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Background: This cross-sectional study investigated the relationship between genetic variations in monocarboxylate transporter genes and blood lactate production and removal after high-intensity efforts in humans. The study was conducted to explore how genetic variations in the MCT1, MCT2, and MCT4 genes influenced lactate dynamics and to advance the field of sports genetics by pinpointing critical genetic markers that can enhance athletic performance and recovery. Methods: 337 male athletes from Poland and the Czech Republic underwent two intermittent all-out Wingate tests. Before the tests, DNA samples were taken from each participant, and SNP (single nucleotide polymorphism) analysis was carried out. Two intermittent all-out tests were implemented, and lactate concentrations were assessed before and after these tests. Results: Sprinters more frequently exhibited the haplotype TAC in the MCT2 gene, which was associated with an increase in the difference between maximum lactate and final lactate concentration. Additionally, this haplotype was linked to higher maximum lactate concentration and was more frequently observed in sprinters. The genotypic interactions AG/T- and GGxT- (MCT1 rs3789592 x MCT4 rs11323780), TTxTT (MCT1 rs12028967 x MCT2 rs3763979), and MCT1 rs7556664 x MCT4 rs11323780 were all associated with an increase in the difference between maximum lactate concentration and final lactate concentration. Conversely, the AGxGG (MCT1 rs3789592 x MCT2 rs995343) interaction was linked to a decrease in this difference. The relationship between maximum lactate concentration and genotypic interactions can be observed as follows: when ATxTT (MCT2 rs3763980 x MCT4 rs11323780) or CTxCT (MCT1 rs10857983 x MCT2 rs3763979) genotypic combinations are present, it leads to a decrease in maximum lactate concentration. Similarly, the combination of CTxCT (MCT1 rs4301628 x MCT2 rs3763979), CT x TT (MCT1 rs4301628 x MCT4 rs11323780), and CTxTT (MCT1 rs4301628 x MCT2 rs3763979) results in decreased maximum lactate concentration. Conclusions: The TAC haplotype (rs3763980, rs995343, rs3763979) in the MCT2 gene is associated with altered lactate clearance in sprinters, potentially affecting performance and recovery by elevating post-exercise lactate concentrations. While MCT4 rs11323780 is also identified as a significant variant in lactate metabolism, suggesting its role as a biomarker for sprinting performance, further investigation is necessary to clarify underlying mechanisms and consider additional factors. Based on elite male athletes from Poland and the Czech Republic, the study may not generalize to all sprinters or diverse athletic populations. Although genetic variants show promise as biomarkers for sprinting success, athletic performance is influenced by a complex interplay of genetics, environment, and training extending beyond MCT genes. [ABSTRACT FROM AUTHOR]

Melasma is a chronic skin disorder characterized by hyperpigmentation, predominantly affecting women with darker skin types, including those of African descent. This study investigates the association between genetic variants in SLC45A2, TYR, HERC2, and SLC24A5 genes and the severity of melasma in women of reproductive age. Forty participants were divided into two groups: twenty with facial melasma and twenty without. Deoxyribonucleic acid (DNA) was extracted from blood samples and genotyped using TaqMan assays to identify allele frequencies and genotype distributions. Significant associations were observed for the TYR gene (rs1042602), HERC2 gene (rs1129038), and SLC24A5 gene (rs1426654) polymorphisms, highlighting their potential roles in melasma susceptibility. For example, the rs1042602 Single Nucleotide Polymorphisms (SNP) in the TYR gene showed a strong association with melasma, with the AA genotype conferring a markedly increased risk. Similarly, the rs1129038 SNP in the HERC2 gene and the rs1426654 SNP in the SLC24A5 gene revealed significant genetic variations between groups in women of African descent. These findings underscore the influence of genetic polymorphisms on melasma's pathogenesis, emphasizing the need for personalized approaches to its treatment, particularly for women with darker skin types. [ABSTRACT FROM AUTHOR]

Celiac disease is attributable to a combination of genetic predisposition and exposure to dietary gluten, with immune system involvement. The incidence is increasing globally, and the societal economic burden of celiac disease stretches beyond the cost of gluten-free food. This enteropathy that affects the small intestine has been related to different disorders and comorbidities. Thus, the implications of suffering from this disease are multidimensional and need further consideration. Celiac disease is a serious condition that remains under-recognized, resulting in an increased need for programs for better management. This review aims to summarize the current evidence regarding celiac diseases, with special emphasis on clinical implications, diagnosis, dietary management, socioeconomical aspects, and future perspectives. [ABSTRACT FROM AUTHOR]

Macular telangiectasia type 2 (MacTel) is a slowly progressive macular disorder that is often diagnosed late due to the gradual onset of vision loss. Recent advances in diagnostic techniques have facilitated earlier detection and have shown that MacTel is more common than initially thought. The disease is genetically complex, and multiple variants contribute incrementally to the overall risk. The familial occurrence of the disease prompted the investigation of the genetic background of MacTel. To better understand the molecular milieu of the disease, a literature review of the clinical reports and publications investigating the genetic factors of MacTel was performed. To date, disease-associated variants have been found in genes involved in amino acid (glycine/serine) metabolism and transport, urea cycle, lipid metabolism, and retinal vasculature and thickness. Variants in genes implicated in sphingolipid metabolism and fatty acid/steroid/retinol metabolism have been found in patients with neurological disorders who also have MacTel. Retinal metabolism involves complex biochemical processes that are essential for maintaining the high energy requirements of the retina. Genetic alterations can disrupt key metabolic pathways, leading to retinal cell degradation and the subsequent vision loss that characterizes several retinal disorders, including MacTel. This review article summarizes genetic findings that may allow MacTel to be further investigated as an inherited retinal disorder. [ABSTRACT FROM AUTHOR]

Tick-bite hypersensitivity encompasses a range of clinical manifestations, from localized allergic reactions to systemic conditions like alpha-gal syndrome (AGS), an IgE-mediated allergy to galactose-α-1,3-galactose (α-Gal). This study investigated the clinical, molecular, immunological, and genetic features of two hypersensitivity cases. Two cases were analyzed: a 30-year-old woman with fixed drug reaction (FDR)-like hypersensitivity and a 10-year-old girl with AGS exhibiting borderline α-Gal-specific IgE. Diagnostic methods included allergen-specific IgE quantification, HLA genotyping, histopathological examination, and the molecular detection of tick-borne pathogens using microfluidic PCR. Case I demonstrated histopathological features of chronic lymphocytic inflammation and eosinophilic infiltrates, with HLA-B13 and DRB113 alleles indicating genetic susceptibility to hypersensitivity, while histological findings suggested a localized FDR-like reaction. Case II exhibited borderline α-Gal-specific IgE, resolving completely with a mammalian-free diet. The presence of HLA-DRB101 and DQB1*05 in the second patient indicated a genetic predisposition to AGS and other atopic conditions. No infectious etiology was identified in either case. These findings emphasize the heterogeneity of tick-related hypersensitivity and the importance of HLA genotypes in susceptibility. Comprehensive molecular, immunological, and genetic profiling offers valuable insights into the mechanisms of hypersensitivity, supporting personalized approaches for the diagnosis and management of tick-induced allergic conditions. [ABSTRACT FROM AUTHOR]

