed large differences in lung adenocarcinoma cells., Conclusion: These results highlighted the causal effects of chemokines on lung cancer and suggested a mediating role of smoking behavior in the association between chemokines and lung cancer., (© 2024. The Author(s).)

Determining whether someone has cardiometabolic disease (CMD), especially in the early stages, can be complicated. Risk stratification ordinarily depends on an extended process relying on medical history that typically considers blood pressure, cholesterol, smoking and diabetes status. Physicians have long relied on these key patient characteristics to assess CMD risk. However, these widely used clinical assessments are often identified later in life and by definition, in those individuals with progressed disease. This is partly because the onset of CMD naturally occurs in adulthood, however, the underlying processes can occur much earlier in life, even in the absence of obvious symptoms. For one thing, the pathways towards pathology may exist for years before symptom onset. Thus, among other things, there are opportunities to provide doctors with better insights into future disease prediction especially in younger adults with diabetes. The rapid rise in CMD together with the increased rates of obesity and diabetes in this population only emphasises the importance of predictive molecular biomarkers. One notable aspect is that traditional risk scores, such as those based on cholesterol measurements, are frequently found to be within normal ranges in younger populations. At the same time, given the significant overlap in risk factors for cardiovascular disease (CVD) and diabetes, the unmet clinical need is for early biomarkers of CMD that may help improve risk assessment in younger adults. This editorial highlights advances in the use of polygenic risk scores and emerging utility of genetic biomarkers to define intermediate CMD phenotypes discussing new classification criteria involving DNA methylation of genes to improve risk assessment. CMD is the number one cause of mortality and accounts for 31% of all global deaths. CMD is also multifactorial, comprising cardiovascular disease (CVD) and diabetes that have significant overlap in risk factors and disease biology. Diabetes is arguably the strongest risk factor for CVD development. Accounting for almost 90% of diabetes cases worldwide, type 2 diabetes (T2D) affects about 527 million people. The global economic burden is estimated at 1.3 trillion USD annually and is close to 1.8% of global GDP [1]. Despite the progress in preventive and therapeutic measures of CVD, the increasing CMD rates only underscore the important need of molecular biomarkers for early detection [2]. Determining whether someone has CMD usually involves an extended diagnostic process that has become essential for risk stratification and disease prevention [3]. While the onset of CMD typically occurs in adulthood, disease development commences much earlier, and this has scientists questioning whether molecular biomarkers could improve current prognostic risk scores. Predicting which people with T2D are most likely to develop CVD remains a significant challenge despite the recent advances in genetic mapping., (© 2024. The Author(s).)

The strongest genetic risk factor for Alzheimer's disease (AD) is the ε4 allele of apolipoprotein E (ApoE ε4). A high fat diet also adds to the risk of dementia and AD. In addition, there are sex differences as women carriers have a higher risk of an earlier onset and rapid decline in memory than men. The present study looked at the effect of the genetic risk of ApoE ε4 together with a high fat/high sucrose diet (HFD/HSD) on brain function in male and female rats using magnetic resonance imaging. We hypothesized female carriers would present with deficits in cognitive behavior together with changes in functional connectivity as compared to male carriers. Four-month-old wildtype and human ApoE ε4 knock-in (TGRA8960), male and female Sprague Dawley rats were put on a HFD/HSD for four months. Afterwards they were imaged for changes in function using resting state BOLD functional connectivity. Images were registered to, and analyzed, using a 3D MRI rat atlas providing site-specific data on 173 different brain areas. Resting state functional connectivity showed male wildtype had greater connectivity between areas involved in feeding and metabolism while there were no differences between female and male carriers and wildtype females. The data were unexpected. The genetic risk was overshadowed by the diet. Male wildtype rats were most sensitive to the HFD/HSD presenting with a deficit in cognitive performance with enhanced functional connectivity in neural circuitry associated with food consumption and metabolism., (© 2024. The Author(s).)

Background: Current observational data indicates that ischemic stroke (IS) affects a significant proportion of people with COVID-19. The current study sought to evaluate the causal relationship between COVID-19 and IS., Methods: A two-sample Mendelian randomization (2 S-MR) approach was used to probe the relationship between genetic determinants of three COVID-19 parameters (SARS-CoV-2 infection, COVID-19 hospitalization, and severe COVID-19) and the incidence of IS based on genome-wide association studies (GWAS) data. Using this 2 S-MR technique, expression quantitative trait loci (eQTL) and GWAS studies were further assessed for overlap to identify common causative genes associated with severe COVID-19 and IS., Results: IVW approaches indicated the genetic variants linked to COVID-19 hospitalization (OR 1.04, 95% CI 1.01-1.08, p = 0.023) and severe COVID-19 (OR 1.03, 95% CI 1.01-1.05, p = 0.007) were both significantly linked to greater odds of IS. In contrast, there was no causal association between genetic SARS-CoV-2 infection susceptibility and the occurrence of IS (OR 0.99, 95% CI 0.92-1.06, p = 0.694). Ten shared causal genes (TNFSF8, CFL2, TPM1, C15orf39, LHFPL6, FAM20C, SPAG9, KCNJ2, PELI1, and HLA-L) were established as possible mediators of the interplay between severe COVID-19 and the development of IS, with these genes primarily being enriched in immune-related and renin-angiotensin-aldosterone system pathways., Conclusion: These findings indicate a possible causative relationship between IS risk and COVID-19 severity, offering crucial new information for managing COVID-19 patients. Promising options for therapeutic therapies for severe COVID-19 complicated by IS include the common genes found in the present study., (© 2024. The Author(s).)

Genetically determined disorders are highly heterogenous in clinical presentation and underlying molecular mechanism. The evidence underpinning these conditions in the peer-reviewed literature requires robust critical evaluation for diagnostic use. Here, we present a structured curation process for Gene2Phenotype (G2P). This draws on multiple lines of clinical, bioinformatic and functional evidence. The process utilises and extends existing terminologies, allows for precise definition of the molecular basis of disease, and confidence levels to be attributed to a given gene-disease assertion. In-depth disease curation using this process will prove useful in applications including in diagnostics, research and development of targeted therapeutics. G2P: www.ebi.ac.uk/gene2phenotype ., (© 2024. The Author(s).)

Background: Polycystic ovary syndrome (PCOS) is a complex heterogenous disorder manifesting with various reproductive, endocrine, and metabolic derangements such as insulin resistance and hyperglycemia. The arginine vasopressin peptide (AVP), also called or antidiuretic hormone (ADH), modulates metabolic functions such as glucose hemostasis, insulin sensitivity, and lipid metabolism via binding to two central and peripheral receptors (AVPR1A and AVPR1B). In the present study, we aimed to detect whether the AVPR1A and AVPR1B genes confer risk for PCOS., Methods: In peninsular Italian families, we tested 7 variants in the AVPR1B gene and 2 variants in the AVPR1A gene via Pseudomarker for linkage and linkage joint to association (i.e.., linkage disequilibrium) with PCOS., Results: We identified two risk variants in each gene, significantly associated with the risk of PCOS., Conclusion: To the best of our knowledge, this is the first study to report risk variants in AVPR1A and AVPR1B genes in association with PCOS. However, replication in other ethnic groups as well as functional studies are needed to confirm these results., (© 2024. The Author(s).)

