Exome sequencing identifies novel genetic variants associated with varicose veins.

BACKGROUND: Varicose veins (VV) are one of the common human diseases, but the role of genetics in its development is not fully understood. METHODS: We conducted an exome-wide association study of VV using whole-exome sequencing data from the UK Biobank, and focused on common and rare variants using single-variant association analysis and gene-level collapsing analysis. FINDINGS: A total of 13,823,269 autosomal genetic variants were obtained after quality control. We identified 36 VV-related independent common variants mapping to 34 genes by single-variant analysis and three rare variant genes (PIEZO1, ECE1, FBLN7) by collapsing analysis, and most associations between genes and VV were replicated in FinnGen. PIEZO1 was the closest gene associated with VV (P = 5.05 × 10-31), and it was found to reach exome-wide significance in both single-variant and collapsing analyses. Two novel rare variant genes (ECE1 and METTL21A) associated with VV were identified, of which METTL21A was associated only with females. The pleiotropic effects of VV-related genes suggested that body size, inflammation, and pulmonary function are strongly associated with the development of VV. CONCLUSIONS: Our findings highlight the importance of causal genes for VV and provide new directions for treatment.

Loss of PBX1 function in Leydig cells causes testicular dysgenesis and male sterility.

Leydig cells are essential components of testicular interstitial tissue and serve as a primary source of androgen in males. A functional deficiency in Leydig cells often causes severe reproductive disorders; however, the transcriptional programs underlying the fate decisions and steroidogenesis of these cells have not been fully defined. In this study, we report that the homeodomain transcription factor PBX1 is a master regulator of Leydig cell differentiation and testosterone production in mice. PBX1 was highly expressed in Leydig cells and peritubular myoid cells in the adult testis. Conditional deletion of Pbx1 in Leydig cells caused spermatogenic defects and complete sterility. Histological examinations revealed that Pbx1 deletion impaired testicular structure and led to disorganization of the seminiferous tubules. Single-cell RNA-seq analysis revealed that loss of Pbx1 function affected the fate decisions of progenitor Leydig cells and altered the transcription of genes associated with testosterone synthesis in the adult testis. Pbx1 directly regulates the transcription of genes that play important roles in steroidogenesis (Prlr, Nr2f2 and Nedd4). Further analysis demonstrated that deletion of Pbx1 leads to a significant decrease in testosterone levels, accompanied by increases in pregnenolone, androstenedione and luteinizing hormone. Collectively, our data revealed that PBX1 is indispensable for maintaining Leydig cell function. These findings provide insights into testicular dysgenesis and the regulation of hormone secretion in Leydig cells.

Molecular characterization and antimicrobial activity of NK-lysin in black scraper (Thamnaconus modestus).

NK-lysin (NKL) is a positively charged antimicrobial peptide with broad-spectrum bactericidal activities. In this study, the cDNA sequence of NKL (TmNKL) from black scraper (Thamnaconus modestus) was cloned, which encodes a predicted polypeptide of 150 amino acids that contains a surfactant protein B domain with three disulfide bonds. Phylogenetically, TmNKL was most closely related to its teleost counterpart from tiger puffer (Takifugu rubripes). Expression analysis demonstrated that TmNKL transcripts were constitutively expressed in all tested tissues, with the highest expression levels in the gills. Its expression was significantly upregulated in the gills, head kidney, and spleen after infection with Vibrio parahaemolyticus. A linear peptide (TmNKLP40L) and a disulfide-type peptide (TmNKLP40O) were further synthesized and results showed that disulfide bonds are not essential for bactericidal activities of TmNKL, and that both forms of TmNKL exhibited potent bactericidal activities against 4 gram- negative bacteria, including V. parahaemolyticus, V. alginolyticus, Edwardsiella tarda, and V. harveyi. Observed antimicrobial activities are likely due to the effects of TmNKLP40L and TmNKLP40O treatment on disrupting the integrity of both inner and outer membrane of V. parahaemolyticus, resulting in hydrolysis of bacterial genomic DNA. Damaged cell membranes and leakage of intracellular contents were further confirmed using scanning and transmission microscopy. Moreover, administration of 1.0 µg/g TmNKLP40L or TmNKLP40O significantly decreased bacterial load in tissues and thus, pronouncedly enhanced the survival of V. parahaemolyticus-infected fish. Overall, our results demonstrated that TmNKL is a potent innate effector and provides protective effects against bacterial infection.

