Genetic Susceptibility Research Articles

Blood and Tissue Levels of Persistent Organic Pollutants and Genetic Susceptibility in Patients with Breast Cancer

We investigated possible associations between the internal concentrations of POPs and correlations between blood and tumor tissue concentrations in patients who underwent surgery for breast cancer and breast reduction as controls. Genetic variations in CYP1A1, GSTP1, GSTM1, and GSTT1 and hOGG1 were evaluated to determine whether they represent risk factors for breast cancer. Certain POPs have been found to be associated with breast cancer development. GST-P1 polymorphism represented a significant risk for breast cancer with unadjusted OR. However, the GSTT1 null polymorphism represented a significant risk for breast cancer when OR adjusted for age and smoking status. CYP1A1 polymorphism was a significant risk factor for breast cancer, regardless of whether the OR was adjusted. These results suggest that exposure to certain POPs, GSTT1 and CYP1A1 polymorphisms, age, and smoking status are risk factors for breast cancer. In addition, the blood concentrations of some POPs represent surrogates for breast tissue concentrations.

Sleep Pattern, Genetic Susceptibility, and Abdominal Aortic Aneurysm in UK Biobank Participants: Large-Scale Cohort Study

BackgroundAbdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality. ObjectivesThe authors aimed to explore the associations between sleep patterns and genetic susceptibility to AAA. MethodsWe included 344,855 UK Biobank study participants free of AAA at baseline. A sleep pattern was defined by chronotype, sleep duration, insomnia, snoring, and daytime sleepiness, and an overall sleep score was constructed with a range from 0 to 5, where a high score denotes a healthy sleep pattern. Polygenic risk score based on 22 single nucleotide polymorphisms was categorized into tertiles and used to evaluate the genetic risk for AAA. Cox proportional hazards regression models were used to assess the association between sleep, genetic factors, and the incidence of AAA. ResultsDuring a median of 12.59 years of follow-up, 1,622 incident AAA cases were identified. The HR per 1-point increase in the sleep score was 0.91 (95% CI: 0.86-0.96) for AAA. Unhealthy sleep patterns, defined as a sleep score ranging from 0 to 3, were found to be associated with a higher risk of AAA for the intermediate (HR: 1.18, 95% CI: 1.06-1.31) and poor sleep patterns (HR: 1.40, 95% CI: 1.13-1.73), respectively, compared to the healthy pattern. Participants with poor sleep patterns and high genetic risks had a 2.5-fold higher risk of AAA than those with healthy sleep patterns and low genetic risk. ConclusionsIn this large prospective study, healthy sleep patterns were associated with a lower risk of AAA among participants with low, intermediate, or high genetic risk.

Tackling Non-Small Cell Lung Cancer in Young Adults: From Risk Factors and Genetic Susceptibility to Lung Cancer Profile and Outcomes.

Lung cancer has traditionally been associated with advanced age; however, its increasing incidence among young adults raises concerning questions regarding its etiology and unique considerations for this population. In contrast to the older population, the onset of lung cancer at younger age may be attributed to a complex interplay of incompletely understood individual susceptibility and prevalent environmental risk factors beyond tobacco smoke exposure, such as radon gas and air pollution, which are widespread globally. Consequently, this leads to distinct clinical and molecular profiles, requiring a tailored approach. Furthermore, a diagnosis of cancer represents a threatening event during the prime years of a young person's life, prompting concern about career development, social aspects, fertility aspirations, and physical independence. This poses significant additional challenges for health care professionals in a field that remains underexplored. This comprehensive review recognizes lung cancer in young adults as a distinct entity, exploring its clinical and molecular characteristics, diverse predisposing factors, and priorities in terms of quality of life, with the aim of providing practical support to oncologists and enhancing our understanding of this under-researched population.

