Genetic Markers of Acute Childhood B-Lineage Lymphoblastic Leukemia in the Kazakh Population.

INTRODUCTION: To investigate the genetic contribution of 24 GWAS-associated polymorphic gene variants on the development of children's B-lineage acute lymphoblastic leukemia (B-ALL) in an ethnically homogeneous population of Kazakhs. METHODS: A study of 205 children with B-ALL and 204 healthy children was conducted. Genotyping of polymorphic loci was carried out using the TaqMan method. RESULTS: Significant associations (p < 0.05) with the risk of childhood B-ALL were found for twelve variants, including rs6457327 of the HLA gene, rs4251961 of the IL1RN gene, and rs1800630 of the TNF gene. Carriage of the minor allele A of the protective rs1801157 polymorphism A of the CXCL12 gene reduces the risk of B-ALL in the Kazakh population by 40%. DISCUSSION: The results reveal significant associations of polymorphic genetic variants, which can serve as a basis for the development of effective methods for predicting the risk of B-ALL, early diagnosis, and timely treatment.

The Burden of Hereditary Angioedema in a Large Family in Brazil.

INTRODUCTION: Hereditary angioedema (HAE) is a rare genetic disease characterized by submucosal and subcutaneous edema with high morbidity and possibility of mortality. This study presents the sociodemographic characteristics of a large Brazilian family with HAE. METHODS: Descriptive cross-sectional study with patients from two family branches coming from the same city and HAE diagnosis was carried out. Clinical, laboratory, and treatment data of patients have been collected. Genetic testing was performed on some individuals. Correlation tests and comparisons between variables were applied using IBM SPSS Statistics® 2.0 program. RESULTS: We provide a detailed characterization of two families affected by HAE due to C1-INH deficiency, residing in a small town in southern Brazil. These families harbor an identified mutation in the SERPING1 gene (c.1104del, p.Asp369ThrfsTer2). The mean age at HAE diagnosis was 16.7 (±14.0) years, with the mean onset of symptoms at 6.0 (±6.1) years of age. A correlation was observed between patients' current age and age at HAE diagnosis, with older patients being diagnosed later than younger individuals (p < 0.0001). On average, there were 16.8 emergency visits in the past year (±24.8), and 53.5% of patients reported at least one lifetime hospitalization. Notably, treatment modalities often diverged from consensus recommendations regarding optimal prophylaxis and management of HAE attacks. CONCLUSIONS: This study describes one of the largest known families with HAE in Brazil and highlights the significant impact of unfavorable social conditions on disease control.

Genetic Risk Loci and Familial Associations in Migraine: A Genome-Wide Association Study in the Han Chinese Population of Taiwan.

BACKGROUND AND PURPOSE: Migraine is a condition that is often observed to run in families, but its complex genetic background remains unclear. This study aimed to identify the genetic factors influencing migraines and their potential association with the family medical history. METHODS: We performed a comprehensive genome-wide association study of a cohort of 1,561 outpatients with migraine and 473 individuals without migraine in Taiwan, including Han Chinese individuals with or without a family history of migraine. By analyzing the detailed headache history of the patients and their relatives we aimed to isolate potential genetic markers associated with migraine while considering factors such as sex, episodic vs. chronic migraine, and the presence of aura. RESULTS: We revealed novel genetic risk loci, including rs2287637 in DEAD-Box helicase 1 and long intergenic non-protein coding RNA 1804 and rs12055943 in engulfment and cell motility 1, that were correlated with the family history of migraine. We also found a genetic location downstream of mesoderm posterior BHLH transcription factor 2 associated with episodic migraine, whereas loci within the ubiquitin-specific peptidase 26 exonic region, dual specificity phosphatase 9 and pregnancy-upregulated non-ubiquitous CaM kinase intergenic regions, and poly (ADP-ribose) polymerase 1 and STUM were linked to chronic migraine. We additionally identified genetic regionsassociated with the presence or absence of aura. A locus between LINC02561 and urocortin 3 was predominantly observed in female patients. Moreover, three different single-nucleotide polymorphisms were associated with the family history of migraine in the control group. CONCLUSIONS: This study has identified new genetic locations associated with migraine and its family history in a Han Chinese population, reinforcing the genetic background of migraine. The findings point to potential candidate genes that should be investigated further.