Background and Objectives: Hereditary hearing loss is the most common genetic disorder in children. Nearly 120 genes associated with auditory impairment have been identified. Although the disease is clinically and genetically complex, the chances of identifying deafness-causing loci increase when studying consanguineous families. Materials and Methods: Whole-exome sequencing was performed to identify genetic variants underlying sensorineural hearing loss in affected individuals from a family with third-degree consanguineous practices. Results: A homozygous deletion of 250.285 kb was identified in the 16p12.2 region encompassing three genes, METTL9, IGSF6, and OTOA, and a partial deletion of the NPIPB4 gene co-segregated within the family. Conclusions: This study highlighted the genetic heterogeneity of hearing loss in consanguineous families. Future research should focus on the OTOA mutational spectrum in South Indian populations with hearing loss. [ABSTRACT FROM AUTHOR]

Normal tissue reactions vary significantly among patients receiving the same radiation treatment regimen, reflecting the multifactorial etiology of late radiation toxicity. Predicting late radiation toxicity is crucial, as it aids in the initial decision-making process regarding the treatment modalities. For patients undergoing radiotherapy, anticipating late toxicity allows for planning adjustments to optimize individualized care. Various dosimetric parameters have been shown to influence the incidence of late toxicity, and the literature available on this topic is extensive. This narrative review examines patient-related determinants of late toxicity following external beam radiotherapy for pelvic tumors, with a focus on prostate and cervical cancer patients. In Part I, we address various methods for quantifying radiation toxicity, providing context for interpreting toxicity data. Part II examines the current insights into the clinical risk factors for late toxicity. While certain factors—such as previous abdominal surgery, smoking behavior, and severe acute toxicity—have consistently been reported, most of the others show inconsistent associations. In Part III, we explore the influence of genetic factors and discuss promising predictive assays. Single-nucleotide polymorphisms (SNPs) likely elevate the risk in specific combinations. Advances in artificial intelligence now allow for the identification of SNP patterns from large datasets, supporting the development of polygenic risk scores. These innovations hold promise for improving personalized treatment strategies and reducing the burden of late toxicity in cancer survivors. [ABSTRACT FROM AUTHOR]

Little evidence exists regarding the associations between clinical parameter‐based biological aging and the incidence and outcome of chronic kidney disease (CKD). Thus, we aimed to assess the associations between biological aging, genetic risk, and the risk of CKD, as well as investigate the impact of accelerated biological aging on life expectancy. 281,363 participants free of kidney diseases from the UK Biobank were included in this prospective study. Biological age was measured from clinical traits using the KDM‐BA and PhenoAge algorithms, and the discrepancies from chronological age were defined as biological age accelerations. A polygenic score was calculated to indicate the genetic predisposition of the estimated glomerular filtration rate (eGFR). A cause‐specific competing risk model was used to estimate hazard ratios (HRs) and the corresponding confidence intervals (CIs) of incident CKD. We found that individuals with more pronounced accelerations in biological age exhibited an elevated risk of developing CKD (HRQuartile 4 vs. Quartile 1, 1.90; 95% CI, 1.77–2.05 for KDM‐BA acceleration and HRQuartile 4 vs. Quartile 1, 2.79; 95% CI, 2.58–3.01 for PhenoAge acceleration), with nonlinear relationships. Notably, there were positive additive interactions between biological aging and genetic risk on CKD risk. Among the CKD population, accelerated biological aging was associated with a further decline in life expectancy. Advanced biological aging may potentially increase the vulnerability to developing CKD in individuals aged midlife and beyond, particularly among those with high genetic risk for abnormal kidney function, and could reduce the life expectancy of CKD patients. [ABSTRACT FROM AUTHOR]

Background: Crohn's disease (CD) and Ankylosing Spondylitis (AS) are chronic conditions with overlapping inflammatory pathways. This research investigates the genetic association between AS and the requirement for more aggressive therapeutic interventions in CD, suggesting a likelihood of increased severity in CD progression among individuals diagnosed with AS. Methods: This study utilized two-sample Mendelian randomization (TSMR) to analyze GWAS datasets for AS and CD requiring second-line treatment. Instrumental variables were selected based on single-nucleotide polymorphisms of genome-wide significance. Analytical methods included inverse-variance weighted (IVW), MR Egger, and other MR approaches, alongside sensitivity analysis, to validate the findings. Results: Our results indicated a significant association between AS genetic predisposition and the increased need for second-line treatments in CD. The IVW method showed an Odds Ratio (OR) of 2.16, and MR Egger provided an OR of 2.71, both were statistically significant. This association persisted even after the exclusion of influential outlier SNP rs2517655, confirming the robustness of our findings. Conclusions: This study suggests that genetic factors contributing to AS may influence the progression of CD, potentially necessitating more intensive treatment strategies. These findings underscore the importance of early screening in patients with co-existing AS and CD for tailoring treatment approaches, thus advancing personalized medicine in the management of these complex conditions. [ABSTRACT FROM AUTHOR]

Introduction and Purpose: Varicose veins in the lower limbs are common, particularly among those with prolonged standing occupations, contributing to chronic venous insufficiency (CVI). CVI affects about 60% of adults, with varicose veins present in 25–33% of women and 10–20% of men, increasing with age. Understanding and addressing this condition is crucial as it impacts daily life and raises the risk of thrombosis. Effective treatments are essential to alleviate these health issues. State of Knowledge: Varicose veins result from a mix of genetic, hemodynamic, and vein wall factors. Family history plays a significant role, increasing susceptibility. Hemodynamic issues include malfunctioning venous valves and elevated venous pressure. Vein wall changes and thrombotic activity also contribute. Symptoms range from cosmetic concerns to pain and complications like venous ulcers. Understanding these factors is key for effective management. Conclusions: Surgical treatments like high ligation and stripping are standard but have drawbacks such as scarring and long recovery. Valvuloplasty addresses deep venous valve issues but is limited. Minimally invasive options, such as endovenous laser therapy and sclerotherapy, offer promising alternatives but with some recurrence risk. Compression therapies, including elastic stockings and pneumatic compression, aid recovery and symptom relief. Elastic bandage therapy is effective but requires precise application to avoid complications. Each method has pros and cons, underscoring the need for tailored treatment approaches. [ABSTRACT FROM AUTHOR]