The association between HLA-B variants and amoxicillin-induced severe cutaneous adverse reactions in Chinese han population

BackgroundAmoxicillin (AMX) is among the most prescribed and the best tolerated antimicrobials worldwide. However, it can occasionally trigger severe cutaneous adverse reactions (SCAR) with a significant morbidity and mortality. The genetic factors that may be relevant to AMX-induced SCAR (AMX-SCAR) remain unclear. Identification of the genetic risk factor may prevent patients from the risk of AMX exposure and resume therapy with other falsely implicated drugs.MethodologyFour patients with AMX-SCAR, 1,000 population control and 100 AMX-tolerant individuals were enrolled in this study. Both exome-wide and HLA-based association studies were conducted. Molecular docking analysis was employed to simulate the interactions between AMX and risk HLA proteins.ResultsCompared with AMX-tolerant controls, a significant association of HLA-B*15:01 with AMX-SCAR was validated [odds ratio (OR) = 22.9, 95% confidence interval (CI): 1.68–1275.67; p = 7.34 × 10−3]. Moreover, 75% carriers of HLA-B*15:01 in four patients with AMX-SCAR, and the carrier frequency of 10.7% in 1,000 control individuals and 11.0% in 100 AMX-tolerant controls, respectively. Within HLA-B protein, the S140 present in all cases and demonstrated the strongest association with AMX-SCAR [OR = 53.5, p = 5.18 × 10−4]. Molecular docking results also confirmed the interaction between AMX and S140 of the HLA-B protein, thus eliminating the false-positive results during in association analysis.ConclusionOur findings suggest that genetic susceptibility may be involved in the development of AMX-SCAR in Han Chinese. However, whether the HLA-B variants observed in this study can be used as an effective genetic marker of AMX-induced SCAR still needs to be further explored in larger cohort studies and other ethnic populations.

Relationship between gut microbiota and the pathogenesis of gestational diabetes mellitus: a systematic review

IntroductionGestational diabetes mellitus (GDM) is a form of gestational diabetes mellitus characterized by insulin resistance and abnormal function of pancreatic beta cells. In recent years, genomic association studies have revealed risk and susceptibility genes associated with genetic susceptibility to GDM. However, genetic predisposition cannot explain the rising global incidence of GDM, which may be related to the increased influence of environmental factors, especially the gut microbiome. Studies have shown that gut microbiota is closely related to the occurrence and development of GDM. This paper reviews the relationship between gut microbiota and the pathological mechanism of GDM, in order to better understand the role of gut microbiota in GDM, and to provide a theoretical basis for clinical application of gut microbiota in the treatment of related diseases.MethodsThe current research results on the interaction between GDM and gut microbiota were collected and analyzed through literature review. Keywords such as "GDM", "gut microbiota" and "insulin resistance" were used for literature search, and the methodology, findings and potential impact on the pathophysiology of GDM were systematically evaluated.ResultsIt was found that the composition and diversity of gut microbiota were significantly associated with the occurrence and development of GDM. Specifically, the abundance of certain gut bacteria is associated with an increased risk of GDM, while other changes in the microbiome may be associated with improved insulin sensitivity. In addition, alterations in the gut microbiota may affect blood glucose control through a variety of mechanisms, including the production of short-chain fatty acids, activation of inflammatory pathways, and metabolism of the B vitamin group.DiscussionThe results of this paper highlight the importance of gut microbiota in the pathogenesis of GDM. The regulation of the gut microbiota may provide new directions for the treatment of GDM, including improving insulin sensitivity and blood sugar control through the use of probiotics and prebiotics. However, more research is needed to confirm the generality and exact mechanisms of these findings and to explore potential clinical applications of the gut microbiota in the management of gestational diabetes. In addition, future studies should consider the interaction between environmental and genetic factors and how together they affect the risk of GDM.

An isoform quantitative trait locus in SBNO2 links genetic susceptibility to Crohn’s disease with defective antimicrobial activity

Despite major advances in linking single genetic variants to single causal genes, the significance of genetic variation on transcript-level regulation of expression, transcript-specific functions, and relevance to human disease has been poorly investigated. Strawberry notch homolog 2 (SBNO2) is a candidate gene in a susceptibility locus with different variants associated with Crohn’s disease and bone mineral density. The SBNO2 locus is also differentially methylated in Crohn’s disease but the functional mechanisms are unknown. Here we show that the isoforms of SBNO2 are differentially regulated by lipopolysaccharide and IL-10. We identify Crohn’s disease associated isoform quantitative trait loci that negatively regulate the expression of the noncanonical isoform 2 corresponding with the methylation signals at the isoform 2 promoter in IBD and CD. The two isoforms of SBNO2 drive differential gene networks with isoform 2 dominantly impacting antimicrobial activity in macrophages. Our data highlight the role of isoform quantitative trait loci to understand disease susceptibility and resolve underlying mechanisms of disease.