Intrauterine chromium exposure and cognitive developmental delay: The modifying effect of genetic predisposition.

There is limited evidence on the effects of intrauterine chromium (Cr) exposure on children's cognitive developmental delay (CDD). Further, little is known about the genetic factors in modifying the association between intrauterine Cr exposure and CDD. The present study involved 2361 mother-child pairs, in which maternal plasma Cr concentrations were assessed, a polygenic risk score for the child was constructed, and the child's cognitive development was evaluated using the Bayley Scales of Infant Development. The risks of CDD conferred by intrauterine Cr exposure in children with different genetic backgrounds were evaluated by logistic regression. The additive interaction between intrauterine Cr exposure and genetic factors was evaluated by calculating the relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (SI). According to present study, higher intrauterine Cr exposure was significantly associated with increased CDD risk [each unit increase in ln-transformed maternal plasma Cr concentration (ln-Cr): adjusted OR (95 % CI), 1.18 (1.04-1.35); highest vs lowest quartile: adjusted OR (95 % CI), 1.57 (1.10-2.23)]. The dose-response relationship of intrauterine Cr exposure and CDD for children with high genetic risk was more prominent [each unit increased ln-Cr: adjusted OR (95 % CI), 1.36 (1.09-1.70)]. Joint effects between intrauterine Cr exposure and genetic factors were found. Specifically, for high genetic risk carriers, the association between intrauterine Cr exposure and CDD was more evident [highest vs lowest quartile: adjusted OR (95 % CI), 2.33 (1.43-3.80)]. For those children with high intrauterine Cr exposure and high genetic risk, the adjusted AP was 0.39 (95 % CI, 0.07-0.72). Conclusively, intrauterine Cr exposure was a high-risk factor for CDD in children, particularly for those with high genetic risk. Intrauterine Cr exposure and one's adverse genetic background jointly contribute to an increased risk of CDD in children.

Polymorphism Patterns and Socioeconomic Characteristics and Their Influence on the Risk of Preeclampsia.

Background: Preeclampsia (PE) is a critical condition affecting pregnancies worldwide. Understanding its etiology, particularly the genetic factors, is vital. This study aims to investigate the association between ACE gene polymorphisms, specifically the ACE G2350A (rs4343) variant, and the predisposition to PE, offering insights into the genetic predisposition towards this complex condition. Methods: A case-control study was conducted with 140 participants without PE (Control Group) and 128 participants diagnosed with PE (PE Group). The study focused on comparing the prevalence of the rs4343 polymorphism between the groups. Results: The analysis identified a significantly reduced risk associated with the AG genotype and an insignificant increase in risk with the AA genotype. Statistically significant differences in demographic and clinical characteristics, such as BMI and marital status, were observed between the groups, suggesting a multifaceted risk profile for PE that includes genetic, environmental, and socio-economic factors. Conclusions: The study highlight the significant role of genetic variations, specifically the ACE G2350A (rs4343) polymorphism, in influencing PE predisposition. It highlights the intricate interplay between genetic predispositions and other risk factors in the development of PE. Further research is encouraged to expand on these findings and explore a wider range of genetic polymorphisms and their interactions with environmental factors.

T2DM/CKD genetic risk scores and the progression of diabetic kidney disease in T2DM subjects.