Molecular and functional characterization of a ladderlectin-like molecule from ayu (Plecoglossus altivelis).

Ladderlectin is a member of C-type lectins (CTLs) in teleost fish and involved in innate immune defense. In this study, ayu (Plecoglossus altivelis) ladderlecin-like (PaLL-like) sequence was cloned, which encodes a polypeptide of 172 amino acids that includes a signal peptide and characteristic C-type lectin-like domains (CTLDs). Phylogenetically, PaLL-like was most closely related to its teleost counterpart from shishamo smelt (Spirinchus lanceolatus). Expression analysis revealed a ubiquitous expression profile, with highest expression detected in liver and its expression was up-regulated following Vibiro anguillarum infection. Similar to canonical CTLs, PaLL-like exhibited carbohydrate-binidng capacities to a wide range of well-defined mono-/di-saccharides and likely confer PaLL-like the ability to agglutinate all tested bacterial, including three Gram-positive species (i.e., Listeria monocytogenes, Staphylococcus aureus and Streptococcus iniae) and eight Gram-negative species (i.e., Edwardsiella tarda, Aeromonas (A.) hydrophila, Escherichia coli, Vibrio (V.) harveyi, V. anguillarum, V. parahemolyticus, A. versoni and V. vulnificus), in a calcium-dependent manner. Further functional studies revealed that PaLL-like displayed immunomodulatory activities leading to enhanced bactericidal activity of serum, pathogen opsonization and macrophage activation with increased expression of pro-inflammatory cytokines (i.e., PaIL-1ß and PaTNF-α). Collectively, these immunomodulatory activities of PaLL-like suppressed proliferations of V. anguillarum in targeted tissued in vivo and likely contributed to the increased survival rate of infected-fish. Overall, our results demonstrated PaLL-like is a critical component of innate immunity and provides protective effects against bacterial infection.

Molecular characterization, expression and functional analysis of large yellow croaker (Larimichthys crocea) peroxisome proliferator-activated receptor gamma.

The peroxisome proliferator-activated receptor gamma (PPARγ) are nuclear receptors with distinct roles in energy metabolism and immunity. Although extensively studied in mammals, immunomodulatory roles of this molecule in teleost fish remain to be investigated. In this study, large yellow croaker (Larimichthys crocea) PPARγ (LcPPARγ) sequence was cloned, which encodes a polypeptide of 541 amino acids that include signature domains belonging to the nuclear receptor superfamily. Phylogenetically, LcPPARγ was most closely related to PPARγ derived from European sea bass (Dicentrarchus labrax). Quantitative analysis shown a ubiquitous expression of this molecule, with highest expression level detected in the intestine. The expression of LcPPARγ was decreased in the intestine, muscle, body kidney, spleen and head kidney-derived monocytes/macrophages (MO/MФs) over the course of Vibrio alginolyticus (V. alginolyticus) infection. In contrast, an up-regulation of LcPPARγ was observed in head kidney-derived MO/MФs following docosahexaenoic acid (DHA) treatment. This increase in LcPPARγ leads to an up-regulation of LcCD11b and LcCD18 and an enhancement of complement-mediated phagocytosis. Furthermore, cytokine secretions of V. alginolyticus-stimulated MO/MФs were modulated following LcPPARγ activations that up-regulated the expression of LcIL-10, while decreased the expression of LcIL-1ß, LcTNF-α and LcTGF-ß1. Overall, our results indicated that LcPPARγ plays a role in regulating functions of MO/MФs and likely contribute to MO/MФs polarization.