Alzheimer's disease associated isoforms of human CD33 distinctively modulate microglial cell responses in 5XFAD mice.

Microglia play diverse pathophysiological roles in Alzheimer's disease (AD), with genetic susceptibility factors skewing microglial cell function to influence AD risk. CD33 is an immunomodulatory receptor associated with AD susceptibility through a single nucleotide polymorphism that modulates mRNA splicing, skewing protein expression from a long protein isoform (CD33M) to a short isoform (CD33m). Understanding how human CD33 isoforms differentially impact microglial cell function in vivo has been challenging due to functional divergence of CD33 between mice and humans. We address this challenge by studying transgenic mice expressing either of the human CD33 isoforms crossed with the 5XFAD mouse model of amyloidosis and find that human CD33 isoforms have opposing effects on the response of microglia to amyloid-β (Aβ) deposition. Mice expressing CD33M have increased Aβ levels, more diffuse plaques, fewer disease-associated microglia, and more dystrophic neurites compared to 5XFAD control mice. Conversely, CD33m promotes plaque compaction and microglia-plaque contacts, and minimizes neuritic plaque pathology, highlighting an AD protective role for this isoform. Protective phenotypes driven by CD33m are detected at an earlier timepoint compared to the more aggressive pathology in CD33M mice that appears at a later timepoint, suggesting that CD33m has a more prominent impact on microglia cell function at earlier stages of disease progression. In addition to divergent roles in modulating phagocytosis, scRNAseq and proteomics analyses demonstrate that CD33m+ microglia upregulate nestin, an intermediate filament involved in cell migration, at plaque contact sites. Overall, our work provides new functional insights into how CD33, as a top genetic susceptibility factor for AD, modulates microglial cell function.

Genetic susceptibility to optic neuropathy in patients with alcohol use disorder

BackgroundThe pathophysiology of toxico-nutritional optic neuropathies remains debated, with no clear understanding of the respective roles played by the direct alcohol toxicity, smoking and the often associated vitamin deficiencies, which are risk factors for optic neuropathy. Our aim was to investigate genetic susceptibility in patients with bilateral infraclinical optic neuropathy associated with chronic alcohol use disorder.MethodsThis retrospective cohort study included 102 visually asymptomatic patients with documented alcohol use disorder from a French reference center. Optic neuropathy was identified with optical coherence tomography (OCT), after which genetic susceptibility in the group of affected patients was investigated. Genetic testing was performed using panel sequencing of 87 nuclear genes and complete mitochondrial DNA sequencing.ResultsOptic neuropathy was detected in 36% (37/102) of the included patients. Genetic testing of affected patients disclosed two patients (2/30, 6.7%) with optic neuropathy associated with pathogenic variants affecting the SPG7 gene and five patients (5/30, 16.7%) who harbored variants of uncertain significance close to probable pathogenicity in the genes WFS1, LOXL1, MMP19, NR2F1 and PMPCA. No pathogenic mitochondrial DNA variants were found in this group.ConclusionsOCT can detect presence of asymptomatic optic neuropathy in patients with chronic alcohol use disorder. Furthermore, genetic susceptibility to optic neuropathy in this setting is found in almost a quarter of affected patients. Further studies may clarify the role of preventative measures in patients who might be predisposed to avoidable visual loss and blindness.

Review of the cost-effectiveness of surveillance for hereditary pancreatic cancer.

Individuals with hereditary pancreatic cancer risk include high risk individuals (HRIs) with germline genetic susceptibility to pancreatic cancer (PC) and/or a strong family history of PC. Previously, studies have shown that PC surveillance in HRIs can downstage PC diagnosis and extend survival leading to pancreatic surveillance being recommended for certain HRIs. However, the optimal surveillance strategy remains uncertain, including which modalities should be used for surveillance, how frequently should surveillance be performed, and which sub-groups of HRIs should undergo surveillance. Additionally, in the ideal world PC surveillance should also be cost-effective. Cost-effectiveness analysis is a valuable tool that can consider the costs, potential health benefits, and risks among various PC surveillance strategies. In this review, we summarize the cost-effectiveness of various PC surveillance strategies for HRIs for hereditary pancreatic cancer and provide potential avenues for future work in this field. Additionally, we include cost-effectiveness studies among individuals with new-onset diabetes (NoD), a high-risk group for sporadic PC, as a comparison.