Introduction: Ovarian cancer is a significant global health concern for women. More than 85-90% of ovarian cancer cases originates from epithelial causes. Dysfunctional p53 is a hallmark of many cancers, including ovarian cancer. Alteration in functioning of p53 gene has been connected to the onset and spread of ovarian cancer. Aim: To analyse the Immunohistochemical (IHC) expression of p53 gene and clinicopathological features of Low-grade Serous Ovarian Cancer (LGSOC) and High-grade Serous Ovarian Cancer (HGSOC). Materials and Methods: This cohort study was conducted on 37 histopathologically confirmed cases of serous carcinomas of ovary in Department of Genetics, Maharshi Dayanand University, Rohtak, in collaboration with Department of Pathology, Pandit Bhagwat Dayal Sharma University of Health Sciences, Rohtak, Haryana, India during the period 2019 to 2023. Study was approved by the Institutional Human Ethical Research Committee (Ref no-IHEC/19/07). Parameters of study included clinical features of ovarian cancer patients, histological types, the Federation of Gynaecology and Obstetrics stage, survival of patients and prognostic factors. Analysis of p53 expression was analysed immunohistochemically. Statistical analysis was performed using GraphPad PRISM Version 8.0.1. Results: A total of 37 cases of serous carcinoma were analysed, including 26 cases of HGSOC and 11 cases of LGSOC. Comparative analysis revealed advanced-stage disease in patients HGSOC, 20 cases (76.92%) compared to 4 cases (36.36%) in LGSOC. Additionally, higher median CA125 levels were found in HGSOC patients (median 269 U/mL vs. 27 U/mL) and a higher rate of postsurgery residual disease (57.69% vs. 27.27%). Among all serous carcinoma cases, 17 cases (45.95%) showed null p53 expression, 16 cases (43.24%) showed diffuse p53 expression, and four cases (10.81%) had focal positive expression (wild type). Statistically significant differences (p-value=0.02) between the grade of serous ovarian cancer and the expression of p53 were observed. However, median Overall Survival (OS) between the two groups (39 months for HGSOC vs. 41 months for LGSOC) showed a statistically non significant difference (p-value=0.51). Log-rank statistical analysis showed a non significant association between the overall survival time of the two grades, with a Hazard Ratio of 1.384 (0.5-3.5) at 95% confidence interval with p-value=0.51. Conclusion: The significant difference in p53 IHC expression between LGSOC and HGSOC highlighted the role of p53 mutation in pathogenesis of HGSOC. However, by understanding genetic predisposition of ovarian tumour preventive steps as well as planning of early treatment can reduce the mortality rate. [ABSTRACT FROM AUTHOR]

Alzheimer's disease(AD) is a multifactorial neurodegenerative disorder characterized by the progressive loss of neurons and synaptic dysfunction, primarily affecting the cortex and hippocampus. The etiology of AD is complex, involving the continuous and intricate interaction between genetic and non-genetic environmental factors. Genetic predisposition plays a significant role, with approximately 60-80% of AD risk attributed to hereditary factors. Familial early-onset AD(EOAD), with autosomal-dominant mutations in APP, PSEN1, and PSEN2, represents about 1-5% of cases and typically manifests before age 65. Rare autosomal-recessive mutations, like A673V(APP gene), are also implicated. Late-onset AD(LOAD), more common, is influenced by a combination of genetic and environmental factors, with the APOE ε4 allele being a major risk factor. Protective factors, such as the APOE ε2 allele and rare mutations like Ala673Thr, can reduce AD risk. The interplay between genetic variants, environmental influences, and pathological processes underpins the disease's progression. This study highlights the importance of understanding the genetic and non-genetic determinants of AD to advance personalized treatment and early detection strategies. Future research and personalized medicine approaches are essential for mitigating AD risks and improving management outcomes. [ABSTRACT FROM AUTHOR]

Aims Aortic aneurysms (AA) frequently involve dysregulation of transforming growth factor β (TGF-β)-signalling in the aorta. Here, FURIN was tested as aneurysm predisposition gene given its role as proprotein convertase in pro-TGF-β maturation. Methods and results Rare FURIN variants were detected by whole-exome sequencing of 781 unrelated aortic aneurysm patients and affected relatives. Thirteen rare heterozygous FURIN variants occurred in 3.7% (29) unrelated index AA patients, of which 72% had multiple aneurysms or a dissection. FURIN maturation and activity of these variants were decreased in vitro. Patient-derived fibroblasts showed decreased pro-TGF-β processing, phosphorylation of downstream effector SMAD2 and kinases ERK1/2, and steady-state mRNA levels of the TGF-β-responsive ACTA2 gene. In aortic tissue, collagen and fibrillin fibres were affected. One variant (R745Q), observed in 10 unrelated cases, affected TGF-β signalling variably, indicating effect modification by individual genetic backgrounds. Conclusion FURIN is a novel, frequent genetic predisposition for abdominal-, thoracic-, and multiple aortic or middle sized artery aneurysms in older patients, by affecting intracellular TGF-β signalling, depending on individual genetic backgrounds. [ABSTRACT FROM AUTHOR]

Abstract Background Psoriasis is an immune-mediated chronic inflammatory disease associated with multiple factors. To evaluate the extent to which C-reactive protein (CRP) and genetic predisposition affect the incidence of psoriasis. Methods The cohort study retrieved 420,040 participants without psoriasis at baseline from the UK Biobank. Serum CRP was categorized into two levels: < 2 mg/L (normal) and ≥ 2 mg/L (elevated). The polygenic risk score (PRS) was used to estimate genetic predisposition, and was characterized as low, moderate and high PRS. The possible interaction and joint associations between CRP and PRS were assessed using Cox proportional hazards models. Results Participants with high CRP levels had an increased risk of incident psoriasis compared to those with low CRP levels (HR: 1.26, 95% CI: 1.18–1.34). Participants with high CRP levels and high PRS had the highest risk of incident psoriasis [2.24 (95% CI: 2.01, 2.49)], compared with those had low CRP levels and low PRS. Significant additive and multiplicative interaction were found between CRP and PRS in relation to the incidence of psoriasis. Conclusions Our results suggest that higher CRP concentration may be associated with higher psoriasis incidence, with a more pronounced association observed in individuals with high PRS for psoriasis. So, clinicians should be aware that the risk of incident psoriasis may increase in general population with high CRP levels and high PRS, so that early investigation and intervention can be initiated.