This study aimed at understanding the predictive potential of genetic risk scores (GRS) for diabetic kidney disease (DKD) progression in patients with type 2 diabetes mellitus (T2DM) and Major Cardiovascular Events (MCVE) and All-Cause Mortality (ACM) as secondary outcomes. We evaluated 30 T2DM and CKD GWAS-derived single nucleotide polymorphisms (SNPs) and their association with clinical outcomes in a central European cohort (n = 400 patients). Our univariate Cox analysis revealed significant associations of age, duration of diabetes, diastolic blood pressure, total cholesterol and eGFR with progression of DKD (all P < 0.05). However, no single SNP was conclusively associated with progression to DKD, with only CERS2 and SHROOM3 approaching statistical significance. While a single SNP was associated with MCVE - WSF1 (P = 0.029), several variants were associated with ACM - specifically CANCAS1, CERS2 and C9 (all P < 0.02). Our GRS did not outperform classical clinical factors in predicting progression to DKD, MCVE or ACM. More precisely, we observed an increase only in the area under the curve (AUC) in the model combining genetic and clinical factors compared to the clinical model alone, with values of 0.582 (95 % CI 0.487-0.676) and 0.645 (95 % CI 0.556-0.735), respectively. However, this difference did not reach statistical significance (P = 0.06). This study highlights the complexity of genetic predictors and their interplay with clinical factors in DKD progression. Despite the promise of personalised medicine through genetic markers, our findings suggest that current clinical factors remain paramount in the prediction of DKD. In conclusion, our results indicate that GWAS-derived GRSs for T2DM and CKD do not offer improved predictive ability over traditional clinical factors in the studied Czech T2DM population.

Childhood maltreatment, genetic risk, and subsequent risk of arrhythmias: a prospective cohort study.

Background: Emerging evidence has linked childhood maltreatment with cardiovascular disease risk; however, the association between childhood maltreatment and cardiac arrhythmias remains unclear. Moreover, any genetic predispositions to atrial fibrillation (AF), a common cardiac arrhythmia associated with an elevated risk of stroke, heart failure, and mortality, that modify such associations have been undocumented.Purpose: To examine the associations between childhood maltreatment and incident arrhythmias, and whether a genetic predisposition to arrhythmias modifies these associations.Methods: This prospective analysis included 151,741 participants from the UK Biobank (mean age 55.8 years, 43.4% male). Childhood maltreatment, including five types, was measured using the Childhood Trauma Screener (CTS). Incident arrhythmias (AF, ventricular arrhythmias [VA], and bradyarrhythmia [BA]) were documented through linked hospital admission and death registry. Weighted AF genetic risk score was calculated. Cox proportional hazard models were conducted to test for associations between childhood maltreatment and incident arrhythmias.Results: During a median follow-up of 12.21 years (interquartile range, 11.49-12.90 years), 6,588 AF, 2,093 BA, and 742 VA events occurred. Compared with the absence of childhood maltreatment, having 3-5 types of childhood maltreatment was associated with an increased risk of incident AF (HR, 1.23; 95%CI 1.09-1.37), VA (HR, 1.39; 95%CI 1.03-1.89), and BA (HR, 1.32; 95%CI 1.09-1.61) after adjusting demographic, socioeconomic and lifestyle factors. The associations between cumulative type of childhood maltreatment and the risk of AF (Poverall < .001; Pnonlinear = .674) and BA (Poverall = .007; Pnonlinear = .377) demonstrated a linear pattern. There was a gradient association between childhood maltreatment and AF risks across the intermediate and high genetic risk groups (both Ptrend < .05) but not within the low genetic risk group (Ptrend = .378), irrespective of non-significant interaction effect (Pinteraction = .204).Conclusion: Childhood maltreatment was associated with higher risks of incident arrhythmias, especially AF and BA. Genetic risk of AF did not modify these associations.

Previous studies indicate that childhood maltreatment is associated with cardiovascular disease risk.Childhood maltreatment was associated with an increased risk of incident arrhythmias, particularly atrial fibrillation and bradyarrhythmia. Genetic predisposition to atrial fibrillation did not significantly modify these associations.Childhood maltreatment could be a new psychological risk factor for cardiac arrhythmias in later life. Inquiries into childhood maltreatment and subsequent referral to psychological services may be helpful.