Molecular cascades and cell type-specific signatures in ASD revealed by single-cell genomics.

Genomic profiling in postmortem brain from autistic individuals has consistently revealed convergent molecular changes. What drives these changes and how they relate to genetic susceptibility in this complex condition are not well understood. We performed deep single-nucleus RNA sequencing (snRNA-seq) to examine cell composition and transcriptomics, identifying dysregulation of cell type-specific gene regulatory networks (GRNs) in autism spectrum disorder (ASD), which we corroborated using single-nucleus assay for transposase-accessible chromatin with sequencing (snATAC-seq) and spatial transcriptomics. Transcriptomic changes were primarily cell type specific, involving multiple cell types, most prominently interhemispheric and callosal-projecting neurons, interneurons within superficial laminae, and distinct glial reactive states involving oligodendrocytes, microglia, and astrocytes. Autism-associated GRN drivers and their targets were enriched in rare and common genetic risk variants, connecting autism genetic susceptibility and cellular and circuit alterations in the human brain.

Oral cavity disorders in traditional, ethnic and original people communities

This chapter describes a worrying scenario and the territory of multidisciplinary health work in Brazil, a diverse country: the knowledge on the part of the dentist and the multidisciplinary team about the health of the black population corresponds to a demand in health, since this group has a predisposition to certain diseases, which if diagnosed early, will be possible to contribute to better therapeutic planning, predictability, and a favorable prognosis in certain clinical manifestations. However, such semiological methodological research may also contribute to the investigation and better understanding of oral cavity disorders that occur in members of traditional communities, in addition to displaced people (indigenous and gypsies), in an urban presence in Rio de Janeiro/Brazil. , envisioning better health outcomes for these vulnerable populations. Periodontal disease can be defined as a multifactorial chronic inflammatory process that affects the protective and supporting tissues of the teeth. Several factors related to this process are currently recognized, such as environmental, genetic, socioeconomic, systemic, ethnic factors and individual susceptibility of the host (very well covered technically by Semiology and repertorization). The manifestations of periodontal disease in people of African descent and the possible causal relationships that make them more susceptible (as described for sickle cell anemia) were presented, thus indicating the need for an individualized preventive approach to this population. Habits that are harmful to the health of the oral cavity were also listed. Finally, we emphasize the culminating point that was the meeting in the health space of the 7th ward of the Homeopathy Service of the Hospital Geral Santa Casa da Misericórdia in Rio de Janeiro, when it was possible to talk about the importance of interventions on habits that compromise the style of life and quality of life also contribute to the emergence of oral cavity neoplasms. The path of health promotion via multidisciplinary health education carried out jointly by professionals who are members of Homeopathy institutions in Rio de Janeiro stood out in relevance.

Clinical characteristics and genetic substrate of lone atrial fibrillation: a single center experience

Abstract Background Juvenile-onset lone atrial fibrillation (LAF) may be the initial manifestation of a concealed channelopathy or cardiomyopathy (CMP) or it may be due to an atrial specific genetic susceptibility. Clinical characteristics, genetic background and proper management are still largely unknown. Purpose Aim of the present study is to describe the clinical and genetic characteristics of patients with juvenile-onset LAF. Methods We enrolled patients referred to our center for ablation between 1/2018 and 11/2023 with a first diagnosis of LAF before the age of 60, a structurally normal heart (absence of known CMP, ischemic, valvular, congenital heart disease) and no overt channelopathy. A concealed Brugada syndrome was systematically excluded. Genetic testing was performed using Next Genome Sequencing and a dedicated gene panel. Results 89 patients were included (84% male, LAF onset 43 ± 8 years, BMI 25 ± 7 kg/m2): 32% had a first-degree family history of AF (including 15% below 60 years), 18% of sudden death, 8% of cardiac conduction disorders and 2% of CMP. Cardiovascular risk factors included arterial hypertension in 24%, smoking in 47% and obstructive sleep apnea syndrome in 4%; 20% were competitive athletes. Most patients (89%) presented with paroxysmal AF and 92% were symptomatic (mainly palpitations). At presentation LVEF was 61±5% and LAVI 35±14 ml/m2. Median follow-up time after the first AF episode was 6 years (IQR 4-10). Most patients (81, 91%) underwent at least one transcatheter ablation procedure after failed anti-arrhythmic drug (AAD) therapy (mostly IC). The first procedure (73% radiofrequency, 27% cryoablation) included pulmonary veins isolation (PVI) in all and additional lesions in 5%; the second procedure (n=18, 22% of the ablation group) included PV re-isolation in all (mostly due to multiple vein reconnections) and additional lesions in 17%; the third procedure (n=8, 10% of the ablation group) included PV re-isolation in 25% and additional lesions in 75%. The remaining 8 patients were treated with AAD only (mostly IC). By the last follow-up, 7% of patients in the ablation group and 25% in the AAD group had documented recurrences (even though 50% of those who received ablation were still on AAD). Among the 35 patients subjected to genetic investigation, 10 have available results: 30% tested positive for C4-C5 variants (2 for KCNQ1, 1 for TTN), 50% for C3 variants (RYR2, ABCC9, LMNA, KCNH2 and RMB20) and 20% were negative. Conclusions In the present single center cohort of patients with juvenile-onset LAF, a positive family history was found in almost one third of patients. Despite prompt diagnosis and treatment (including >1 ablation in 20% of patients), recurrences rate is not trivial. The yield of genetic test so far is high, supporting its use in this population.