Background: Asthma and allergic diseases (such as allergic rhinitis) are multifactorial chronic respiratory diseases, and have many common pathogenic mechanisms. This study aimed to assess the joint effects of breastfeeding and genetic susceptibility on asthma, allergic disease in children and adolescents and sought to examine whether the effect of breastfeeding was consistent under distinct levels of genetic risk., Methods: A total of 351,931 UK Biobank participants were analyzed. Firstly, Cox proportional hazards model was used to evaluate the relation between breastfeeding and asthma, allergic disease and their comorbidity. Next, we incorporated the polygenic risk score as an additional covariate into the model. Then, we explored the role of breastfeeding at each stage of asthma and allergic disease through a multi-state model. Meanwhile, several sensitivity analyses were conducted to evaluate the robustness of our results. Finally, we calculated the attributable protection and population attributable protection of breastfeeding., Results: Breastfeeding was related to a reduced risk of occurring asthma (adjusted hazard ratio [HR] = 0.89, 95% confidence interval [CI] 0.86 ~ 0.93), allergic disease (HR = 0.89, 95%CI 0.87 ~ 0.91) and comorbidity (HR = 0.89, 95%CI 0.83 ~ 0.94). The effect of breastfeeding was almost unchanged after considering PRS and did not substantially differ across distinct genetic risk levels. Breastfeeding showed a stronger risk-decreased impact on individuals who developed from allergic rhinitis to comorbidity (HR = 0.83, 95%CI 0.73 ~ 0.93). Further, the influence of breastfeeding was robust against covariates considered and the confounding influence of adolescent smoking. Finally, due to breastfeeding, 12.0%, 13.0% or 13.0% of the exposed population would not suffer from asthma, allergic diseases and the comorbidity, while 7.1%, 7.6% or 7.6% of the general population would not suffer from these diseases., Conclusions: This study provided supportive evidence for the risk-reduced effect of breastfeeding on asthma, allergic diseases, and the comorbidity in children and adolescents, and further revealed that such an influence was consistent across distinct genetic risk levels., (© 2024. The Author(s).)

Background: Chronic myeloid leukaemia (CML) is a type of blood cancer that begins in the hematopoietic stem cells. It is primarily characterized by a specific chromosomal aberration, the Philadelphia chromosome. While the fusion gene is a major contributor to CML, several other genes including ADGRE2, that are reported as highly expressed in hematopoietic stem cells and could be utilized as a therapeutic marker in leukemic patients are implicated in the disease's progression. Until recently, little research had been conducted to identify single nucleotide polymorphisms (SNPs) associated with CML. Therefore, this study aims to investigate the influence of non-synonymous variants on the structure and function of the gene encoding adhesion G protein-coupled receptor E2, ADGRE2, and to evaluate their association with CML and its clinical and pathological characteristics., Methods: Non-synonymous SNPs of ADGRE2 were retrieved from the ENSEMBL, COSMIC, and gnomAD genome browsers, and the pathogenicity of deleterious variants was assessed using several established computational tools, including SIFT, CADD, REVEL, PolyPhen, and MetaLR., Results: Various in silico analyses explored the impact of damaging SNP on the function, stability, and structure of EGF-like modules containing mucin-like hormone receptor-like2 (EMR2) protein encoded by the ADGRE2 gene. Genotype analysis was performed on collected blood samples, revealing that altered genotype TT of variant rs765071211 (C/T) was associated significantly with CML patients compared to the control. Further in vitro and in vivo analyses suggest that this SNP holds potential for clinical translation., (© 2024. The Author(s).)

Polycystic ovary syndrome (PCOS) is defined as a chronic low-grade inflammatory reproductive endocrine disorder. PCOS can induce various metabolic disorders, which are associated with a state of mild and slow-acting inflammation. Nevertheless, the causal relationship between polycystic ovary syndrome and inflammatory factors is uncertain. The causality between inflammatory cytokines and PCOS was analyzed by bidirectional Mendelian randomization (MR) in this current probe. We performed an interactive MR study to assess the causal relationships between 91 inflammatory cytokines and PCOS using Genome Wide Association Study (GWAS) data. We underwent dual-sample MR analysis with inverse variance weights (IVW) as the predominant MR methodology with multiple validity and heterogeneity analyses. MR-Egger, weighted median, simple mode, weighted mode and MR-PRESSO were analyzed as multiple likelihood sensitivity analyses to enhance the final results.The results came out interleukin-1-alpha (IL-1 A) levels (odds ratio [OR] = 1.051, 95% fiducial interval [95% CI] = 1.009-1.095, P = 0.02) and oncostatin-M (OSM) levels ( [OR] = 1.041, [95% CI] = 1.001-1.082, P = 0.04) were positively associated with the development of PCOS. Moreover, interleukin-7 (IL-7) levels ([OR] = 0.935, [95% CI] = 0.884-0.989, P = 0.02); interleukin-15 receptor subunit alpha (IL15RA) levels ([OR] = 0.959, [95% CI] = 0.929-0.99, P = 0.01); and C-X-C motif chemokine 11 (CXCL11) levels ([OR] = 0.959, [95% CI] = 0.922-0.996. P = 0.03) were strongly negatively associated with PCOS. However, we did not find any strong positive results in the reverse analysis, suggesting that although inflammatory factors contribute to the pathogenesis of PCOS, PCOS itself does not trigger inflammatory factor production.Our study provides genetic evidence for the connection between systemic inflammatory regulators and PCOS. Treatments targeting specific inflammatory factors may help to mitigate the risk of PCOS. The levels of five of the 91 inflammatory factors included in this study, namely, IL1A and OSM, were associated with PCOS. IL1A and OSM contribute to the progression of PCOS while IL-7, IL15RA, and CXCL11 levels are negatively correlated with the development of PCOS., (© 2024. The Author(s).)

Background: Type II diabetes mellitus (T2DM) is strongly linked with a heightened risk of coronary artery disease (CAD). Exploring biological targets common to T2DM and CAD is essential for CAD intervention strategies., Methods: RNA transcriptome data from CAD and T2DM patients and single-cell transcriptional data from myocardial tissue of CAD patients were used for bioinformatics analysis. Differential analysis and Weighted Gene Co-expression Network Analysis (WGCNA) were conducted to identify hub genes associated with the CAD Index (CADi) in these cells. We then intersected these genes with differentially expressed genes in the T2DM dataset to validate the key gene FGF7. Additional analyses included immune analysis, drug sensitivity, competing endogenous RNA (ceRNA) networks, and smooth muscle cell -related functional analysis., Results: An abnormally high proportion of smooth muscle cells was observed in CAD tissues compared to normal cardiomyocytes. The gene FGF7, which encodes the keratinocyte growth factor 7 protein, showed increased expression in both CAD and T2DM and was significantly positively correlated with the CADi (correlation = 0.24, p < 0.05). FGF7 expression was inversely correlated with CD4 + and CD8 + T-cell immune infiltration and correlated with the cardiovascular drugs. Overexpression of FGF7 in CAD samples enhanced interactions with mononuclear macrophages and influenced the metabolism of alanine, glutamate, nicotinamide, and retinol. We also identified that hsa-miR-15a-5p, hsa-miR-373-3p, hsa-miR-20a-5p, and hsa-miR-372-3p could regulate FGF7 expression., Conclusion: FGF7 serves as a critical shared biological target for T2DM and CAD, playing a significant role in CAD progression with potential therapeutic implications., (© 2024. The Author(s).)