Identification of RAD17 as a candidate cancer predisposition gene in families with histories of pancreatic and breast cancers.

BACKGROUND: Among the 10% of pancreatic cancers that occur in a familial context, around a third carry a pathogenic variant in a cancer predisposition gene. Genetic studies of pancreatic cancer predisposition are limited by high mortality rates amongst index patients and other affected family members. The genetic risk for pancreatic cancer is often shared with breast cancer susceptibility genes, most notably BRCA2, PALB2, ATM and BRCA1. Therefore, we hypothesized that additional shared genetic etiologies might be uncovered by studying families presenting with both breast and pancreatic cancer. METHODS: Focusing on a multigene panel of 276 DNA Damage Repair (DDR) genes, we performed next-generation sequencing in a cohort of 41 families with at least three breast cancer cases and one pancreatic cancer. When the index patient with pancreatic cancer was deceased, close relatives (first or second-degree) affected with breast cancer were tested (39 families). RESULTS: We identified 27 variants of uncertain significance in DDR genes. A splice site variant (c.1605 + 2T > A) in the RAD17 gene stood out, as a likely loss of function variant. RAD17 is a checkpoint protein that recruits the MRN (MRE11-RAD50-NBS1) complex to initiate DNA signaling, leading to DNA double-strand break repair. CONCLUSION: Within families with breast and pancreatic cancer, we identified RAD17 as a novel candidate predisposition gene. Further genetic studies are warranted to better understand the potential pathogenic effect of RAD17 variants and in other DDR genes.

Physical frailty, genetic predisposition, and the risks of severe non-alcoholic fatty liver disease and cirrhosis: a cohort study.

BACKGROUND: Frailty, defined as a phenotype of decreased physiological reserves and diminished ability to respond to stressors, has been linked to the development of chronic diseases. Epidemiological evidence connecting frailty to non-alcoholic fatty liver disease (NAFLD) and cirrhosis risks remain sparse. We aimed to assess the longitudinal associations of frailty with the risks of severe NAFLD and cirrhosis in middle-aged to older adults and further explore the modification role of genetic risk on these associations. METHODS: This study included a total of 398 386 participants from the UK Biobank. Incident cases of severe NAFLD and cirrhosis were ascertained through linked hospital records and death registries. Frailty status was assessed by a modified version of the frailty phenotype, encompassing five key components: weight loss, tiredness, physical activity, gait speed, and grip strength. Participants were classified as pre-frailty if they met one or two of these criteria, and as frailty if they met three or more. Genetic predisposition to NAFLD and cirrhosis was estimated by genetic risk score (GRS) and further categorized into high, intermediate, and low genetic risk levels according to tertiles of GRSs. Cox proportional hazards regression model was employed to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for their associations. RESULTS: The mean (standard deviation) age of the study population was 56.6 (8.03) years. 214 408 (53.8%) of the participants was female; 14 924 (3.75%) of participants met the criteria for frailty, 170 498 (42.8%) for pre-frailty, and 212 964 (53.5%) for non-frailty. Over a median follow-up of 12.0 years, we documented 4439 incident severe NAFLD and 3323 incident cirrhosis cases, respectively. Compared with non-frailty, both pre-frailty (HR: 1.50; 95% CI: 1.40-1.60) and frailty (HR: 1.98; 95% CI: 1.77-2.21) were associated with increased risk of NAFLD. Similar associations were observed for cirrhosis, the corresponding HRs (95% CIs) for non-frailty, pre-frailty, and frailty were 1.00 (reference), 1.29 (1.20, 1.38), and 1.90 (1.66, 2.18). Such associations were consistent across all genetic risk levels, with no observed interactions between frailty and GRSs (all P for interactions ≥0.10). Compared with participants with frailty and a low level of genetic risk, the greatest risk increasement in developing severe NAFLD (HR: 3.36; 95% CI: 2.83-3.99) and cirrhosis (HR: 2.81; 95% CI: 2.29-3.44) was both observed in those with frailty and a high level of genetic risk. CONCLUSIONS: Our findings indicate that frailty is a significant predictor of severe NAFLD and cirrhosis, irrespective of genetic predisposition.