Sleep patterns, genetic susceptibility, and digestive diseases: A large-scale longitudinal cohort study.

Sleep problems are prevalent. However, the impact of sleep patterns on digestive diseases remains uncertain. Moreover, the interaction between sleep patterns and genetic predisposition with digestive diseases has not been comprehensively explored. 410,586 participants from UK Biobank with complete sleep information were included in the analysis. Sleep patterns were measured by sleep scores as the primary exposure, based on five healthy sleep behaviors. Individual sleep behaviors were secondary exposures. Genetic risk of the digestive diseases was characterized by polygenic risk score. Primary outcome was incidence of 16 digestive diseases. Healthy sleep scores showed dose-response associations with reduced risks of digestive diseases. Compared to participants scoring 0-1, those scoring 5 showed a 28% reduced risk of any digestive disease, including a 50% decrease in irritable bowel syndrome, 37% in non-alcoholic fatty liver disease, 35% in peptic ulcer, 34% in dyspepsia, 32% in gastroesophageal reflux disease, 28% in constipation, 25% in diverticulosis, 24% in severe liver disease, and 18% in gallbladder disease, whereas no correlation was observed with inflammatory bowel disease and pancreatic disease. Participants with poor sleep and high genetic risk exhibited approximately a 60% increase in the risk of digestive diseases. A healthy sleep pattern is linked to lower digestive disease risk in participants of all genetic risk levels. In this large population-based cohort, a healthy sleep pattern was associated with reduced risk of digestive diseases, regardless of the genetic susceptibility. Our findings underscore the potential impact of healthy sleep traits in mitigating the risk of digestive diseases.

Polygenic Risk Score-Based Association Analysis Identifies Genetic Comorbidities Associated with Age-Related Hearing Difficulty in Two Independent Samples.