Background: Immune factors are crucial in the pathogenesis of rheumatoid arthritis (RA), and immune cells play a key role in the development of RA. However, there is still disagreement regarding the specific roles of each type of immune cell in the pathological process of RA., Methods: This study used bidirectional two-sample Mendelian randomization (MR) analysis to determine the causal relationship between immune cell characteristics and RA. Utilizing publicly available genetic data, we initially treated immune cell characteristics as exposures to investigate their causal effects on the risk of RA. Subsequently, we performed reverse two-sample MR using the positively selected cells from the initial analysis as outcomes, aiming to identify the core immune cells involved. Finally, a comprehensive sensitivity analysis was conducted to validate the robustness, heterogeneity, and horizontal pleiotropy of the results., Results: Using data from 731 immune cells as exposures and cell SNPs as instruments, we independently conducted two-sample MR analysis for each patient with RA. The main analytical method used was the IVW method, with a significance level set at P < 0.05 for inclusion. In total, we identified 42 immune cell phenotypes that were causally associated with the onset of RA. For the reverse MR analysis, we used RA as the exposure factor and focused on 42 immune cell phenotypes as outcomes. Our analysis revealed causal relationships between the onset of RA and 7 immune cell phenotypes. Among these, 6 showed positive causal relationships, while 1 exhibited a negative causal relationship., Conclusions: Our study emphasized the causal relationship between immune cells and RA through bidirectional two-sample MR analysis, identifying the immune cells causally associated with RA., (© 2024. The Author(s).)

Objectives: This study investigated gene polymorphisms in the interleukin-4 (IL-4) and its receptor alpha (IL-4Rα) gene regions in human hosts with uncomplicated malaria., Data Description: Blood samples were obtained from a case-control study conducted at the Sogakope district hospital in the Volta region of Ghana. Thick blood films were made and used to detect the presence and levels of parasitaemia in the patient samples. Genotyping of IL-4 (150 C/T) and the IL-4Rα (Pro-478-Ser) polymorphisms in the promoter regions and receptor gene was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) after DNA extraction. The data are useful in determining genetic polymorphisms (allele and genotypic frequencies) of IL-4 and its alpha receptor. In addition, they are useful when comparing levels of parasite density and haematological parameters between genotypic variants of IL-4 and IL-4Rα. These data contribute to our understanding of the genetic basis of malaria susceptibility, particularly in the population of the Volta region of Ghana., (© 2024. The Author(s).)

Objective: Ulcerative colitis (UC) and Hashimoto's thyroiditis frequently cooccur in patients with multiple autoimmune conditions, but the specific association between UC and hypothyroidism is unknown. We used Mendelian randomization (MR) methods to determine the causal relationship between UC and hypothyroidism., Methods: We obtained single nucleotide polymorphisms (SNPs) related to ulcerative colitis (UC) and hypothyroidism from genome-wide association studies (GWAS) available in the public database of the Integrated Epidemiology Unit (IEU). To assess the causal relationship between UC and hypothyroidism, we employed MR-Egger, weighted median, inverse variance weighted (IVW), simple mode, and weighted mode methods. Sensitivity analyses were performed using Cochran's Q test, the horizontal pleiotropy test, and the leave-one-out (LOO) method to assess the reliability of the MR data. The genes corresponding to instrumental variables (IVs) were subjected to Gene Ontology (GO) functional annotation, Kyoto Encyclopedia of the Genome (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) analysis to explore the mechanisms behind the causal relationships at the gene level., Results: Forward MR analysis indicated that hypothyroidism was associated with an increased risk of UC (IVW: P = 0.02, OR = 9.71, 95% confidence interval (CI) = 1.36-69.46). In contrast, reverse MR did not demonstrate a causal relationship between UC and hypothyroidism (IVW: P = 0.53). Sensitivity analysis proved the reliability of the results. The PPI network revealed CD247, CD80, and STAT4 as central genes. GO and KEGG analyses revealed significant enrichment of the T cell, gamma interferon (IFN-γ), and programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathways., Conclusion: Hypothyroidism was a risk factor for UC. The balance of T-cell differentiation played an important role in the process of hypothyroidism-induced UC, and IL-21 might be the key to finding a cure. Enrichment of PD-1/PD-L1 might attenuate inflammation by suppressing the immune action of T cells., (© 2024. The Author(s).)

Knee osteoarthritis (KOA) is an important cause of disability in the world and it denotes a public health defiance of the upcoming years.Aim To examine the connection between ADAMTS14 gene rs4747096 polymorphism and KOA and to assess risk factors associated with KOA.Methods A case control study was conducted on 158 patients with KOA and 120 controls with comparable age and sex randomly recruited from National Research Centre employees. All participants were subjected to full history taking, assessment of KOA severity using WOMAC scoring system, and thorough clinical examination. Blood sample was collected for detection of ADAMTS14/rs4747096 gene polymorphism.Results The frequency of ADAMTS14 gene rs4747096 genotypes among patients with KOA was 73.5% for AA, 25.7% for AG, and 0.7% for GG compared to controls 963%, 31.3%, and 5.6% respectively and the frequency of alleles among patients was 86.4% for A and 78.7% for G compared to controls (78.7% and 21.3% respectively, P < 0.05. The study found that the median levels of total WOMAC score and its domains were significantly higher among KOA patients than controls. The logistic regression analysis revealed that age ≥ 50 years, BMI ≥ 35, and long standing at work were predictive factors for KOA (P < 0.05). Regarding different genetic patterns, only the A recessive pattern of inheritance was found to be a predictive risk factor for KOA.Conclusion For ADAMTS14 rs4747096 genotype, the AA and AG genotypes significantly increased the risk of KOA. The recessive pattern of inheritance, older age, morbid obesity, and prolonged standing at work were the predictive risk factors for KOA. Further studies with larger sample size are encouraged to investigate the mechanism by which this genotype can affect the development of KOA., (© 2024. The Author(s).)

Background: Inflammatory bowel disease (IBD) is occasionally associated with ophthalmic diseases, including iridocyclitis (IC). The co-occurrence of IBD and IC has been increasingly observed, possibly due to shared genetic structures., Methods: A three-part analysis was executed utilizing genome-wide association study (GWAS) data on IBD and IC. First, the overall genetic correlation between the two traits was observed using linkage disequilibrium score regression (LDSC). Subsequent to this, a local genetic correlation analysis was conducted utilizing the heritability estimation from summary statistics (HESS) methodology. Finally, the conditional/conjunctional false discovery rate (cond/conjFDR) statistical framework was utilized to ascertain the degree of genetic overlap between the two traits., Results: Positive overall correlations were observed among IBD, ulcerative colitis (UC), and IC, encompassing both acute/subacute and chronic IC presentations. While a significant correlation was identified between Crohn's disease (CD) and IC, it was not evident for acute/subacute or chronic IC (P > 0.05). Notably, IBD (encompassing CD and UC) demonstrated local genetic correlations with IC and acute/subacute IC, with pronounced enrichment notably on chromosomes 1 and 6, though such correlations were not observed with chronic IC. The conjFDR analysis confirmed the genetic overlap between the two diseases. The shared genes overlapping between IBD (encompassing CD and UC) and IC were IL23R, GPR35, and ERAP1. For acute/subacute IC and chronic IC, there were six overlapping genes (GPR35, RPL23AP12, IL23R, SNAPC4, ERAP1, and INAVA) and one overlapping gene (INAVA), respectively., Conclusion: This study confirms the existence of a shared genetic structure between IBD and IC, providing a biological basis for their comorbidity. Additionally, this finding has significant implications for preventing and treating these two diseases., (© 2024. The Author(s).)

Background: FLNC gene variants have predominantly been reported in adult populations with cardiomyopathies, and early-onset cases are less common. The genotype-phenotype relationship indicates that dilated cardiomyopathy (DCM) is often associated with FLNC truncating variants., Methods: We conducted a comprehensive genetic analysis using next generation sequencing (NGS) to identify FLNC variants in patients with cardiovascular conditions. Detailed phenotypic and variant analyses were performed to characterize the clinical features and genetic alterations. Minigene assays and structural modeling were used to investigate the pathogenicity caused by the identified variants., Results: In a cohort of 58 patients, novel heterozygous FLNC variants, c.3962A > T (p.Glu1321Val) and c.7543C > T (p.Leu2515Phe), were identified in patients presenting with dilated and mixed restrictive/hypertrophic cardiomyopathies, respectively. The c.3962A > T variant disrupted normal splicing, as demonstrated through the splicing prediction tool and minigene studies, further emphasizing its pathogenic potential., Conclusion: For missense variants of FLNC in patients with DCM, the splicing effect of the variant should be carefully checked. Early detection and intervention are crucial given the high risk of sudden cardiac death and severe cardiac complications., (© 2024. The Author(s).)