Developing the Chinese version problem areas in diabetes-teen for measuring diabetes distress in adolescents with type 1 diabetes.

PURPOSE: To translate the 26-item English version Problem Areas in Diabetes-Teen (PAID-T) into a Chinese version and then to examine its psychometrical properties for measuring diabetes distress in adolescents with type 1 diabetes (T1D). DESIGN AND METHODS: The 26-item English version PAID-T was translated into a Chinese version guided by the translation model for cross-cultural research. A cross-sectional design was used and 203 adolescents with T1D were recruited from four hospitals in Taiwan. Content validity, exploratory factor analysis, and item analysis were used to ensure the item quality and build the factor structure of the Chinese version PAID-T. Confirmatory factor analysis, concurrent validity, and reliability testing were also used to examine its psychometric properties. RESULTS: The three second-order factors of the 18-item Chinese version PAID-T were developed. The correlation coefficients of the three-factor Chinese version PAID-T with self-management and glycosylated hemoglobin levels were all significant and ranged from -0.32 to -0.45 and 0.18 to 0.33 respectively. Cronbach's α and the test-retest reliability of the three-factor Chinese version PAID-T ranged from 0.85 to 0.93 and from 0.89 to 0.94 respectively. CONCLUSIONS: The Chinese version PAID-T with good translation quality was a reliable and valid scale to screen and assess diabetes distress for adolescents with T1D. PRACTICE IMPLICATIONS: Nurses could use the Chinese version PAID-T to track diabetes distress and tailor interventions for adolescents with T1D; also, the Chinese version PAID-T could facilitate the conducting of research on diabetes distress for adolescents with T1D.

A high-throughput cell-based gaussia luciferase reporter assay for measurement of CYP1A1, CYP2B6, and CYP3A4 induction.

The induction of cytochrome P450s can result in reduced drug efficacy and lead to potential drug-drug interactions. The xenoreceptors-aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), and pregnane X receptor (PXR)-play key roles in CYP induction by xenobiotics. In order to be able to rapidly screen for the induction of three enzymes (CYP1A1, CYP2B6, and CYP3A4), we generated a stable AhR-responsive HepG2 cell line, a stable CAR-responsive HepG2 cell line, and a stable PXR-responsive HepG2 cell line.To validate these stable xenoreceptor-responsive HepG2 cell lines, we evaluated the induction of the different Gaussia reporter activities, as well as the mRNA and protein expression levels of endogenous CYPs in response to different inducers.The induction of luciferase activity in the stable xenoreceptor-responsive HepG2 cell lines by specific inducers occurred in a concentration dependent manner. There was a positive correlation between the induction of luciferase activities and the induction endogenous CYP mRNA expression levels. These xenoreceptor-responsive HepG2 cell lines were further validated with known CYP1A1, CYP2B6, and CYP3A4 inducers.These stable xenoreceptor-responsive HepG2 cell lines may be used in preclinical research for the rapid and sensitive detection of AhR, CAR, and PXR ligands that induce CYP450 isoforms.

The effect of new preoperative preparation method compared to conventional method in complex acetabular fractures: minimum 2-year follow-up.

OBJECTIVE: This study aimed to compare the efficacy and safety of the new method including 3D printing-based preoperative planning, surgical workshop, and contouring of the plate versus conventional method in the surgical treatment of complex acetabular fractures. METHODS: We retrospectively analyzed the data in a cohort of 88 patients of complex acetabular fracture with mean 29.95 ± 4.84 months (24-41 months) follow-up. Patients were divided into two groups. Group 1 consisting of 41 patients were performed previewed surgery with a 3D printing-based pre-contoured plate on a 3D printing model. Group 2, comprised of 47 patients, were treated by the traditional contoured plate technique. The quality of reduction was assessed using criteria described by Matta. Functional outcome was evaluated using Modified Postel Merle D'Aubigne score. A custom-made quiz was used to evaluate the chief assistant. RESULTS: The study showed no significant differences in measured preoperative variables except for the age between the Group 1 and Group 2 (p > 0.05). Compared with the Group 2, the intraoperative blood loss, operative time was significantly decreased in Group 1 (p < 0.05). There were no significant statistical differences in the quality of reduction and Modified Postel Merle D'Aubigne score (p > 0.05). The result of evaluation of assistant in Group 1 was significantly high than in Group 2 (p < 0.05). CONCLUSION: 3D printing-based pre-contoured plate is a more effective and reliable method than traditional contoured plate technique for treating the complex acetabular fractures. Meanwhile, the 3D printing is a useful orthopedic surgical education tool which can improve the understanding of the complex acetabular fracture for a young surgeon.