Age-related hearing loss is the most common form of permanent hearing loss that is associated with various health traits, including Alzheimer's disease, cognitive decline, and depression. The present study aims to identify genetic comorbidities of age-related hearing loss. Past genome-wide association studies identified multiple genomic loci involved in common adult-onset health traits. Polygenic risk scores (PRS) could summarize the polygenic inheritance and quantify the genetic susceptibility of complex traits independent of trait expression. The present study conducted a PRS-based association analysis of age-related hearing difficulty in the UK Biobank sample (N = 425,240), followed by a replication analysis using hearing thresholds (HTs) and distortion-product otoacoustic emissions (DPOAEs) in 242 young adults with self-reported normal hearing. We hypothesized that young adults with genetic comorbidities associated with age-related hearing difficulty would exhibit subclinical decline in HTs and DPOAEs in both ears. A total of 111,243 participants reported age-related hearing difficulty in the UK Biobank sample (> 40years). The PRS models were derived from the polygenic risk score catalog to obtain 2627 PRS predictors across the health spectrum. HTs (0.25-16kHz) and DPOAEs (1-16kHz, L1/L2 = 65/55dB SPL, F2/F1 = 1.22) were measured on 242 young adults. Saliva-derived DNA samples were subjected to low-pass whole genome sequencing, followed by genome-wide imputation and PRS calculation. The logistic regression analyses were performed to identify PRS predictors of age-related hearing difficulty in the UK Biobank cohort. The linear mixed model analyses were performed to identify PRS predictors of HTs and DPOAEs. The PRS-based association analysis identified 977 PRS predictors across the health spectrum associated with age-related hearing difficulty. Hearing difficulty and hearing aid use PRS predictors revealed the strongest association with the age-related hearing difficulty phenotype. Youth with a higher genetic predisposition to hearing difficulty revealed a subclinical elevation in HTs and a decline in DPOAEs in both ears. PRS predictors associated with age-related hearing difficulty were enriched for mental health, lifestyle, metabolic, sleep, reproductive, digestive, respiratory, hematopoietic, and immune traits. Fifty PRS predictors belonging to various trait categories were replicated for HTs and DPOAEs in both ears. The study identified genetic comorbidities associated with age-related hearing loss across the health spectrum. Youth with a high genetic predisposition to age-related hearing difficulty and other related complex traits could exhibit sub-clinical decline in HTs and DPOAEs decades before clinically meaningful age-related hearing loss is observed. We posit that effective communication of genetic risk, promoting a healthy lifestyle, and reducing exposure to environmental risk factors at younger ages could help prevent or delay the onset of age-related hearing difficulty at older ages.

#2639 Unraveling complement activation profiles on endothelial cells in healthy donors using an ex vivo model

Abstract Background and Aims Complement is involved in numerous kidney diseases. However, functional approaches to properly examine individual's susceptibility to complement dysregulation are limited. Method We assessed ex vivo complement activation induced by sera from 38 healthy donors on resting microvascular endothelial cells (HMEC-1) with or without complement dysregulation by an anti-FH monoclonal antibody (OX-24 mAb). Following incubation, immunofluorescence was used to reveal and quantify membrane-bound C3c (evaluating C3b/iC3b) and C5b-9 with a computer-assisted method (H-score). Additionally, complement anaphylatoxins (C3a and C5a) were quantified in cell supernatants by ELISA. Further exploration of ex vivo complement activation profiles were conducted by next generation sequencing of a panel of alternative pathway genes in 32 donors. Results Increase in complement deposition on HMEC-1 surface was defined for a H-scoreC3c > 50 and/or a H-scoreC5b-9 > 30. Combined analysis of C3b/iC3b and C5b-9 deposition in 35 donors showed that one donor (2.8%) had an isolated increase in C3b/iC3b deposits, 3 (8.6%) had an isolated increase in C5b-9 deposits and one other (2.8%) had both increased C3b/iC3b and C5b-9 deposition. Genetic analysis of 32/38 donors revealed 3 heterozygous rare or low frequency missense variants in CFH (p.N1050Y and p.R1210C) and CFI (p.A76G) in 3/5 donors (60%) with increased complement deposition. Conclusion Our ex vivo model for measuring complement activation allowed the identification of distinct complement activation profiles among healthy donors, revealing genetic susceptibility in 3 donors. This new dynamic and functional model provides an exciting avenue for exploring the mechanisms governing complement dysregulation in various kidney diseases in research.

MINOR GENETIC OVERLAP BETWEEN RHEUMATOID ARTHRITIS, MYOCARDIAL INFARCTION AND ITS RISK DETERMINANTS.

To investigate whether a shared genetic susceptibility exists between rheumatoid arthritis (RA) and myocardial infarction (MI) - including major MI risk factors - and to quantify the degree of any such overlap. Genome-wide association study (GWAS) data for RA was constructed from a sample of 26,637 Swedish RA cases and RA-free controls. For MI, GWAS data was obtained from a previously published meta-analysis. Genome-wide genetic correlation was estimated via LD score regression. LAVA was employed to estimate local genetic correlations in ~2500 non-overlapping loci, including the major histocompatibility complex (MHC). The RA-free controls were used for reference panel data. We also assessed stratified estimates of both genome-wide and local genetic correlation, based on subsamples of seropositive and seronegative RA. Furthermore, genome-wide genetic correlation was estimated between RA and selected cardiovascular risk factors, to elucidate pleiotropic relationships. Following quality control, our RA GWAS consisted of 25,826 individuals. Genome-wide genetic correlation between RA and MI was estimated to rg=0.13 (95%CI -0.03-0.29). Six regions exhibited significant local rg though none harbored any known risk SNPs for either of the two traits. Estimates were similar in both seropositive and seronegative RA. No statistically significant rg were observed between RA and any of the MI risk factors. Our findings indicate that genetic overlap between RA and MI is minor. Furthermore, genetic overlap between RA and MI risk factors seem unlikely to provide a major contribution to the increased risk of MI observed in RA.