Genetic association between long non-coding RNA MIAT polymorphism and ischemic stroke susceptibility in the Chinese population.

OBJECTIVES: The genetic association of long non-coding RNAs (lncRNAs) polymorphism with ischemic stroke (IS) susceptibility is not fully understood. To explore whether lncRNA MIAT rs1894720 polymorphism can predict the susceptibility of IS in the Chinese Han population. MATERIALS AND METHODS: 200 IS cases and 200 healthy controls were enrolled. Serum MIAT levels were tested via qRT-PCR. Rs1894720 genotyping was accomplished through Sanger sequencing. RESULTS: MIAT rs1894720 genotypes were differentially distributed in IS and control groups. Rs1894720 TT genotype was considered to be a protective factor for IS risk in dominant model (GT + TT vs GG: OR = 0.630, 95 % CI = 0.412-0.962, P = 0.032). Further stratification results showed that individuals carrying the rs1894720 G allele in people older than 65 years, men, smokers, or those with hypertension had a higher risk of IS. MIAT rs1894720 GG genotype was positively related to the susceptibility to IS of LAA subtype compared with the healthy controls. GG genotype carriers had high serum MIAT levels compared to those with GT and TT genotypes. CONCLUSIONS: MIAT rs1894720 polymorphism was associated with the risk of IS in the Chinese Han population, especially for LAA subtype. Rs1894720 GG genotype carriers were at greater risk of developing IS.

Bilateral Uveal Melanoma: An Insight into Genetic Predisposition in Four New Unrelated Patients and Review of Published Cases.

Background: Primary bilateral uveal melanoma (BUM) is an exceptionally rare form of uveal melanoma (UM). This study aimed to explore the potential existence of a genetic predisposition towards the development of BUM. Methods: We employed an exome sequencing approach on germline DNA from four unrelated patients diagnosed with BUM, seeking pathogenic or likely pathogenic variants indicative of a genetic predisposition to UM. Results: None of the patients exhibited pathogenic variants in the BAP1 gene. However, loss-of-function (LoF) variants in the TERF2IP and BAX genes were identified in two of the BUM patients. For patients BUM1 and BUM2, no pathogenic/likely pathogenic variants of significant clinical relevance to BUM were found to warrant inclusion in this report. Conclusions: Our findings suggest the presence of yet-to-be-discovered genes that may contribute to UM predisposition, as evidenced by the absence of pathogenic variants in known UM predisposition genes among the four BUM patients studied. The TERF2IP and BAX genes emerge as noteworthy candidates for further investigation regarding their role in genetic predisposition to UM. Specifically, the potential role of UM as a candidate cancer within the spectrum of cancers linked to pathogenic variants in the TERF2IP gene and other genes associated with the shelterin complex warrants further examination. Additional functional studies are necessary to support or challenge this hypothesis.

Genomic Newborn Screening for Pediatric Cancer Predisposition Syndromes: A Holistic Approach.

As next-generation sequencing (NGS) has become more widely used, germline and rare genetic variations responsible for inherited illnesses, including cancer predisposition syndromes (CPSs) that account for up to 10% of childhood malignancies, have been found. The CPSs are a group of germline genetic disorders that have been identified as risk factors for pediatric cancer development. Excluding a few "classic" CPSs, there is no agreement regarding when and how to conduct germline genetic diagnostic studies in children with cancer due to the constant evolution of knowledge in NGS technologies. Various clinical screening tools have been suggested to aid in the identification of individuals who are at greater risk, using diverse strategies and with varied outcomes. We present here an overview of the primary clinical and molecular characteristics of various CPSs and summarize the existing clinical genomics data on the prevalence of CPSs in pediatric cancer patients. Additionally, we discuss several ethical issues, challenges, limitations, cost-effectiveness, and integration of genomic newborn screening for CPSs into a healthcare system. Furthermore, we assess the effectiveness of commonly utilized decision-support tools in identifying patients who may benefit from genetic counseling and/or direct genetic testing. This investigation highlights a tailored and systematic approach utilizing medical newborn screening tools such as the genome sequencing of high-risk newborns for CPSs, which could be a practical and cost-effective strategy in pediatric cancer care.