Background: Cardiomyopathies are clinically important conditions, with a strong genetic component. National genomic initiatives such as 100,000 Genome Project (100KGP) provide opportunity to study these rare conditions at scale beyond conventional research studies., Methods: We present the clinical and molecular characteristics of the 100KGP cohort, comparing paediatric and adult probands with diverse cardiomyopathies. We assessed the diagnostic yield and spectrum of genetic aetiologies across clinical presentations. We re-analysed existing genomic data using an updated analytical strategy (revised gene panels; unbiased analyses of de novo variants; and improved variant prioritisation strategies) to identify new causative variants in genetically unsolved children., Results: We identified 1918 individuals (1563 probands, 355 relatives) with cardiomyopathy (CM) in 100KGP. Probands, comprising 273 children and 1290 adults, were enrolled under > 55 different recruitment categories. Paediatric probands had higher rates of co-existing congenital heart disease (12%) compared to adults (0.9%). Diagnostic yield following 100KGP's initial analysis was significantly higher for children (19%) than for adults (11%) with 11% of diagnoses overall made in genes not on the existing UK paediatric or syndromic CM panel. Our re-analysis of paediatric probands yields a potential diagnosis in 40%, identifying new probable or possible diagnoses in 49 previously unsolved paediatric cases. Structural and intronic variants accounted for 11% of all potential diagnoses in children while de novo variants were identified in 17%., Conclusions: 100KGP demonstrates the benefit of genome sequencing over a standalone panel in CM. Re-analysis of paediatric CM probands allowed a significant uplift in diagnostic yield, emphasising the importance of iterative re-evaluation in genomic studies. Despite these efforts, many children with CM remain without a genetic diagnosis, highlighting the need for better gene-disease relationship curation and ongoing data sharing. The 100KGP CM cohort is likely to be useful for further gene discovery, but heterogeneous ascertainment and key technical limitations must be understood and addressed., (© 2024. The Author(s).)

Background: Although previous observational studies have shown an association between venous thromboembolism (VTE) and atrial fibrillation (AF), the underlying causal relationship between them remains uncertain., Methods and Results: This two-sample bidirectional Mendelian randomization (MR) analysis was performed to investigate the causal relationship between VTE and AF. The VTE dataset were obtained from FinnGen, including 9,176 cases and 209,616 controls. Meanwhile a genome-wide association study (GWAS) of 60,620 individuals with AF and 970,216 control subjects identified genetic variations associated with AF. The principal MR analytic approach used in this study is the inverse-variance weighting (IVW) method. Furthermore, we performed complementary MR analyses, including the MR-Egger, Weighted median (WM), and Weighted Mode. MR pleiotropy residual sum was applied to identify pleiotropy. The MR analysis showed suggestive causal associations between VTE and the risk of AF (p = 0.0245, OR [95%CI]: 1.027 [1.003, 1.051]). The reverse MR analysis found that genetic susceptibility to AF was not significantly associated with VTE, as determined by the IVW method (p = 0.7773). The robustness of these findings was corroborated through MR sensitivity analyses., Conclusions: There is a unidirectional causal relationship between VTE and AF, meaning that VTE is a causal risk factor for AF, whereas no effect of AF on VTE was identified., (© 2024. The Author(s).)

Objective: Cytochrome P450 2C19 (CYP2C19) plays an vital role in the course of cardiovascular and cerebrovascular diseases by affecting lipid metabolism. Triglyceride-glucose (TyG) is a comprehensive index composed of triglyceride and blood glucose, has relationship with some diseases. There was no research report on the association CYP2C19 polymorphisms, TyG with premature cerebral infarction (CI) (onset ≤ 65 years old) susceptibility., Methods: This study retrospectively analyzed 1953 CI patients aged ≤ 65 years old from December 2018 to March 2024, and 1919 age-matched individuals with non-CI as controls. The relationship between CYP2C19 polymorphisms, TyG and premature CI risk were analyzed., Results: The proportion of hypertension, and diabetes mellitus in patients with premature CI was higher than those in controls. The serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein-cholesterol (LDL-C), and TyG levels in patients with premature CI were significantly higher than those in controls (all p < 0.05). The patients had lower CYP2C19 *1 allele frequency (63.3% vs. 69.6%, p < 0.001) and higher CYP2C19 *2 allele frequency (31.3% vs. 25.4%, p < 0.001) than controls. Logistic regression analysis showed that smoking history (odds ratio (OR): 1.193, 95% confidence interval (CI): 1.002-1.422, p = 0.048), hypertension (OR: 3.371, 95% CI: 2.914-3.898, p < 0.001), diabetes mellitus (OR: 1.911, 95% CI: 1.632-2.237, p < 0.001), CYP2C19 intermediate metabolizer (IM) + poor metabolizer (PM) phenotypes (OR: 1.424, 95% CI: 1.243-1.631, p < 0.001), and dyslipidemia (OR: 1.294, 95% CI: 1.077-1.554, p = 0.006) were independent risk factors for premature CI., Conclusions: History of smoking, hypertension, diabetes mellitus, dyslipidemia, and CYP2C19 IM + PM phenotypes were independently associated with premature CI susceptibility., (© 2024. The Author(s).)

Background: Interpreting genetic variants remains a challenge in prostate cancer (PCa). Although many annotation tools are available for prioritizing causal variants, the clinical relevance of these variants is rarely studied., Methods: We collected a cohort study that included 274 PCa patients from June 2017 to December 2020 and sequenced 19 DNA damage repair (DDR) genes in these patients and explored the clinical consequence of these different approaches. We also examined all-cause and PCa-specific survival in DDR gene mutation carriers compared to non-carriers after androgen receptor (AR)-directed therapy., Results: We identified 13 variants from 19 DDR genes in a total of 14 (5.1%) patients who had at least one presumed pathogenic mutation using different annotation methods. Four variants were annotated as pathogenic, 11 variants were predicted as protein-truncating variants (PTVs), four variants received proxy-deleterious (Combined Annotation-Dependent Depletion scores of > 30), and only one variant was identified as a pathogenic variant or as having a functional effect by all three methods. PCa patients with PTVs were significantly associated with early onset, high cancer stage, and a worse response to AR-directed treatment. However, patients carrying a proxy-deleterious variant were only associated with a higher T (tumor) stage and N (node) stage than those without such a variant, but not associated with other clinical characteristics. In patients treated with AR-directed therapy, patients with a PTV showed an increased risk of all-cause death (adjusted hazard ratio (aHR) = 3.51, 95% confidence interval (CI): 1.06 ~ 11.56) and PCa-specific death (aHR = 4.49, 95% CI: 1.87 ~ 10.77) compared to non-PTV carriers after adjustment. We were unable to examine gene-specific risks due to the small number of patients., Conclusions: PTVs may assist in guiding treatment and early screening in PCa, while population-specific data for pathogenic variants are still being amassed., (© 2024. The Author(s).)