#1450 Polygenic risk score of native IgA nephropathy predicts risk of post-transplant disease recurrence

Abstract Background and Aims IgA nephropathy (IgAN) is a polygenic immune-mediated progressive glomerular disease. Recent GWAS reported that high genome-wide polygenic risk score (IgAN GPS), including 1 249 077 variants mapping to systemic immune pathways, was associated with risk of end stage kidney disease (ESKD). Post transplant (KTx) IgAN recurrence occurs in 30% of cases and it is a major cause of graft loss. Pathogenesis and predictors of IgAN recurrence are still not well defined. Herein, we studied the role of native IgAN GPS and clinical factors in predicting post-KTx IgAN recurrence and graft failure in a large cohort of KTx recipients. Method Four thousand one hundred eighty six KTx recipients from 6 sites were genome wide genotyped and imputed against multi-ancestry reference panels, retrieving >10 million variants. In each recipient, native IgAN GPS was computed and standard-normalized (i.e. expressed in units of standard deviations from the mean distribution in matched controls). Native kidney disease diagnosis, clinical parameters, and post-KTx outcome data were retrieved retrospectively from clinical charts. The IgAN GPS was tested as predictor of native IgAN in the entire KTx cohort in a logistic regression model adjusted for sex, age, recruitment site, and first 5 PCs. IgAN GPS was tested as predictor of age at transplantation (proxy for age at ESKD) among KTx recipients with native IgAN in a linear regression model adjusted for sex, recruitment site, and first 5 PCs. In recipients with native IgAN, recipient and donor parameters were individually tested as predictors for time to IgAN recurrence and time to graft failure in Cox proportional hazards models adjusted for recruitment site and first 5 PCs. Predictors with P-value < .1 were included in the multivariable models. Recipient IgAN GPS was added to the clinical models and tested for prediction of time-to IgAN recurrence, and, among KTx recipients with IgAN recurrence, of time-to subsequent graft failure. Results Three hundred sixty nine KTx recipients were affected by native IgAN, 271 were of male sex, median age at transplantation was 45 years, and 149 received a living donor KTx. Over a median follow-up time of 46 months, 96 IgAN recurrence events occurred, and, among KTx recipients with recurrent IgAN, 27 subsequent graft failure events occurred after 100 months post KTx. IgAN GPS significantly predicted native IgAN cases among all KTx recipients (OR [95% CI]: 1.95 [1.76,2.16], p = 5.60E-07, AUROC 0.73), and lower age at transplantation among recipients with native IgAN (beta [s.e.]: −1.11[0.55], p = 0.04). Clinical model for IgAN recurrence included age, sex, year of transplant, HLA mismatch, recruitment site, and first 5 PCs; clinical model for graft failure included age, sex, year of transplant, HLA mismatch, type of donation, donor age, sex, rejection events, recruitment site, and first 5 PCs. At the multivariable analysis, IgAN GPS, lower age at transplantation, lower HLA mismatch, and higher year of transplant were independently associated with time to IgAN recurrence (Fig. 1a). Among KTx recipients with recurrent IgAN, higher IgAN GPS predicted time-to graft failure independently from clinical factors (Fig. 1b), but not in non-recurrent cases. Conclusion In the KTx setting, IgAN GPS was an independent predictor of IgAN recurrence, suggesting shared genetic susceptibility between native and recurrent IgAN. In addition, associations of IgAN GPS with lower age at transplantation, and with graft failure among recurrent IgAN cases, suggest that IgAN GPS may be predictive of a more aggressive native as well as recurrent disease. Associations with lower HLA mismatch advocate donor-recipient genetic similarities as potential additional predictors of IgAN recurrence. These data, which need external validation, may provide potential new insights into the pathobiology and prediction of recurrent IgAN.

Outdoor walking, genetic predisposition, and the risk of incident osteoporosis among older adults: A prospective large population-based cohort study.