Route of administration of exogenous progesterone for luteal support does not significantly affect the serum concentration in assisted reproductive technology.

The objective of this research is to study the guiding role of serum progesterone level on exogenous luteal support protocols. In the retrospective study, a total of 537 infertile women undergoing IVF/ICSI were recruited. Serum samples were obtained for serum progesterone measurements. The results demonstrated that the progesterone levels of all women gradually decreased over the course of 7 days after ET. The progesterone level of the pregnant women reached a nadir on day 7 after ET and subsequently began to rise, while the progesterone level of the non-pregnant women continued to decrease. Even with different routes of administration of exogenous progesterone, the progesterone levels followed the same patterns. The serum progesterone level does not represent the adequacy of exogenous progesterone supplementation. Therefore, there is no need to measure serum progesterone levels frequently after embryo transfer or adjust the dose according to serum progesterone levels.

Potential influence of COVID-19/ACE2 on the female reproductive system.

The 2019 novel coronavirus (2019-nCoV) appeared in December 2019 and then spread throughout the world rapidly. The virus invades the target cell by binding to angiotensin-converting enzyme (ACE) 2 and modulates the expression of ACE2 in host cells. ACE2, a pivotal component of the renin-angiotensin system, exerts its physiological functions by modulating the levels of angiotensin II (Ang II) and Ang-(1-7). We reviewed the literature that reported the distribution and function of ACE2 in the female reproductive system, hoping to clarify the potential harm of 2019-nCoV to female fertility. The available evidence suggests that ACE2 is widely expressed in the ovary, uterus, vagina and placenta. Therefore, we believe that apart from droplets and contact transmission, the possibility of mother-to-child and sexual transmission also exists. Ang II, ACE2 and Ang-(1-7) regulate follicle development and ovulation, modulate luteal angiogenesis and degeneration, and also influence the regular changes in endometrial tissue and embryo development. Taking these functions into account, 2019-nCoV may disturb the female reproductive functions through regulating ACE2.

Comparison of posterior ring fixation with combined anterior and posterior ring fixation for the treatment of lateral compression type 2 pelvic fractures.

PURPOSE: The aim of surgical treatment for lateral compression type 2 (LC-2) pelvic fractures is to enable early mobilization and provide pain relief. Anterior and posterior ring fixation is usually performed simultaneously, with the goal of providing good biomechanical stability. However, it is unclear whether anterior ring fixation is necessary. This study therefore aimed to determine the feasibility of isolated posterior ring fixation for LC-2 pelvic fractures. METHODS: Records of patients with LC-2 pelvic fractures were extracted from a medical database. Patients who underwent posterior pelvic ring fixation alone (PR fixation group) or anterior and posterior ring fixation (APR fixation group) were included. Patients' operative characteristics, time to clinical healing, length of hospital stay, time to weight bearing, and complications were recorded at follow-up. Radiography was used to assess healing and fracture displacement. Functional outcomes were evaluated using the Majeed grading system. RESULTS: The PR fixation group included 44 patients, and the APR fixation group included 49 patients. Operative time, intra-operative blood loss, units of blood transfused, intra-operative fluid administered, and post-operative drainage were lower in the PR fixation group than in the APR fixation group. Length of hospital stay was also shorter in the PR fixation group than in the APR fixation group. Although the frequency (8/44) of fracture displacement in the superior ramus prior to union was high in the PR fixation group, no significant differences in time to weight bearing, time to clinical healing, or Majeed scores were found between the groups at follow-up. CONCLUSIONS: Isolated posterior ring fixation for LC-2 pelvic fractures is feasible; patients who underwent treatment with this technique had functional outcomes similar to that of those who underwent anterior and posterior ring fixation.