Management and Clinical Outcomes of Breast Cancer in Women Diagnosed with Hereditary Cancer Syndromes in a Clinic-Based Sample from Colombia.

This study aimed to investigate prognosis and survival differences in 82 breast cancer patients with germline pathogenic/likely pathogenic variants (PVs) treated and followed at the Breast Unit of the Instituto Nacional de Cancerología, Colombia (INC-C) between 2018 and 2021. Median age at diagnosis was 46 years, with 62.2% presenting locally advanced tumors, 47.6% histological grade 3, and 35.4% with triple-negative breast cancer (TNBC) subtype. Most carriers, 74.4% (61/82), had PVs in known breast cancer susceptibility genes (i.e., "associated gene carriers" group, considered inherited breast cancer cases): BRCA2 (30), BRCA1 (14), BARD1 (4), RAD51D (3), TP53 (2), PALB2 (2), ATM (2), CHEK2 (1), RAD51C (1), NF1 (1), and PTEN (1). BRCA1-2 represented 53.7%, and homologous recombination DNA damage repair (HR-DDR) genes associated with breast cancer risk accounted for 15.9%. Patients with PVs in non-breast-cancer risk genes were combined in a different category (21/82; 25.6%) (i.e., "non-associated gene carriers" group, considered other breast cancer cases). Median follow-up was 38.1 months, and 24% experienced recurrence, with 90% being distant. The 5-year Disease-Free Survival (DFS) for inherited breast cancer cases was 66.5%, and for other breast cancer cases it was 88.2%. In particular, for carriers of PVs in the BRCA2 gene, it was 37.6%. The 5-year Overall Survival (OS) rates ranged from 68.8% for those with PVs in BRCA2 to 100% for those with PVs in other HR-DDR genes. Further studies are crucial for understanding tumor behavior and therapy response differences among Colombian breast cancer patients with germline PVs.

The impact of the European Society of Cardiology guidelines and whole exome sequencing on genetic testing in hereditary cardiac diseases.

In the last decade, an incredible improvement has been made in elucidating the genetic bases of cardiomyopathies. Here we report the impact of either the European Society of Cardiology (ESC) guidelines or the use of whole exome sequencing (WES) in terms of a number of variants of uncertain significance (VUS) and missed diagnoses in a series of 260 patients affected by inherited cardiac disorders. Samples were analyzed using a targeted gene panel of 128 cardiac-related genes and/or WES in a subset of patients, with a three-tier approach. Analyzing (i) only a subset of genes related to the clinical presentation, strictly following the ESC guidelines, 20.77% positive test were assessed. The incremental diagnostic rate for (ii) the whole gene panel, and (iii) the WES was 4.71% and 11.67%, respectively. The diverse analytical approaches increased the number of VUSs and incidental findings. Indeed, the use of WES highlights that there is a small percentage of syndromic conditions that standard analysis would not have detected. Moreover, the use of targeted sequencing coupled with "narrow" analytical approach prevents the detection of variants in actionable genes that could allow for preventive treatment. Our data suggest that genetic testing might aid clinicians in the diagnosis of inheritable cardiac disorders.

Beyond the Tailbone: A Family's Journey Through Caudal Regression Syndrome-A Triple Sibship.