Aim: to present literature data on the genetic underpinnings of inflammatory bowel disease (IBD), focusing on key genetic variants such as NOD2, ATG16L1, and IL23R; The objective of this was to understand how these genetic factors contribute to immune dysregulation, epithelial barrier dysfunction, and mucosal homeostasis in IBD.Key points. IBD, encompassing Crohn's disease and ulcerative colitis, is intricately shaped by a nexus of genetic and environmental factors, and its global prevalence is increasing. Genetic research has identified pivotal variants — NOD2, ATG16L1, and IL23R — linked to IBD, influencing key pathways, such as autophagy, interleukin signaling, and bacterial management. These genetic variants, integral to IBD's etiology of IBD, have functional significance because they perturb immune regulation, compromise epithelial barrier integrity, and disrupt mucosal homeostasis, collectively contributing to intestinal inflammation through diverse mechanisms. Early detection of IBD is paramount for arresting disease progression and underscoring the importance of prognostic testing and genetic screening, especially in cases with familial predispositions or very early onset IBD. Additionally, the use of certain IBD medications, such as corticosteroids, azathioprine, and infliximab, may have implications for male fertility, necessitating a nuanced understanding of these potential effects for informed decision-making in IBD management. This comprehensive understanding of the genetic landscape, functional implications, and diagnostic strategies is vital for advancing personalized treatments and improving outcomes in individuals with IBD.Conclusion. IBD is a complex gastrointestinal disorder influenced by a combination of genetic and environmental factors. Genetic variants, including NOD2, ATG16L1, and IL23R, contribute to dysregulation of immune responses, epithelial barrier function, and mucosal homeostasis. While progress has been made in understanding the genetic landscape of IBD, ongoing research is needed to elucidate the functional consequences of these variants, identify causal genes, and explore gene-environment interactions. This deeper understanding holds the potential for more precise diagnostics and personalized treatments, ultimately improving outcomes in individuals living with IBD.

Background and objective: Genetic predisposition is a factor in 40–70% of cases of benign prostatic hyperplasia (BPH) and voiding symptoms. However, informal reviews summarizing genes and variants imparting genetic disposition to BPH are not yet available. Methods: We conducted an informal narrative review of genes and variants associated with BPH or voiding symptoms in candidate gene studies, genome-wide association studies (GWAS), and Mendelian randomization studies. A literature search of PubMed was performed using the terms “BPH heritability”, “LUTS heritability”, “BPH risk variant”, “LUTS genetic risk”, “GWAS BPH”, and “genome-wide BPH”. Key findings and limitations: Candidate gene studies focused on variants related to the vitamin D receptor, steroid metabolism, detoxification, inflammation, cytokines, and growth factors, which were previously found to be associated with prostate cancer. Despite overall limited conclusiveness of candidate gene approaches, some recent studies point to population-dependent contributions of single variants to genetic BPH predisposition. Four GWAS and two Mendelian randomization studies for BPH identified correlation of BPH and voiding symptoms with variants related to testosterone, prostate-specific antigen, progesterone, transcription factors, the cell cycle, neuronal organization, and thyroid-stimulating hormone. Conclusions and clinical implications: The drug targetability of most of the genes identified in the BPH setting is precluded by predictable unbalanced side effects, low efficacy, unknown organ specificity, and a lack of characterization in the prostate. Meta-analyses of GWAS are not yet available for BPH. Unless calculated using quantitative approaches, specific contributions of the risk variants identified to the overall risk of BPH remain uncertain. Patient summary: While age is a risk factor for benign enlargement of the prostate in all affected patients, genetic factors may be involved in 39–72% of patients. Research has identified a number of possible risk genes, but is still at a very early stage. It is unlikely that drugs could be used to target these genes because of expected side effects that would be tolerated for cancer treatment, but not for benign diseases, or low efficacy in previous clinical trials.

Background & Aims: Type 1 diabetes mellitus (T1DM) is an autoimmune condition characterized by the destruction of pancreatic β-cells. While environmental factors and autoantibodies play a role, genetic predisposition, particularly involving HLA class II alleles (DR and DQ), is significant. This study aimed to evaluate the frequency of DRB1 and DQB1 genotypes associated with T1D, with a focus on gender differences. Materials & Methods: A total of 187 Sudanese subjects, aged 5 to 18 years, were enrolled, including 87 T1D cases and 100 non-diabetic controls. The study was conducted in diabetes hospitals in Khartoum State. HLA gene polymorphisms were assessed using the allele-specific refractory mutation system-polymerase chain reaction (ARMS-PCR) method. Results: Genotype frequencies for C/C, G/G, and G/C were 11.8%, 66.7%, and 21.6% in females, and 10.2%, 67.3%, and 22.4% in males, respectively. Statistical analysis showed no significant gender-related differences in genotype distributions (Chi-square, p = 0.968). Conclusion: The study found no significant association between genotype distributions and gender in Sudanese children with T1D. This suggests that gender does not significantly influence the distribution of DRB1 and DQB1 genotypes related to T1D in the study population.

Abstract Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by abdominal pain, diarrhea, rectal bleeding, and weight loss. The pathogenesis and treatment of UC remain key areas of research interest. Various factors, including genetic predisposition, immune dysregulation, and alterations in the gut microbiota, are believed to contribute to the pathogenesis of UC. Current treatments for UC include 5-aminosalicylic acids, corticosteroids, immunosuppressants, and biologics. However, study reported that the one-year clinical remission rate is only around 40%. It is necessary to prompt the exploration of new treatment modalities. Biologic therapies, such as anti-TNF-α monoclonal antibody and JAK inhibitor, primarily consist of small molecules targeting specific pathways, effectively inducing and maintaining remission. Given the significant role of the gut microbiota, research into intestinal microecologics, such as probiotics and prebiotics, and fecal microbiota transplantation (FMT) shows promising potential in UC treatment. Additionally, medicinal herbs, such as chili pepper and turmeric, used in complementary therapy have shown promising results in UC management. This article reviews recent findings on the mechanisms of UC, including genetic susceptibility, immune cell dynamics and cytokine regulation, and gut microbiota alterations. It also discusses current applications of biologic therapy, herbal therapy, microecologics, and FMT, along with their prospects and challenges.