BMP4 inhibits myogenic differentiation of bone marrow-derived mesenchymal stromal cells in mdx mice.

BACKGROUND AIMS: Bone marrow-derived mesenchymal stromal cells (BMSCs) are a promising therapeutic option for treating Duchenne muscular dystrophy (DMD). Myogenic differentiation occurs in the skeletal muscle of the mdx mouse (a mouse model of DMD) after BMSC transplantation. The transcription factor bone morphogenic protein 4 (BMP4) plays a crucial role in growth regulation, differentiation and survival of many cell types, including BMSCs. We treated BMSCs with BMP4 or the BMP antagonist noggin to examine the effects of BMP signaling on the myogenic potential of BMSCs in mdx mice. METHODS: We added BMP4 or noggin to cultured BMSCs under myogenic differentiation conditions. We then injected BMP4- or noggin-treated BMSCs into the muscles of mdx mice to determine their myogenic potential. RESULTS: We found that the expression levels of desmin and myosin heavy chain decreased after treating BMSCs with BMP4, whereas the expression levels of phosphorylated Smad, a downstream target of BMP4, were higher in these BMSCs than in the controls. Mdx mouse muscles injected with BMSCs pretreated with BMP4 showed decreased dystrophin expression and increased phosphorylated Smad levels compared with muscles injected with non-treated BMSCs. The opposite effects were seen after pretreatment with noggin, as expected. CONCLUSIONS: Our results identified BMP/Smad signaling as an essential negative regulator of promyogenic BMSC activity; inhibition of this pathway improved the efficiency of BMSC myogenic differentiation, which suggests that this pathway might serve as a target to regulate BMSC function for better myogenic differentiation during treatment of DMD and degenerative skeletal muscle diseases.

MicroRNA-370 Attenuates Hepatic Fibrogenesis by Targeting Smoothened.

BACKGROUND AND AIMS: Recent research shows that abnormal expression of microRNA plays an important role in the process of hepatic fibrosis . miR-370 has been reported to be involved in liver function and is suppressed during hepatic carcinogenesis. The aim of this study was to investigate the role of miR-370 in hepatic fibrosis. METHODS: The expression levels of miR-370 in rat fibrotic livers and activated hepatic stellate cells (HSCs) were evaluated by quantitative real-time PCR. The effect of miR-370 on the activation of HSCs was analyzed by flow cytometric analyses, real-time PCR and Western blot. Adenovirus carrying miR-370 was injected through the tail vein to access the effect of miR-370 on hepatic fibrosis induced by CCl4 in rats. The downstream targets of miR-370 were predicted by the Target Scan database and verified by luciferase assays, real-time PCR and Western blot in HSCs and were further confirmed by immunohistochemistry in vivo. RESULTS: Real-time PCR showed that miR-370 expression was significantly reduced in rat fibrotic livers and TGFß1-stimulated HSCs. Overexpression of miR-370 inhibited the proliferation of HSC-T6 cells via inducing cell apoptosis and suppressed the activation of HSCs. Upregulation of miR-370 obviously attenuated the CCl4-induced liver fibrosis in rats. miR-370 was directly bound to the 3'UTR of Smoothened (SMO) and suppressed the expression of SMO in HSCs and fibrotic livers. CONCLUSIONS: Our study demonstrated that miR-370 plays an inhibitory role in hepatic fibrogenesis by targeting SMO. Restoration of miR-370 may have beneficial effects on the treatment of liver fibrosis.

Health-related quality of life in fathers of children with or without developmental disability: the mediating effect of parental stress.