Background: There is evidence that inflammatory arthritis in the form of ankylosing spondylitis (AS), psoriatic arthritis (PsA), and rheumatoid arthritis are both positively and negatively associated with certain female-specific cancers. However, the study results are very heterogeneous., Methods: Based on up to 375,814 European women, we performed an iterative two-sample Mendelian randomization to assess causal effects of the occurrence of the inflammatory arthritis on the risk of female-specific cancer in form of breast, endometrial, and ovarian cancer sites as well as their subtypes. Evidence was strengthened by using similar exposures for plausibility or by replication with a subsequent meta-analysis. P-values were Bonferroni adjusted., Results: Genetic liability to AS was associated with ovarian cancer (OR = 1.03; 95% CI: [1.01; 1.04]; [Formula: see text]=0.029) and liability to PsA with breast cancer (OR = 1.02; CI: [1.01; 1.04]; [Formula: see text]=0.002). Subgroup analyses revealed that the high-grade serous ovarian cancer (OR = 1.04; CI: [1.02; 1.06]; [Formula: see text]=0.015) and the ER- breast cancer (OR = 1.04; CI: [1.01; 1.07]; [Formula: see text]=0.118) appeared to drive the observed associations, respectively. No further associations were found between the remaining inflammatory arthritis phenotypes and female-specific cancers., Conclusions: This study suggests that AS is a risk factor for ovarian cancer, while PsA is linked to an increased breast cancer risk. These results are important for physicians caring women with inflammatory arthritis to advise their patients on cancer screening and preventive measures., (© 2024. The Author(s).)

Background: Understanding genetic-metabolite associations has translational implications for informing cardiovascular risk assessment. Interrogating functional genetic variants enhances our understanding of disease pathogenesis and the development and optimization of targeted interventions., Methods: In this study, a total of 187 plasma metabolite levels were profiled in 4974 individuals of European ancestry of the GCAT| Genomes for Life cohort. Results of genetic analyses were meta-analysed with additional datasets, resulting in up to approximately 40,000 European individuals. Results of meta-analyses were integrated with reference gene expression panels from 58 tissues and cell types to identify predicted gene expression associated with metabolite levels. This approach was also performed for cardiovascular outcomes in three independent large European studies (N = 700,000) to identify predicted gene expression additionally associated with cardiovascular risk. Finally, genetically informed mediation analysis was performed to infer causal mediation in the relationship between gene expression, metabolite levels and cardiovascular risk., Results: A total of 44 genetic loci were associated with 124 metabolites. Lead genetic variants included 11 non-synonymous variants. Predicted expression of 53 fine-mapped genes was associated with 108 metabolite levels; while predicted expression of 6 of these genes was also associated with cardiovascular outcomes, highlighting a new role for regulatory gene HCG27. Additionally, we found that atherogenic metabolite levels mediate the associations between gene expression and cardiovascular risk. Some of these genes showed stronger associations in immune tissues, providing further evidence of the role of immune cells in increasing cardiovascular risk., Conclusions: These findings propose new gene targets that could be potential candidates for drug development aimed at lowering the risk of cardiovascular events through the modulation of blood atherogenic metabolite levels., (© 2024. The Author(s).)

The abundance of Lp(a) protein holds significant implications for the risk of cardiovascular disease (CVD), which is directly impacted by the copy number (CN) of KIV-2, a 5.5 kbp sub-region. KIV-2 is highly polymorphic in the population and accurate analysis is challenging. In this study, we present the DRAGEN KIV-2 CN caller, which utilizes short reads. Data across 166 WGS show that the caller has high accuracy, compared to optical mapping and can further phase approximately 50% of the samples. We compared KIV-2 CN numbers to 24 previously postulated KIV-2 relevant SNVs, revealing that many are ineffective predictors of KIV-2 copy number. Population studies, including USA-based cohorts, showed distinct KIV-2 CN, distributions for European-, African-, and Hispanic-American populations and further underscored the limitations of SNV predictors. We demonstrate that the CN estimates correlate significantly with the available Lp(a) protein levels and that phasing is highly important., (© 2024. The Author(s).)

Background: Coffee and tea consumption account for most caffeine intake and 2-3 billion cups are taken daily around the world. Caffeine dependence is a widespread but under recognized problem., Objectives: To conduct a systematic review on the genetic susceptibility factors affecting caffeine metabolism and caffeine reward and their association with caffeine intake., Methodology: We conducted PubMed and Embase searches using the terms "caffeine", "reward", "gene", "polymorphism", "addiction", "dependence" and "habit" from inception till 2024. The demographics, genetic and clinical data from included studies were extracted and analyzed. Only case-control studies on habitual caffeine drinkers with at least 100 in each arm were included., Results: A total of 2552 studies were screened and 26 studies involving 1,851,428 individuals were included. Several genes that were involved with caffeine metabolism such as CYP1A2, ADORA2A, AHR, POR, ABCG2, CYP2A6, PDSS2 and HECTD4 rs2074356 (A allele specific to East Asians and monomorphic in Europeans, Africans and Americans) were associated with habitual caffeine consumption with effect size difference of 3% to 32% in number of cups of caffeinated drink per day per effect allele. In addition, ALDH2 was linked to the Japanese population. Genes associated with caffeine reward included BDNF, SLC6A4, GCKR, MLXIPL and dopaminergic genes such as DRD2 and DAT1 which had around 2-5% effect size difference in number of cups of caffeinated drink for each allele per day., Conclusion: Several genes that were involved in caffeine metabolism and reward were associated with up to 30% effect size difference in number of cups of caffeinated drink per day, and some associations were specific to certain ethnicities. Identification of at-risk caffeine dependence individuals can lead to early diagnosis and stratification of at-risk vulnerable individuals such as pregnant women and children, and can potentially lead to development of drug targets for dependence to caffeine., (© 2024. The Author(s).)

Background: Loneliness has garnered significant attention globally, with extensive exploration of its association with cardiovascular disease. However, a notable research gap persists concerning loneliness and its potential link to atrial fibrillation (AF)., Methods: This prospective cohort study utilized data from the UK Biobank (UKB), encompassing 441,056 participants. Loneliness was assessed through self-reported questionnaires gauging feelings of isolation and willingness to confide. AF diagnoses were ascertained using hospitalization records and cause-of-death registry data. The association between loneliness and AF risk was analyzed through multivariable Cox proportional hazard models., Results: Over a median follow-up period of 13.9 years, 25,386 AF cases were identified. In comparison to individuals without reported loneliness, those in the loneliness group exhibited a significantly higher risk of AF (loneliness vs. non-loneliness: hazard ratio [HR]: 1.11, 95% confidence interval [CI] 1.07-1.16). Subgroup analysis revealed that the association between loneliness and increased AF risk was significant solely in individuals without heart valve disease (HR: 1.12, 95% CI 1.07-1.16). Additionally, significant associations between loneliness and heightened AF risk were noted across strata of genetic susceptibility to AF, with no observable impact on these associations by genetic susceptibility (P for interaction = 0.070)., Conclusions: This study establishes a robust association between loneliness and an elevated long-term risk of AF. Notably, this association is particularly pronounced in individuals without valvular disease and does not appear to be influenced by genetic predisposition to AF., (© 2024. The Author(s).)

Periodontitis is a highly prevalent inflammatory illness that leads to the destruction of tooth supporting tissue structures and has been associated with an increased risk of cardiovascular disease (CVD). Precision medicine, an emerging branch of medical treatment, aims can further improve current traditional treatment by personalizing care based on one's environment, genetic makeup, and lifestyle. Genomic databases have paved the way for precision medicine by elucidating the pathophysiology of complex, heritable diseases. Therefore, the investigation of novel periodontitis-linked genes associated with CVD will enhance our understanding of their linkage and related biochemical pathways for targeted therapies. In this article, we highlight possible mechanisms of actions connecting PD and CVD. Furthermore, we delve deeper into certain heritable inflammatory-associated pathways linking the two. The goal is to gather, compare, and assess high-quality scientific literature alongside genomic datasets that seek to establish a link between periodontitis and CVD. The scope is focused on the most up to date and authentic literature published within the last 10 years, indexed and available from PubMed Central, that analyzes periodontitis-associated genes linked to CVD. Based on the comparative analysis criteria, fifty-one genes associated with both periodontitis and CVD were identified and reported. The prevalence of genes associated with both CVD and periodontitis warrants investigation to assess the validity of a potential linkage between the pathophysiology of both diseases., (© 2024. The Author(s).)