BACKGROUND: Caudal regression syndrome (CRS), also known as caudal agenesis, results from abnormal development of the caudal aspect of the spinal cord and vertebral column due to an earlier abnormality of gastrulation. RESULTS: This report showcases a unique scenario where three siblings, devoid of any prior family history or identifiable risk factors, exhibit symptoms of CRS and receive care at a government-run tertiary facility dedicated to children's health. In establishing a concrete diagnosis, we relied on skeletal surveys, comprehensive symptom evaluation, and medical history assessment. Additionally, we recommended further investigation through magnetic resonance imaging and genetic testing to attain a more in-depth understanding and confirmation of the condition. Unfortunately, the financial constraints faced by the parents led to the unfeasibility of pursuing these advanced diagnostic options. Given the rarity of this syndrome and the limited existing literature, our report is a significant contribution. It marks the first comprehensive exploration of CRS from the genetic and familial predisposition perspective, shedding new light on this rare condition. CONCLUSION: This case series pioneers our understanding of the familial and genetic connections between CRS and sacral agenesis. Strikingly, each subsequent generation has experienced more severe manifestations earlier, furnishing compelling evidence that underpins the genetic predisposition to CRS.

Air pollution, genetic factors, and chronic rhinosinusitis: A prospective study in the UK Biobank.

BACKGROUND: Chronic rhinosinusitis (CRS) is a prevalent upper respiratory condition that manifests in two primary subtypes: CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). While previous studies indicate a correlation between air pollution and CRS, the role of genetic predisposition in this relationship remains largely unexplored. We hypothesized that higher air pollution exposure would lead to the development of CRS, and that genetic susceptibility might modify this association. METHODS: This cohort study involving 367,298 adult participants from the UK Biobank, followed from March 2006 to October 2021. Air pollution metrics were estimated at residential locations using land-use regression models. Cox proportional hazard models were employed to explore the associations between air pollution exposure and CRS, CRSwNP, and CRSsNP. A polygenic risk score (PRS) was constructed to evaluate the joint effect of air pollution and genetic predisposition on the development of CRS. RESULTS: We found that the risk of CRS increased under long-term exposure to PM2.5 [the hazard ratios (HRs) with 95 % CIs: 1.59 (1.26-2.01)], PM10 [1.64 (1.26-2.12)], NO2 [1.11 (1.04-1.17)], and NOx [1.18 (1.12-1.25)], respectively. These effects were more pronounced among participants with CRSwNP, although the differences were not statistically significant. Additionally, we found that the risks for CRS and CRSwNP increased in a graded manner among participants with higher PRS or higher exposure to PM2.5, PM10, or NOx concentrations. However, no multiplicative or additive interactions were observed. CONCLUSIONS: Long-term exposure to air pollution increases the risk of CRS, particularly CRSwNP underscoring the need to prioritize clean air initiatives and environmental regulations.

Genetic Predisposition to Vaccine-Induced Immune Thrombotic Thrombocytopenia: is there a Family Link?

Background: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare life-threatening thrombotic reaction to COVID-19 vaccines. Case description: Two young male first cousins, with a family history of idiopathic thrombocytopenic purpura, developed VITT after the Ad26.COV2.S vaccine. Both had a favourable clinical and analytical outcome. We investigated the genetic factors that could be associated with a genetic predisposition to VITT. Conclusions: There are no published cases where the VITT patients were relatives. The genetic study did not reveal any likely pathogenic variants, although the prevalent polymorphism c.497A>G (p.(His166Arg)) in the FCGR2A gene was found in a homozygous state. More studies are required to better understand VITT's pathophysiology and any underlying genetic predispositions. LEARNING POINTS: Vaccine-induced immune thrombotic thrombocytopenia (VITT), a rare but life-threatening disease, emerged with COVID-19 vaccines.The genetic analyses revealed the FCGR2A gene in a homozygous state.These cases may raise new questions about a family predisposition to VITT.

Mechanisms of complex regional pain syndrome.