The available cross-sectional data and small-scale studies indicate that outdoor walking benefits bone metabolism. Nevertheless, there is a scarcity of comprehensive prospective research investigating the enduring correlation between outdoor walking and osteoporosis. This study aims to conduct a prospective analysis of the correlation between outdoor walking and osteoporosis while also examining potential variations influenced by genetic susceptibility to osteoporosis. 24,700 older adults without osteoporosis at baseline were enrolled. These individuals were followed up until December 31, 2021, during which data on outdoor walking was gathered. The genetic risk score for osteoporosis was comprised of 14 single-nucleotide polymorphisms. 4,586 cases of osteoporosis were identified throughout a median follow-up period of 37.3months. Those who walked outside for > 30 but ≤ 60min per day had a hazard ratio (HR) of 0.83 (95% confidence interval (CI): 0.72-0.95) for incident osteoporosis, whereas those who walked outside for > 60min per day had an HR of 0.60 (95% CI: 0.39-0.92). We found that osteoporosis risk exhibited a declining trend in individuals with low genetic risk. Individuals walking outside for > 60min per day tended to have the lowest overall osteoporosis risk among those with high genetic risk. A significant negative correlation exists between an extended period of daily outdoor walking and osteoporosis incidence risk. This correlation is particularly pronounced among individuals with low genetic risk. The results above underscore the significance of outdoor walking as a simple and economical adjunct to public health programs to prevent osteoporosis.

Genetic determinants of renal scarring in children with febrile UTI.

Febrile urinary tract infections (UTIs) are among the most severe bacterial infections in infants, in which a subset of patients develops complications. Identifying infants at risk of recurrent infections or kidney damage based on clinical signs is challenging. Previous observations suggest that genetic factors influence UTI outcomes and could serve as predictors of disease severity. In this study, we conducted a nationwide survey of infant genotypes to develop a strategy for infection management based on individual genetic risk. Our aims were to identify genetic susceptibility variants for renal scarring(RS) and genetic host factors predisposing to dilating vesicoureteral reflux (VUR) and recurrent UTIs. To assess genetic susceptibility, we collected and analyzed DNA from blood using exome genotyping. Disease-associated genetic variants were identified through bioinformatics analysis, including allelic frequency tests and odds ratio calculations. Kidney involvement was defined using dimercaptosuccinic acid (DMSA) scintigraphy. In this investigation, a cohort comprising 1087 infants presenting with their first episode of febrile UTI was included. Among this cohort, a subset of 137 infants who underwent DMSA scanning was subjected to gene association analysis. Remarkable genetic distinctions were observed between patients with RS and those exhibiting resolved kidney involvement. Notably, the genetic signature indicative of renal scarring prominently featured mitochondrial genes. In this nationwide study of genetic susceptibility to RS after febrile UTIs in infancy, we identified a profile dominated by mitochondrial polymorphisms. This profile can serve as a predictor of future complications, including RS and recurrent UTIs.

Construction of the chronic temporomandibular disorder patients: the association between neural and psychological pathways.

Chronic temporomandibular disorder (cTMD) as a term based on the diagnostic criteria for temporomandibular disorders (DC/TMD) classification refers, in this paper, to the condition listed that has a non-mechanical association without any obvious organic cause. Specifically, this is the condition that falls under the International Classification of Diseases 11th revision (ICD-11) classification of chronic primary and chronic secondary pains. This implies that there is increased responsiveness of nociceptive neurons in the central nervous system, a phenomenon known as central sensitisation. cTMD patients may have their beginning with genetic susceptibility to pain. Although no single gene is exclusively linked to cTMD, various genes associated with nervous and musculoskeletal systems are believed to play a role. Environmental triggers and epigenetic changes are also thought to contribute to cTMD development. The biopsychosocial model emphasises the need to comprehensively address biological, psychological and social factors in cTMD assessment and management. In this study, we leverage the cyclic causation framework within the biopsychosocial model to illuminate the intricate interplay between biological and psychosocial factors in the context of cTMD. The conceptualisation of cTMD involves the dynamic evolution of genetic predispositions, influenced by life events and other biological susceptibilities. These factors collectively contribute to the emergence of nociplastic changes, ultimately manifesting as the distinctive features observed in individuals afflicted with cTMD.