Background and Objective: The aim of this study was to investigate potential hub genes for dilated cardiomyopathy (DCM)., Methods: Five DCM-related microarray datasets were downloaded from the Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were used for identification. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, disease ontology, gene ontology annotation and protein-protein interaction (PPI) network analysis were then performed, while a random forest was constructed to explore central genes. Artificial neural networks were used to compare with known genes and to develop new diagnostic models. 240 population blood samples were collected and expression of hub genes was verified in these samples using RT-PCR and demonstrated by Nomogram., Results: After differential analysis, 33 genes were statistically significant (adjusted P < 0.05). Functional enrichment of these differential genes resulted in 85 Gene Ontology (GO) functions identified and 6 pathways enriched for the KEGG pathway. PPI networks and molecular complex assays identified 10 hub genes (adjusted P < 0.05). Random forest identified SMOC2 and SFRP4 as the most important, followed by FCER1G and FRZB. NeuraHF models (SMOC2, SFRP4, FCER1G and FRZB) were selected by artificial neural network model and had better diagnostic efficacy for the onset of DCM, compared with the traditional KG-DCM models (MYH7, ACTC1, TTN and LMNA). Finally, SFRP4 and FRZB were expressed higher in DCM verified by RT-PCR and as a factor for DCM identified by Nomogram., Conclusions: We performed an integrated analysis and identified SFRP4 and FRZB as a new factor for DCM. But the exact mechanism still needs further experimental verification., (© 2024. The Author(s).)

Background: Chronic Kidney Disease (CKD) impacts over 10% of the global population, and recent advancements in high-throughput analytical technologies are uncovering the complex physiology underlying this condition. By integrating Genome-Wide Association Studies (GWAS), RNA sequencing (RNA-seq/RNA array), and single-cell RNA sequencing (scRNA-seq) data, our study aimed to explore the genes and cell types relevant to CKD traits., Methods: GWAS summary data for end-stage renal failure (ESRD) and decreased eGFR (CKD) with or without diabetes and (micro)proteinuria were obtained from the GWAS Catalog and the UK Biobank (UKB) database. Two gene Expression Omnibus (GEO) transcriptome datasets were used to establish glomerular and tubular gene expression differences between CKD patients and healthy individuals. Two scRNA-seq datasets were utilized to obtain the expression of key genes at the single-cell level. The expression profile, differentially expressed genes (DEGs), gene-gene interaction, and pathway enrichment were analysed for these CKD risk genes., Results: A total of 779 distinct SNPs were identified from GWAS across different CKD traits, involving 681 genes. While many of these risk genes are specific to the CKD traits of renal failure, decreased eGFR, and (micro)proteinuria, they share common pathways, including extracellular matrix (ECM). ECM modeling was enriched in upregulated glomerular and tubular DEGs from CKD kidneys compared to healthy controls, with the expression of relevant collagen genes, such as COL1A2, prevalent in fibroblasts/myofibroblasts. Additionally, immune responses, including T cell differentiation, were dysregulated in CKD kidneys. The late podocyte signature gene THSD7A was enriched in podocytes but downregulated in CKD. We also highlighted that the regulated risk genes of CKD are mainly expressed in tubular cells and immune cells in the kidney., Conclusions: Our integrated analysis highlight the genes, pathways, and relevant cell types associational with the pathogenesis of kidney traits, as a basis for further mechanistic studies to understand the pathogenesis of CKD., (© 2024. The Author(s).)

Background: Several studies pointed out the importance of genetic risk factors such as parental consanguinity (PC) and familial multiple sclerosis (FMS) in the risk of MS. This study aimed to investigate the PC and FMS among people with MS (pwMS) in Isfahan, Iran., Methods: This case-control study was conducted on pwMS from the MS clinic of Kashani Hospital, Isfahan, Iran, in October 2023. A group of healthy controls (HC) were also recruited. Data on demographic and clinical characteristics and history of PC and FMS were collected from participants. The relationships between PC, FMS, and developing MS were assessed using multinomial logistic regression analysis. The odds ratio (OR) with a 95% confidence interval (CI) was computed., Results: A total number of 4264 pwMS and 400 HCs were included. The prevalence of PC and FMS among pwMS were 29.3% and 24%, respectively. Multinomial logistic regression adjusted for age and sex indicated that the odds of developing MS were significantly associated with a history of PC (OR = 3.03, 95% CI 2.23 to 4.13, p < 0.001) and FMS (OR = 5.42, 95% CI 3.51 to 8.38, p < 0.001)., Conclusion: PC and FMS can increase the risk of developing MS. They should be considered along with other risk factors for developing MS. A comprehensive conclusion requires further research., (© 2024. The Author(s).)

Objective: Early identification of modifiable risk factors is crucial for the prevention of constipation. This study systematically investigated the relationship between genetically predicted modifiable risk factors and constipation., Methods: The inverse variance weighting (IVW) method was employed as the primary analytical approach. For similar exposure indicators, the multivariate Mendelian randomization (MVMR) method was used to adjust for potential biases in univariate MR analysis. The robustness of the results was further evaluated using the MR-Egger intercept test, Cochran's Q test, and leave-one-out analysis. Bonferroni correction was applied to reduce the false positive rate in the results., Results: The IVW analysis indicated a significant causal association between genetically predicted gastroesophageal reflux disease [OR (95% CI) = 1.192 (1.079-1.315), P = 0.0005], atorvastatin use [OR (95% CI) = 16.995 (3.327-86.816), P = 0.0007], and constipation. Additionally, there was a potential causal association between education level [OR (95% CI) = 0.859 (0.767-0.964), P = 0.009], major depressive disorder [OR (95% CI) = 1.206 (1.041-1.399), P = 0.013], hypothyroidism [OR (95% CI) = 2.299 (1.327-3.985), P = 0.003], and aspirin use [OR (95% CI) = 4.872 (1.174-20.221), P = 0.029] with constipation. No causal associations were found for the other included indicators. Sensitivity analysis demonstrated the absence of evidence for heterogeneity and pleiotropy in any positive results., Conclusion: This study identified several risk factors that could be targeted for the prevention of constipation, offering valuable insights for public health policies., (© 2024. The Author(s).)

Schizophrenia is a severe psychiatric disorder with high heritability, characterized by positive and negative symptoms as well as cognitive abnormalities. Dysfunction in glutamate synapse is strongly implicated in the pathophysiology of schizophrenia. However, the precise role of the perturbed glutamatergic system in contributing to the cognitive abnormalities of schizophrenia at the synaptic level remains largely unknown. Although our previous work found that Opcml promotes spine maturation and Opcml-deficient mice exhibit schizophrenia-related cognitive impairments, the synaptic mechanism remains unclear. By using whole-cell patch clamp recording, we found that decreased neuronal excitability and alterations in intrinsic membrane properties of CA1 PNs in Opcml-deficient mice. Furthermore, Opcml deficiency leads to impaired glutamatergic transmission in hippocampus, which is closely related to postsynaptic AMPA/NMDA receptors dysfunction, resulting in the disturbances of E/I balance. Additionally, we found that the aripiprazole which we used to ameliorate abnormal cognitive behaviors also rescued the impaired glutamatergic transmission in Opcml-deficient mice. These findings will help to understand the synaptic mechanism in schizophrenia pathogenesis, providing insights into schizophrenia therapeutics with glutamatergic disruption., (© 2024. The Author(s).)