Abstract Background Canine flank alopecia (CFA) is a skin condition in dogs characterized by non-inflammatory, seasonally recurring episodes of localized hair loss and often hyperpigmentation of the affected skin. A genetic basis is suspected because of the predisposition in certain breeds, such as the Rhodesian Ridgeback (RR). This study investigated the possible role of the canine melanophylin (MLPH) gene in CFA among RRs through pedigree analysis and MLPH genotyping. Results We included 24 CFA-affected and 12 non-CFA-affected control RRs. Pedigree analysis revealed inbreeding loops and close family relationships among the CFA-affected dogs, indicating the potential heritability of CFA. MLPH genotyping revealed 3/24 (12.5%) affected dogs and 1/12 (8.3%) control dogs to be heterozygous (Dd) for the dilute (d) allele, indicating no difference between these groups. None of the dogs were found to be homozygous (dd). Statistical analysis did not reveal an association between the MLPH-d allele and CFA. Conclusions The familial patterns among affected RRs observed through pedigree analysis suggest a potential genetic component in CFA. However, our findings from the MLPH genotyping did not reveal that the MLPH gene is involved in this skin condition in RRs. However, further genetic studies are needed to clarify the etiology of CFA in RR dogs.

Abstract Background The American Heart Association recently introduced a novel cardiovascular health (CVH) metric, Life's Essential 8 (LE8), for health promotion. However, the relationship between LE8 and cancer mortality risk remains uncertain. Methods We investigated 17,076 participants from US National Health and Nutrition Examination Survey (US NHANES) and 272,727 participants from UK Biobank, all free of cancer at baseline. The CVH score, based on LE8 metrics, incorporates four health behaviors (diet, physical activity, smoking, and sleep) and four health factors (body mass index, lipid, blood glucose, and blood pressure). Self-reported questionnaires assessed health behaviors. Primary outcomes were mortality rates for total cancer and its subtypes. The association between CVH score (continuous and categorical variable) and outcomes was examined using Cox model with adjustments. Cancer subtypes-related polygenic risk score (PRS) was constructed to evaluate its interactions with CVH on cancer death risk. Results Over 141,526 person-years in US NHANES, 424 cancer-related deaths occurred, and in UK Biobank, 8,872 cancer deaths were documented during 3,690,893 person-years. High CVH was associated with reduced overall cancer mortality compared to low CVH (HR 0.58, 95% CI 0.37–0.91 in US NHANES; 0.51, 0.46–0.57 in UK Biobank). Each one-standard deviation increase in CVH score was linked to a 19% decrease in cancer mortality (HR: 0.81; 95% CI: 0.73–0.91) in US NHANES and a 19% decrease (HR: 0.81; 95% CI: 0.79–0.83) in UK Biobank. Adhering to ideal CVH was linearly associated with decreased risks of death from lung, bladder, liver, kidney, esophageal, breast, colorectal, pancreatic, and gastric cancers in UK Biobank. Furthermore, integrating genetic data revealed individuals with low PRS and high CVH exhibited the lowest mortality from eight cancers (HRs ranged from 0.36 to 0.57) compared to those with high PRS and low CVH. No significant modification of the association between CVH and mortality risk for eight cancers by genetic predisposition was observed. Subgroup analyses showed a more pronounced protective association for overall cancer mortality among younger participants and those with lower socio-economic status. Conclusions Maintaining optimal CVH is associated with a substantial reduction in the risk of overall cancer mortality. Adherence to ideal CVH correlates linearly with decreased mortality risk across multiple cancer subtypes. Individuals with both ideal CVH and high genetic predisposition demonstrated significant health benefits. These findings support adopting ideal CVH as an intervention strategy to mitigate cancer mortality risk and promote healthy aging.

Simple Summary: Identifying individuals at high risk of developing melanoma is a crucial starting point for prevention and early detection, which are still the best treatment options for cutaneous melanoma. However, despite the scientific advances, unraveling the missing heritability of melanoma-prone patients without an inherited pathogenic variant in a known melanoma predisposition gene remains a great challenge. For this reason, we aim to define a polygenic risk score (PRS) that could be associated with the risk of developing melanoma, also considering non-genetic risk factors. Interestingly, we found that individuals with a high PRS are more likely to develop not only one melanoma but also subsequent melanomas. Moreover, our findings are indicative of an association of the PRS with some individual phenotypic/behavioral characteristics and also with a younger age at diagnosis. The PRS, as a new tool to be included in clinical practice, could help stratify patients according to their individual risk of developing melanoma, improving early diagnosis, known to be a key factor in determining the prognosis of patients. Recent genome-wide association studies (GWASs) have identified many single nucleotide polymorphisms (SNPs) that alone weakly affect melanoma risk, but their combined effect on a polygenic risk score (PRS) can have a far bigger impact on estimating risk. However, the PRS is not yet at the stage of being utilized in clinical practice, and further evidence is needed. In this study, 270 melanoma patients fulfilling the criteria for a suspected genetic predisposition but with a negative genetic test for high/medium-penetrance genes were genotyped for 57 SNPs selected in previous GWASs to construct a PRS model. We found a significantly higher mean PRS57 in all melanoma cases than in controls (0.58 vs. 0.00, p < 0.001), and the mean PRS57 in multiple primary melanoma cases was twice that in single melanoma cases (0.689 vs. 0.362, p = 0.025). Interestingly, our results confirm the association of the PRS57 not only with other melanoma risk factors but also with a younger age at diagnosis. This evidence supports the potentially powerful discriminative role of PRS in the selection of high-risk patients who should undergo stricter surveillance protocols. [ABSTRACT FROM AUTHOR]