Complex Regional Pain Syndrome (CRPS) is a chronic pain disorder characterized by a diverse array of symptoms, including pain that is disproportionate to the initial triggering event, accompanied by autonomic, sensory, motor, and sudomotor disturbances. The primary pathology of both types of CRPS (Type I, also known as reflex sympathetic dystrophy, RSD; Type II, also known as causalgia) is featured by allodynia, edema, changes in skin color and temperature, and dystrophy, predominantly affecting extremities. Recent studies started to unravel the complex pathogenic mechanisms of CRPS, particularly from an autoimmune and neuroimmune interaction perspective. CRPS is now recognized as a systemic disease that stems from a complex interplay of inflammatory, immunologic, neurogenic, genetic, and psychologic factors. The relative contributions of these factors may vary among patients and even within a single patient over time. Key mechanisms underlying clinical manifestations include peripheral and central sensitization, sympathetic dysregulation, and alterations in somatosensory processing. Enhanced understanding of the mechanisms of CRPS is crucial for the development of effective therapeutic interventions. While our mechanistic understanding of CRPS remains incomplete, this article updates recent research advancements and sheds light on the etiology, pathogenesis, and molecular underpinnings of CRPS.

Clinical Patterns of Sarcoidosis Patients with and without Uveitis: Insights from a Dutch Sarcoidosis Centre.

PURPOSE: Uveitis is a common ocular manifestation in individuals with sarcoidosis, a multisystem inflammatory disorder. This study aimed to explore clinical and genetic factors associated with the presence or absence of uveitis in sarcoidosis patients. METHODS: Total 625 Dutch sarcoidosis patients were included. Among these, 170 underwent ophthalmic examination, and 61 were diagnosed with uveitis. Demographic and clinical data, including age, gender, race, biopsy status, chest radiography findings, TNF-α inhibitor treatment, and uveitis classification were collected retrospectively from medical records. Genetic data was available for HLA haplotypes, TNF-α G-308A, and BTNL2 G16071A polymorphisms. RESULTS: The majority of the patients presented with bilateral uveitis (80.3%). The proportion of women was higher in the uveitis group compared to the non-uveitis group (67.2% and 47.7%; p = 0.014). Pulmonary involvement (chest radiographic stage II-III) was significantly lower in patients with uveitis (36.1% versus 64.2%; p < 0.001). Patients with uveitis were more often treated with TNF-α inhibitors (67.2% versus 29.4%; p < 0.001) and the outcome was better compared with the non-uveitis group, 92% vs 68%, responders (p < 0.012). Uveitis patients treated with TNF-α inhibitors (either adalimumab or infliximab) were more likely to suffer from intermediate or posterior uveitis than anterior uveitis. Genetic analysis identified a significant association between the BTNL2 G16071A GG genotype and uveitis (p = 0.012). CONCLUSION: This study highlights distinctive demographic, clinical and genetic features associated with uveitis in sarcoidosis patients. Ocular sarcoidosis was more prevalent in women. Further research is warranted to explore the implications of these findings for treatment strategies and prognostic assessments.

A Comprehensive Look at the Development of Asthma in Children.

Asthma, a prevalent chronic respiratory condition affecting millions of children globally, presents a significant health challenge. This review critically examines the developmental pathways of asthma in children, focusing on genetic, environmental, and early-life determinants. Specifically, we explore the impact of prenatal and postnatal factors such as maternal smoking, nutrition, respiratory infections, and allergen exposure on asthma development. Our analysis highlights the intricate interplay of these influences and their contribution to childhood asthma. Moreover, we emphasize targeted strategies and interventions to mitigate its burden, including genetic counseling for at-risk families, environmental modifications to reduce triggers, and early-life immunomodulation. By delving into these preventive measures and interventions, our review aims to provide actionable insights for healthcare professionals in developing tailored strategies to address the complexities of childhood asthma. In summary, this article offers a detailed examination of asthma development in children, aiming to enhance understanding and inform efforts to reduce its burden through targeted interventions.