Objective: This study aims to identify m6A methylation-related and immune cell-related key genes with diagnostic potential for heart failure (HF) by leveraging various bioinformatics techniques., Methods: The GSE116250 and GSE141910 datasets were sourced from the Gene Expression Omnibus (GEO) database. Correlation analysis was conducted between differentially expressed genes (DEGs) in HF and control groups, alongside differential m6A regulatory factors, to identify m6A-related DEGs (m6A-DEGs). Subsequently, candidate genes were narrowed down by intersecting key module genes derived from weighted gene co-expression network analysis (WGCNA) with m6A-DEGs. Key genes were then identified through the Least Absolute Shrinkage and Selection Operator (LASSO) analysis. Correlation analyses between key genes and differentially expressed immune cells were performed, followed by the validation of key gene expression levels in public datasets. To ensure clinical applicability, five pairs of blood samples were collected for quantitative real-time fluorescence PCR (qRT-PCR) validation., Results: A total of 93 m6A-DEGs were identified (|COR| > 0.6, P < 0.05), and five key genes (LACTB2, NAMPT, SCAMP5, HBA1, and PRKAR2A) were selected for further analysis. Correlation analysis revealed that differential immune cells were negatively associated with the expression of LACTB2, NAMPT, and PRKAR2A (P < 0.05), while positively correlated with SCAMP5 and HBA1 (P < 0.05). Subsequent expression validation confirmed significant differences in key gene expression between the HF and control groups, with consistent expression trends observed across both training and validation sets. The expression trends of LACTB2, PRKAR2A, and HBA1 in blood samples from the qRT-PCR assay aligned with the results derived from public databases., Conclusion: This study successfully identified five m6A methylation-related key genes with diagnostic significance, providing a theoretical foundation for further exploration of m6A methylation's molecular mechanisms in HF., (© 2024. The Author(s).)

Background: By the end of December 2019, a new coronavirus, termed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged, and the cause of the disease was named coronavirus disease 2019 (COVID-19). Several genetic factors have been implicated in diverse responses to SARS-CoV-2 infection, such as the C-X-C chemokine receptor 4 (CXCR4) rs2228014 polymorphism, which has been previously studied in various diseases but has not been explored in the context of COVID-19 severity. The current study aimed to assess the association between the rs2228014 polymorphism in the CXCR4 gene and the severity of COVID-19, which has not been previously reported., Method: This cross-sectional study analyzed 300 adult Egyptian COVID-19 patients (156 with mild or moderate and 144 with severe or critical symptoms) admitted to Assiut University Quarantine Hospital from June to September 2022 during the omicron variant. The rs2228014 polymorphism in the CXCR4 gene was detected using real-time PCR with a TaqMan assay probe. Receiver operating characteristic (ROC) curve analysis was used to determine the best cutoff values for C-reactive protein (CRP) that can be used to estimate the severity of COVID-19. P values less than 0.05 were considered to indicate statistical significance., Results: No significant differences in the allelic or genotypic frequencies of CXCR4 rs2228014 were detected between the severity groups. However, the exclusive presence of the AA genotype in mild or moderate cases suggests its potential protective role. Additionally, significant differences in myalgia presentation, leukocyte counts and antibiotic use, were observed among different genotypes. Statistical data showed that the severity of COVID-19 could be predicted at a cutoff value of CRP > 30 mg/L, with a sensitivity of 74.3% and a specificity of 42.9%., Conclusion: The present findings suggest a potential protective role of the AA genotype and A allele of CXCR4 rs2228014 against severe COVID-19. Additionally, factors such as lack of vaccination and comorbidities such as hypertension, renal disease, and diabetes mellitus were associated with increased disease severity., (© 2024. The Author(s).)

Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by atypical patterns of social functioning and repetitive/restricted behaviors. ASD commonly co-occurs with ADHD and, despite their clinical distinctiveness, the two share considerable genetic overlap. Given their shared genetic liability, it is unclear which genetic pathways increase the likelihood of ASD independently of ADHD., Methods: We applied Genomic Structural Equation Modeling (SEM) to GWAS summary statistics for ASD and childhood-diagnosed ADHD, decomposing the genetic variance for ASD into that which is unique to ASD (uASD) and that which is shared with ADHD. We computed genetic correlations between uASD and 83 external traits to estimate genetic overlap between uASD and other clinically relevant phenotypes. We went on to apply Stratified Genomic SEM to identify classes of genes enriched for uASD. Finally, we implemented Transcriptome-Wide SEM (T-SEM) to explore patterns of gene-expression associated with uASD., Results: We observed positive genetic correlations between uASD and several external traits, most notably those relating to cognitive/educational outcomes and internalizing psychiatric traits. Stratified Genomic SEM showed that heritability for uASD was significantly enriched in genes involved in evolutionarily conserved processes, as well as for a histone mark in the germinal matrix. T-SEM revealed 83 unique genes with expression associated with uASD, 34 of which were novel with respect to univariate analyses. These genes were overrepresented in skin-related pathologies., Limitations: Our study was limited by summary statistics derived exclusively from individuals of European ancestry. Additionally, using data based on a general ASD diagnosis limits our ability to understand genetic factors contributing to the pronounced clinical heterogeneity in ASD., Conclusions: Our findings delineate the unique genetic underpinnings of ASD that are independent of ADHD at the genome-wide, functional, and gene expression level of analysis. In addition, we identify novel associations previously masked by their diametric effects on ADHD. Collectively, these results provide insight into the processes that make ASD biologically unique., (© 2024. The Author(s).)

Background: Severe coronary artery disease (CAD) represents an advanced arterial narrowing, often associated with critical complications like myocardial infarction and angina. This study aimed to comprehensively investigate determinants of severe and multi-vessel CAD manifestations., Methods: One thousand nine hundred patients with severe and multivessel CAD (stenosis > 70%) were recruited along with 1,056 controls without stenosis. Associations using a genotyping panel comprising 159 Single Nucleotide Polymorphisms (SNPs) previously implicated in CAD pathogenesis were examined and these associations were replicated using the UK Biobank cohort (N = 29,970)., Results: The investigation identified 14 genetic associations with severe CAD, of which 7 were also associated with multivessel disease. Notably, PHACTR1 SNP (rs9349379*G) showed a higher association with severe and multivessel CAD in individuals aged ≤ 65, indicating a higher risk of early disease onset. Conversely, the APOC1/APOE SNP (rs445925*T) is associated with reduced susceptibility to severe CAD and multivessel disease in individuals aged over 65, indicating a persistent negative association., Conclusions: Following replication of the associations in the large UK Biobank dataset, it was found that patients carrying the rs9349379*G variant in the PHACTR1 gene are at risk of developing severe or multivessel disease. Conversely, the rs445925*T variant in APOC1/APOE is associated with reduced susceptibility to severe CAD and multivessel disease, highlighting the significance of this genetic variant in these specific CAD presentations. This study contributes to a better understanding of CAD heterogeneity, paving the way for tailored management strategies based on genetic profiles., (© 2024. The Author(s).)