Background: Canine flank alopecia (CFA) is a skin condition in dogs characterized by non-inflammatory, seasonally recurring episodes of localized hair loss and often hyperpigmentation of the affected skin. A genetic basis is suspected because of the predisposition in certain breeds, such as the Rhodesian Ridgeback (RR). This study investigated the possible role of the canine melanophylin (MLPH) gene in CFA among RRs through pedigree analysis and MLPH genotyping. Results: We included 24 CFA-affected and 12 non-CFA-affected control RRs. Pedigree analysis revealed inbreeding loops and close family relationships among the CFA-affected dogs, indicating the potential heritability of CFA. MLPH genotyping revealed 3/24 (12.5%) affected dogs and 1/12 (8.3%) control dogs to be heterozygous (Dd) for the dilute (d) allele, indicating no difference between these groups. None of the dogs were found to be homozygous (dd). Statistical analysis did not reveal an association between the MLPH-d allele and CFA. Conclusions: The familial patterns among affected RRs observed through pedigree analysis suggest a potential genetic component in CFA. However, our findings from the MLPH genotyping did not reveal that the MLPH gene is involved in this skin condition in RRs. However, further genetic studies are needed to clarify the etiology of CFA in RR dogs. Plain Language summary: Canine Flank Alopecia is an undesired skin condition in dogs. Affected dogs lose hair, typically on one or both sides of the body, without signs of any other skin disease. The well-demarcated bald patches are often hyperpigmented and non-itchy. The surrounding hair and skin are normal. Hair will usually regrow within 3–8 months after the onset of hair loss, but bald patches will often recur every year. Because some breeds, such as the Rhodesian Ridgeback, are at risk of developing this trait, it is suspected that this condition may have a genetic basis. This study aimed to determine whether a specific gene (the canine Menalophylin gene) may play a role in canine flank alopecia among Rhodesian Ridgebacks. We used pedigree analysis to explore the relationships between family members and disease inheritance patterns within families. We used MLPH genotyping to examine differences in the occurrence of this gene between affected Rhodesian Ridgebacks and healthy ones. In this study, we included 24 affected and 12 healthy control Rhodesian Ridgebacks. The pedigree analysis of the affected dogs revealed close family ties and inbreeding loops. This finding points to a possible heritability of canine flank alopecia. This genetic study did not reveal that the MLPH gene is involved in this skin condition. The cause of CFA may be multifactorial, with both genetic and environmental factors playing a role. We recommend further investigation of the genetic and environmental basis of Canine Flank Alopecia in Rhodesian Ridgebacks. Deeper knowledge could help develop breeding strategies to minimize the frequency of this undesirable skin trait within the Rhodesian Ridgebacks population. [ABSTRACT FROM AUTHOR]

Introduction: Cerebral aneurysm (CA) is a common vascular disease. The risk factors of CA include hypertension, smoking, and a family history of genetic predisposition. Although sleep-related problems have been found to have a strong association with cardiovascular disease, there is a lack of research regarding the causal relationship with cerebral aneurysms. Methods: In this study, we investigated the causal relationship between four sleep-related problems, including snoring, insomnia, narcolepsy, and napping during the day, and CA using a two-sample Mendelian randomization (MR) analysis. Moreover, the potential confounders before sleep problems and CA were further analyzed by multivariate MR (MVMR). Results: The causal relationship between insomnia and CA was obtained analytically by means of six MR analyses. There was a strong causal effect relationship between insomnia and CA, which suggests this as a potential risk factor [odds ratio (OR) = 8.35, 95% confidence interval (CI) = 2.422-28.791, p = 7.772e-04]. On this basis, hypertension was identified as a mediator between insomnia and CA by MVMR, with a mediating effect of 52.538% (OR = 3.05, 95% CI = 1.549-4.55, p = 0.015). Conclusion: The causal relationship between insomnia and CA was predicted using genetic variance data, and insomnia was found to be a potential risk factor. Furthermore, hypertension is a mediator between insomnia and CA. Therefore, focusing on sleep problems and improving sleep quality may be an active and effective strategy to prevent CA. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by abdominal pain, diarrhea, rectal bleeding, and weight loss. The pathogenesis and treatment of UC remain key areas of research interest. Various factors, including genetic predisposition, immune dysregulation, and alterations in the gut microbiota, are believed to contribute to the pathogenesis of UC. Current treatments for UC include 5-aminosalicylic acids, corticosteroids, immunosuppressants, and biologics. However, study reported that the one-year clinical remission rate is only around 40%. It is necessary to prompt the exploration of new treatment modalities. Biologic therapies, such as anti-TNF-α monoclonal antibody and JAK inhibitor, primarily consist of small molecules targeting specific pathways, effectively inducing and maintaining remission. Given the significant role of the gut microbiota, research into intestinal microecologics, such as probiotics and prebiotics, and fecal microbiota transplantation (FMT) shows promising potential in UC treatment. Additionally, medicinal herbs, such as chili pepper and turmeric, used in complementary therapy have shown promising results in UC management. This article reviews recent findings on the mechanisms of UC, including genetic susceptibility, immune cell dynamics and cytokine regulation, and gut microbiota alterations. It also discusses current applications of biologic therapy, herbal therapy, microecologics, and FMT, along with their prospects and challenges. [ABSTRACT FROM AUTHOR]

The expression "Autoimmune/inflammatory syndrome induced by adjuvants (ASIA)" was coined by Shoenfeld and colleagues in 2011. It defines a group of immune-mediated disorders that arise in people, with a genetic predisposition, following exposure to adjuvant agents. This syndrome has been reported after contact with silicone implants, medications, infections, metals, vaccines, and other substances. It typically occurs in individuals with a genetic predisposition, particularly involving genes, such as HLA-DRB1 (major histocompatibility complex, class II, DR beta 1) and PTPN22 (protein tyrosine phosphatase non-receptor type 22). Some stimuli lead to an overactivation of the immune system, prompt the production of autoantibodies, and finally cause autoimmune disorders. This narrative review aims to provide an overview of the ASIA syndrome with a special focus on the role of adjuvants in different vaccines, especially after the COVID-19 pandemic, and insights into development of new treatments. [ABSTRACT FROM AUTHOR]

Background: A predictive assay for late radiation toxicity would allow more personalized treatment planning, reducing the burden of toxicity for the more sensitive minority, and improving the therapeutic index for the majority. In a previous study in prostate cancer patients, the γ-H2AX foci decay ratio (γ-FDR) was the strongest predictor of late radiation toxicity. The current study aimed to validate this finding in a more varied group of patients with pelvic cancer. Additionally, the potential correlation between the γ-FDR and patient-reported outcomes was investigated. Methods: Prostate and gynecological cancer patients with ≥ 24 months of follow-up were included in the current analysis. Toxicity was evaluated by physician (CTCAE version 4) and patient (EORTC questionnaires). γ-FDRs were determined in ex vivo irradiated lymphocytes. Correlation between γ-FDR and toxicity was assessed using both linear and logistic regression analyses. The highest toxicity grade recorded during follow-up was used. The association between global quality of life and γ-FDR was tested by comparing the change in quality of life over time in patients with γ-FDR < or ≥ 3.41, a previously established threshold. Results: Eighty-eight patients were included. Physician-assessed and patient-reported cumulative grade ≥ 2 toxicity was 25% and 29%, respectively; which is much lower than in the previous cohort (i.e., 51% CTCAE grade ≥ 2). Patients with toxicity exhibited less favorable dose-volume parameters. In men, these parameters showed significant improvement compared to the previous cohort. The proportion of patients with a low γ-FDR increased with severity of toxicity, but this trend was not statistically significant. In addition, a γ-FDR < 3.41 was not correlated with the development of moderate to severe toxicity. Post-treatment decline in global quality of life was minimal, and similar for patients with γ-FDR < or ≥ 3.41. Conclusions: In the present study, the γ-H2AX foci decay ratio could not be validated as a predictor of late radiation toxicity in patients with pelvic cancer. Improved radiotherapy techniques with smaller irradiated bladder and bowel volumes have probably resulted in less toxicities. Future studies on genetic markers of toxicity should be powered on these lower incidences. We further recommend taking persistency, next to severity, into consideration. [ABSTRACT FROM AUTHOR]