PURPOSE: The aims of this study were to compare parental stress and health-related quality of life (HRQOL) between Taiwanese fathers of children with and without developmental disabilities (DDs) and to examine the mediating effect of parental stress on the association between having a child with DD and paternal HRQOL within Chinese culture. METHOD: This cross-sectional, prospective, unmatched case-control study included 206 fathers of children with DDs and 207 fathers of healthy children. HRQOL was assessed by the SF-36 short-form questionnaire, and parental stress was assessed by the Chinese version Parental Stress Scale. RESULTS: Fathers of children with DDs experienced poorer mental and physical HRQOL and higher parental stress than fathers of healthy children. Parental stress acted as a complete mediator for paternal physical HRQOL, while parental stress had a partial mediating effect on the relationship between having a child with DD and paternal mental HRQOL. Having a child with DD also directly affected paternal mental HRQOL. CONCLUSIONS: Fathers of children with DDs should be monitored for parental stress and HRQOL, and interventions should be provided to empower them with the knowledge and skills to reduce their stress and to enhance their HRQOL.

Machine learning developed a CD8+ exhausted T cells signature for predicting prognosis, immune infiltration and drug sensitivity in ovarian cancer.

CD8+ exhausted T cells (CD8+ Tex) played a vital role in the progression and therapeutic response of cancer. However, few studies have fully clarified the characters of CD8+ Tex related genes in ovarian cancer (OC). The CD8+ Tex related prognostic signature (TRPS) was constructed with integrative machine learning procedure including 10 methods using TCGA, GSE14764, GSE26193, GSE26712, GSE63885 and GSE140082 dataset. Several immunotherapy benefits indicators, including Tumor Immune Dysfunction and Exclusion (TIDE) score, immunophenoscore (IPS), TMB score and tumor escape score, were used to explore performance of TRPS in predicting immunotherapy benefits of OC. The TRPS constructed by Enet (alpha = 0.3) method acted as an independent risk factor for OC and showed stable and powerful performance in predicting clinical outcome of patients. The C-index of the TRPS was higher than that of tumor grade, clinical stage, and many developed signatures. Low TRPS score indicated a higher level of CD8+ T cell, B cell, macrophage M1, and NK cells, representing a relative immunoactivated ecosystem in OC. OC patients with low risk score had a higher PD1&CTLA4 immunophenoscore, higher TMB score, lower TIDE score and lower tumor escape score, suggesting a better immunotherapy response. Moreover, higher TRPS score indicated a higher score of cancer-related hallmarks, including angiogenesis, EMT, hypoxia, glycolysis, and notch signaling. Vitro experiment showed that ARL6IP5 was downregulated in OC tissues and inhibited tumor cell proliferation. The current study constructed a novel TRPS for OC, which could serve as an indicator for predicting the prognosis, immune infiltration and immunotherapy benefits for OC patients.

Dynamic observation and risk factors analysis of deep vein thrombosis after hip fracture.

OBJECTIVE: To dynamically observe the occurrence of deep vein thrombosis (DVT) after a hip fracture and analyze of the risk factors affecting the dynamic alteration of DVT. METHODS: Data of patients with hip fractures from January 1, 2017 to August 31, 2021 were collected. Patients were divided into DVT and non-DVT groups according to their daily Doppler ultrasonography findings. Survival analysis was used to describe dynamic changes in DVT occurrence with time. Log-rank tests were used to compare the influence of individual factors of patients with DVT occurrence, and a Cox proportional hazards regression model was used to identify the risk factors affecting the dynamic alteration of DVT occurrence. RESULTS: A total of 331 patients were included: 148(44.7%) had preoperative DVT, and 143 (96.6%) had DVT in the first 3days after admission. The probability of DVT was 0.42 on Day 1, 0.11 on Day 2, 0.10 on Day 3, 0.08 on Day 4, 0.20 on Day 5, and 0.00 on Day 6-7, with a median survival time of 3.30 d. Age>70 years, intertrochanteric fracture, admission hemoglobin<130g/L, and admission hematocrit<40% had a significantly higher occurrence rate of DVT. A hematocrit level of <40% (Hazard Ratio 2.079, 95% Confidence Interval:1.148-3.764, P = 0.016) was an independent risk factor for DVT. CONCLUSION: DVT after hip fractures mainly occurred in the first three days after admission, the trend was stabilized within one week, and day 1 had the highest rate of DVT incidence. Age, fracture type, HGB level, and Hct level affected dynamic occurrence of DVT. At constant other factors, Hct<40% was 2.079-fold incidence in the risk of preoperative DVT formation than those with Hct≥40% after hip fracture.