Background: A growing body of evidence supports the comorbidity between depression (DEP) and obesity, yet the genetic mechanisms underlying this association remain unclear. Our study explored the shared genetic architecture and causal associations of DEP with BMI., Methods: We investigated the multigene overlap and genetic correlation between DEP (N > 1.3 million) and BMI (N = 806,834) based on genome-wide association studies (GWAS) and using the bivariate causal mixture model and linkage disequilibrium score regression (LDSC). The causal association was explored by bi-directional Mendelian randomization (MR). Common risk loci were identified through cross-trait meta-analyses. Stratified LDSC and multi-marker gene annotation analyses were applied to investigate single-nucleotide polymorphisms enrichment across tissue types, cell types, and functional categories. Finally, we explored shared functional genes by Summary Data-Based Mendelian Randomization (SMR) and further detected differential expression genes (DEG) in brain tissues of individuals with depression and obesity., Results: We found a positive genetic correlation between DEP and BMI (r g = 0.19, P = 4.07 × 10 -26 ), which was more evident in local genomic regions. Cross-trait meta-analyses identified 16 shared genetic loci, 5 of which were newly identified, and they had influence on both diseases in the same direction. MR analysis showed a bidirectional causal association between DEP and BMI, with comparable effect sizes estimated in both directions. Combined with gene expression information, we found that genetic correlations between DEP and BMI were enriched in 6 brain regions, predominantly in the nucleus accumbens and anterior cingulate cortex. Moreover, 6 specific cell types and 23 functional genes were found to have an impact on both DEP and BMI across the brain regions. Of which, NEGR1 was identified as the most significant functional gene and associated with DEP and BMI at the genome-wide significance level (P < 5 × 10 -8 ). Compared with healthy controls, the expression levels of NEGR1 gene were significant lower in brain tissues of individuals with depression and obesity., Conclusions: Our study reveals shared genetic basis underpinnings between DEP and BMI, including genetic correlations and common genes. These insights offer novel opportunities and avenues for future research into their comorbidities., (© 2024. The Author(s).)

Background: The hippocampus, with its complex subfields, is linked to numerous neuropsychiatric traits. While most research has focused on its global structure or a few specific subfields, a comprehensive analysis of hippocampal substructures and their genetic correlations across a wide range of neuropsychiatric traits remains underexplored. Given the hippocampus's high heritability, considering hippocampal and subfield volumes (HASV) as endophenotypes for neuropsychiatric conditions is essential., Methods: We analyzed MRI-derived volumetric data of hippocampal and subfield structures from 41,525 UK Biobank participants. Genome-wide association studies (GWAS) on 24 HASV traits were conducted, followed by genetic correlation, overlap, and Mendelian randomization (MR) analyses with 10 common neuropsychiatric traits. Polygenic risk scores (PRS) based on HASV traits were also evaluated for predicting these traits., Results: Our analysis identified 352 independent genetic variants surpassing a significance threshold of 2.1 × 10 -9 within the 24 HASV traits, located across 93 chromosomal regions. Notably, the regions 12q14.3, 17q21.31, 12q24.22, 6q21, 9q33.1, 6q25.1, and 2q24.2 were found to influence multiple HASVs. Gene set analysis revealed enrichment of neural differentiation and signaling pathways, as well as protein binding and degradation. Of 240 HASV-neuropsychiatric trait pairs, 75 demonstrated significant genetic correlations (P < 0.05/240), revealing 433 pleiotropic loci. Particularly, genes like ACBD4, ARHGAP27, KANSL1, MAPT, ARL17A, and ARL17B were involved in over 50 HASV-neuropsychiatric pairs. Leveraging Mendelian randomization analysis, we further confirmed that atrophy in the left hippocampus, right hippocampus, right hippocampal body, and right CA1-3 region were associated with an increased risk of developing Parkinson's disease (PD). Furthermore, PRS for all four HASVs were significantly linked to a higher risk of Parkinson's disease (PD), with the highest hazard ratio (HR) of 1.30 (95% CI 1.18-1.43, P = 6.15 × 10⁻⁸) for right hippocampal volume., Conclusions: These findings highlight the extensive distribution of pleiotropic genetic determinants between HASVs and neuropsychiatric traits. Moreover, they suggest a significant potential for effectively managing and intervening in these diseases during their early stages., (© 2024. The Author(s).)

Background: To investigate the association of vitamin D receptor (VDR) gene polymorphism with caries risk in children(< 18 years)., Methods: The electronic databases PubMed, Cochrane, EMBASE, Web of Science, CNKI, Cqvip, and Wanfang were searched for observational studies on the relationship between VDR single nucleotide polymorphism(SNP) and caries, including cohort, case-control, and cross-sectional studies. Quality assessment of selected studies was conducted using the Newcastle Ottawa scale. Odds ratios (OR) with 95% confidence intervals (CI) values for associations of individual VDR SNP with dental caries were calculated based on four genetic models: allelic, recessive, dominant, and over-dominant., Results: Of 79 studies considered, 10 (nine case-control and one cross-sectional) were selected for analysis; the studies involved seven VDR SNPs: ApaI(rs7975232),BsmI(rs1544410),FokI(rs2228570),TaqI(rs731236), TaqI/BglI(rs739837), FokI(rs10735810) and Cdx-2(rs11568820). Alleles C and T of FokI(rs10735810) were significantly differently distributed in the caries and caries-free groups (OR = 1.33, 95% CI: 1.30-2.30, P = 0.03), with CC + CT genotypes at this locus associated with greater risk of developing caries than the TT genotype (OR = 1.87, 95%CI: 1.15-3.04, P = 0.01). Further, TT + CC genotype at TaqI(rs731236) was associated with a 1.33-fold higher risk of caries development than the TC genotype (OR = 1.33, 95%CI: 1.06-1.67, P = 0.02). On subgroup analysis, the association between TaqI(rs731236) and caries risk was affected by dentition type, and ethnicity (permanent dentition: OR = 1.48, 95%CI: 1.07-2.03, P = 0.02; Asian: OR = 1.38, 95%CI: 1.02-1.87, P = 0.03;). Genotype distributions at BsmI(rs1544410), TaqI/BglI(rs739837), FokI(rs2228570), and ApaI(rs7975232) did not differ significantly between the caries and caries-free groups., Conclusions: Caries risk could be associated with TaqI(rs731236) and FokI(rs10735810) genotypes, and TaqI(rs731236) may be a risk factor for permanent teeth caries among Asian people., (© 2024. The Author(s).)

Background: Chronic inflammation is associated with the etiology of various cancers. However, there is a lack of systematic research in urologic cancers. This study aims to use a two-sample Mendelian randomization (MR) approach to evaluate the role of circulating cytokines in the development of urologic cancers., Methods: We obtained the summary-level data for bladder cancer (373,295 cases and 372,016 controls), prostate cancer (462,933 cases and 459,664 controls), and kidney cancer (463,010 cases and 461,896 controls) from the UK Biobank. Genetic variations linked to 41 circulating cytokines were used as instrumental variables (IVs) in meta-analyses of genome-wide association studies (GWASs) involving 8,293 individuals from Finland. We primarily used the inverse-variance weighted (IVW) method to assess the potential associations between the 41 cytokines and the risk of 3 common urologic cancers. Weighted-median method, weighted mode and simple-median method were used to assess the sensitivity. Heterogeneity and pleiotropic outlier were evaluated by Cochran's Q test and MR-Egger regression. Genetic correlation, colocalization analysis and multivariable MR analysis were used to further validate the potential pleiotropy., Results: After the Bonferroni correction, there was an observed association between elevated genetically predicted levels of CCL27 and a heightened risk for bladder cancer. Conversely, IL-12p70 levels were found to have a protective association against the risk of bladder cancer. Sensitivity analyses utilizing various IV sets and MR approach remained robust. Furthermore, we found potential associations of 7 cytokines with urologic cancers (4.07 × 10 -4  ≤ P < 0.05)., Conclusion: Our study supported causal associations between CCL27, IL-12p70 and bladder cancer risk and potential associations of 7 cytokines with the risk of urologic cancers, helping us to further understand the pathogenesis of urologic cancers and providing clues for improving diagnostic accuracy and therapies., (© 2024. The Author(s).)