Background: The American Heart Association recently introduced a novel cardiovascular health (CVH) metric, Life's Essential 8 (LE8), for health promotion. However, the relationship between LE8 and cancer mortality risk remains uncertain. Methods: We investigated 17,076 participants from US National Health and Nutrition Examination Survey (US NHANES) and 272,727 participants from UK Biobank, all free of cancer at baseline. The CVH score, based on LE8 metrics, incorporates four health behaviors (diet, physical activity, smoking, and sleep) and four health factors (body mass index, lipid, blood glucose, and blood pressure). Self-reported questionnaires assessed health behaviors. Primary outcomes were mortality rates for total cancer and its subtypes. The association between CVH score (continuous and categorical variable) and outcomes was examined using Cox model with adjustments. Cancer subtypes-related polygenic risk score (PRS) was constructed to evaluate its interactions with CVH on cancer death risk. Results: Over 141,526 person-years in US NHANES, 424 cancer-related deaths occurred, and in UK Biobank, 8,872 cancer deaths were documented during 3,690,893 person-years. High CVH was associated with reduced overall cancer mortality compared to low CVH (HR 0.58, 95% CI 0.37–0.91 in US NHANES; 0.51, 0.46–0.57 in UK Biobank). Each one-standard deviation increase in CVH score was linked to a 19% decrease in cancer mortality (HR: 0.81; 95% CI: 0.73–0.91) in US NHANES and a 19% decrease (HR: 0.81; 95% CI: 0.79–0.83) in UK Biobank. Adhering to ideal CVH was linearly associated with decreased risks of death from lung, bladder, liver, kidney, esophageal, breast, colorectal, pancreatic, and gastric cancers in UK Biobank. Furthermore, integrating genetic data revealed individuals with low PRS and high CVH exhibited the lowest mortality from eight cancers (HRs ranged from 0.36 to 0.57) compared to those with high PRS and low CVH. No significant modification of the association between CVH and mortality risk for eight cancers by genetic predisposition was observed. Subgroup analyses showed a more pronounced protective association for overall cancer mortality among younger participants and those with lower socio-economic status. Conclusions: Maintaining optimal CVH is associated with a substantial reduction in the risk of overall cancer mortality. Adherence to ideal CVH correlates linearly with decreased mortality risk across multiple cancer subtypes. Individuals with both ideal CVH and high genetic predisposition demonstrated significant health benefits. These findings support adopting ideal CVH as an intervention strategy to mitigate cancer mortality risk and promote healthy aging. [ABSTRACT FROM AUTHOR]

Background and Objectives: Seminoma is the most common solid malignant tumour in young men. Clear-cell kidney carcinoma is the most common malignancy of the genitourinary tract. However, the synchronous occurrence of both of these tumours is rare. Case presentation: We present the case of a 36-year-old patient who presented to a medical facility at the end of 2019 with an enlarged right testicle. A unilateral orchofuniculectomy was performed, and a mass measuring 30 cm was removed. During histological examination, testicular seminoma pT2, R0, was diagnosed. An abdominal computed tomography (CT) scan showed a 6.4 cm × 6.8 cm × 6.7 cm tumour in the right kidney and a metastatic-like lesion in the right adrenal gland. A right nephrectomy and an adrenalectomy and paraaortic and paracaval lymphadenectomies were performed. A histological evaluation confirmed the presence of clear-cell renal carcinoma pT2aR0 G2, adrenal hyperplasia, and seminoma metastases in the removed lymph node. Chemotherapy with a Bleomycin, Etoposide, and Cisplatin (BEP) regimen was carried out. Three years after the last cycle of chemotherapy, a follow-up CT scan showed metastases in the left kidney, the right ischium, and the right lung. A well-differentiated clear-cell carcinoma G1 of the left kidney and metastasis of clear-cell carcinoma G2 in the right ischium were confirmed after the biopsy, and no tumour lesions were found in the lung tissue specimen. Treatment with targeted therapy with Sunitinib was started because the risk was favourable according to the Heng criteria. Genetic testing was performed, and the following genes were analysed: VHL, BAP1, CHEK2, FH, MET, MUTYH, APC, and STK11. The testing did not reveal any pathogenic or potentially pathogenic mutations or sequence changes of unknown clinical significance in the genes analysed. Conclusions: According to the authors, the occurrence of synchronous primary tumours is linked to one's genetic predisposition. DNA sequencing of tumour tissue could provide more information on the corresponding aetiopathogenesis. [ABSTRACT FROM AUTHOR]

Since the early 21st century, bullying has been a central focus for scholars, with various forms, such as relational, physical, cyber, and social bullying, receiving extensive attention. However, the role of genetic and hereditary factors in bullying remains underexplored. This study systematically reviews 31 scholarly articles published between January 2000 and December 2021. Articles were selected based on predefined inclusion criteria, including methodological rigor, relevance to genetic influences on bullying, and clear population samples. Data sources included Google Scholar, ResearchGate, SAGE Journals, and ERIC, with keywords such as “bullying and genetics,” “bullying and hereditary,” and “family genetics involvement.” The findings reveal significant associations between genetic predispositions and bullying behaviors. For example, genetic factors were found to account for approximately 70–77% of bullying perpetration and victimization in multiple studies, highlighting a strong hereditary influence. Traits such as impulsivity and aggression, often linked to genetic predispositions, were also shown to interact with environmental factors such as family dynamics and peer relationships, amplifying bullying tendencies. These results underscore the critical role of genetic and hereditary transmission in shaping bullying behaviors across generations. The study emphasizes the need for a multidisciplinary approach that integrates genetic research with environmental interventions to address bullying effectively. Practical implications include the development of targeted anti-bullying programs that consider individual genetic susceptibility alongside fostering supportive family and school environments to reduce the intergenerational transmission of bullying behaviors.

Abstract 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.