Engineered extracellular vesicles: A new approach for targeted therapy of tumors and overcoming drug resistance.

Targeted delivery of anti-tumor drugs and overcoming drug resistance in malignant tumor cells remain significant clinical challenges. However, there are only few effective methods to address these issues. Extracellular vesicles (EVs), actively secreted by cells, play a crucial role in intercellular information transmission and cargo transportation. Recent studies have demonstrated that engineered EVs can serve as drug delivery carriers and showed promising application prospects. Nevertheless, there is an urgent need for further improvements in the isolation and purification of EVs, surface modification techniques, drug assembly processes, and precise recognition of tumor cells for targeted drug delivery purposes. In this review, we summarize the applications of engineered EVs in cancer treatment and overcoming drug resistance, and current challenges associated with engineered EVs are also discussed. This review aims to provide new insights and potential directions for utilizing engineered EVs as targeted delivery systems for anti-tumor drugs and overcoming drug resistance in the near future.

Large-scale whole-exome sequencing analyses identified protein-coding variants associated with immune-mediated diseases in 350,770 adults.

The genetic contribution of protein-coding variants to immune-mediated diseases (IMDs) remains underexplored. Through whole exome sequencing of 40 IMDs in 350,770 UK Biobank participants, we identified 162 unique genes in 35 IMDs, among which 124 were novel genes. Several genes, including FLG which is associated with atopic dermatitis and asthma, showed converging evidence from both rare and common variants. 91 genes exerted significant effects on longitudinal outcomes (interquartile range of Hazard Ratio: 1.12-5.89). Mendelian randomization identified five causal genes, of which four were approved drug targets (CDSN, DDR1, LTA, and IL18BP). Proteomic analysis indicated that mutations associated with specific IMDs might also affect protein expression in other IMDs. For example, DXO (celiac disease-related gene) and PSMB9 (alopecia areata-related gene) could modulate CDSN (autoimmune hypothyroidism-, psoriasis-, asthma-, and Graves' disease-related gene) expression. Identified genes predominantly impact immune and biochemical processes, and can be clustered into pathways of immune-related, urate metabolism, and antigen processing. Our findings identified protein-coding variants which are the key to IMDs pathogenesis and provided new insights into tailored innovative therapies.

Genetic associations of protein-coding variants in venous thromboembolism.

Previous genetic studies of venous thromboembolism (VTE) have been largely limited to common variants, leaving the genetic determinants relatively incomplete. We performed an exome-wide association study of VTE among 14,723 cases and 334,315 controls. Fourteen known and four novel genes (SRSF6, PHPT1, CGN, and MAP3K2) were identified through protein-coding variants, with broad replication in the FinnGen cohort. Most genes we discovered exhibited the potential to predict future VTE events in longitudinal analysis. Notably, we provide evidence for the additive contribution of rare coding variants to known genome-wide polygenic risk in shaping VTE risk. The identified genes were enriched in pathways affecting coagulation and platelet activation, along with liver-specific expression. The pleiotropic effects of these genes indicated the potential involvement of coagulation factors, blood cell traits, liver function, and immunometabolic processes in VTE pathogenesis. In conclusion, our study unveils the valuable contribution of protein-coding variants in VTE etiology and sheds new light on its risk stratification.