Abstract Background Offspring consistently exhibit similar imaging features as their parents in cases of degenerative lumbar scoliosis (DLS). Nevertheless, the role of genetic factors in the pathogenesis of DLS remains uncertain. Methods A prospective analysis was conducted on 35 patients with DLS and their 36 offspring. Genomic DNA was extracted from 71 blood samples for gene mutation analysis using whole exome sequencin. Various demographic and imaging parameters were compared. Results In 11 pedigrees of the 35 family members with DLS, 13 suspected pathogenic genes were identified. Among the 35 DLS patients, 11/35(31.5%) exhibited susceptibility gene mutations (mutant group), while 24/35(68.5%) had no pathogenic gene mutations (non-mutant group). AVR was more severe in mutant group than that in no-mutant group (p

Abstract Background Juvenile Idiopathic Arthritis (JIA) is a complex autoimmune disease and the most common chronic rheumatological disease affecting children under the age of 16. The etiology of JIA remains poorly understood, but evidence suggests a significant genetic predisposition. Methods We analyzed a Swedish cohort of 329 JIA patients and 728 healthy adult controls using the Illumina OmniExpress array for genotyping. HLA alleles were imputed from GWAS data using the SNP2HLA algorithm. Results Case–control analysis yielded 12 SNPs with genome-wide significant association to JIA, all located on chromosome 6 within the MHC class II gene region. Notably, the top SNP (rs28421666) was located adjacent to HLA-DQA1 and HLA-DRB1. HLA-DRB1*08:01, HLA-DQA1*04:01, and HLA-DQB1*04:02 were the haplotypes most strongly associated with an increased risk of JIA in the overall cohort. When analyzing disease specific subtypes, these alleles were associated with oligoarthritis and RF-negative polyarthritis. Within the complex linkage disequilibrium of the HLA-DRB1-DQA1-DQB1 haplotype, our analysis suggests that HLA-DRB1*08 might be the primary allele linked to JIA susceptibility. The HLA-DRB1*11 allele group was also independently associated with JIA and specifically enriched in the oligoarthritis patient group. Additionally, our study revealed a significant correlation between antinuclear antibody (ANA) positivity and specific HLA alleles. The ANA-positive JIA group showed stronger associations with the HLA-DRB1-DQA1-DQB1 haplotype, HLA-DRB1*11, and HLA-DPB1*02, suggesting a potential connection between genetic factors and ANA production in JIA. Furthermore, logistic regression analysis reaffirmed the effects of HLA alleles, female sex, and lower age at onset on ANA positivity. Conclusions This study identified distinct genetic associations between HLA alleles and JIA subtypes, particularly in ANA-positive patients. These findings contribute to a better understanding of the genetic basis of JIA and provide insights into the genetic control of autoantibody production in ANA-positive JIA patients. This may inform future classification and personalized treatment approaches for JIA, ultimately improving patient outcomes and management of this disease.

Abstract Background Epidemiological evidence on weight change and atrial fibrillation (AF) remains limited and inconsistent. Previous studies on body mass index (BMI) in youth and AF rarely considered subsequent BMI. This study aimed to assess the associations of AF with weight change and BMI in youth, as well as modified effect by genetic susceptibility of AF. Methods The study included 21,761 individuals (mean age 57.8 years) from the Malmö Diet and Cancer cohort. Weight information was obtained at three time points, including recalled weight at age 20 years, measured weight at baseline (middle adulthood), and reported weight at 5-year follow-up examination (late middle adulthood). A weighted genetic risk score of AF was created using 134 variants. Results During a median follow-up of 23.2 years, a total of 4038 participants developed AF. The association between weight change from early to middle adulthood and AF risk was modified by sex (P interaction = 0.004); weight loss was associated with a lower AF risk in females, but not in males. Conversely, weight gain was positively associated with AF risk in a linear manner in females, whereas increased AF risk appeared only when weight gain exceeded a threshold in males. Participants with weight gain of > 5 kg from middle to late middle adulthood had a 19% higher risk of AF relative to those with stable weight, whereas weight loss showed a null association. Compared to individuals with a lower BMI at age 20 years, those with a BMI above 25 kg/m2 had an increased risk of AF (HR = 1.14; 95% CI: 1.02–1.28), after controlling for baseline BMI; this association was more pronounced in males or those with a lower genetic risk of AF. Conclusions Weight gain in middle adulthood was associated with higher AF risk. Weight loss from early to middle adulthood, but not from middle to late middle adulthood, was associated with a lower risk of AF only in females. Higher BMI in youth was associated with an increased risk of AF, particularly among males or those with a lower genetic risk of AF.

The paper presents a description of a clinical case of Gougerot–Hailey–Hailey disease with proven dysregulation of the immune response. The disease, also known as chronic benign familial pemphigus, is a rare genetic disorder that causes bullous skin lesions with intraepidermal localization. It is named after the authors who first described it. In most cases, Gougerot–Hailey–Hailey disease is caused by a mutation in the ATP2C1 gene that disrupts calcium regulation. Calcium accumulation alters normal intercellular adhesion in the skin, resulting in characteristic bullous skin lesions. Gougerot–Hailey–Hailey disease is inherited in an autosomal dominant pattern. The frequency of distribution in the population is 1:50000 people. However, the variety of clinical phenotypes of the disease without a proven hereditary predisposition and the absence of a mutation in this gene allows us to assert the presence of other pathogenic factors, in particular, disorders in the immune system. In the clinical case we are describing, no clear genetic predisposition was revealed, but serious disorders in the immune system were detected. In particular, TNK cells are virtually non-existent. Analysis of subpopulations of natural killer cells indicates a decrease in the relative and absolute numbers of NK cells expressing CD16 and CD56 antigens, NK cells with high cytolytic activity, NK cells expressing the α chain of the CD8 antigen and having the ability to repeatedly perform their cytolytic function. When assessing B cell subpopulations, there is an increase in the relative content of B2 cells and B1 cells associated with production of autoantibodies, in parallel with an increase in the percentage of regulatory T helper cells with immunosuppressive function. Based on the identified changes in the immune system, we performed immunomodulatory therapy: discrete plasmapheresis, 5 procedures in 2 days, then intravenous drip injection of normal human immunoglobulin 25 mL (50 μg/mL) in 3 days, 5 infusions. The dynamics of cutaneous manifestations indicates a moderate positive effect. Obviously, further in-depth study of immune parameters in Gugerout-Haley-Haley disease, presumably in the innate immune system, is required. Probably, success in treatment and achievement of stable remission will be possible with the rational selection of anticytokine therapy.

Abstract 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.

Objectives: Relationship between biological aging and inflammatory bowel disease (IBD) remains unclear. We aimed to explore the associations of biological age and genetic predisposition with IBD and the predictive ability. Methods: Biological age and genetic predisposition were measured by PhenoAge and the polygenic risk score (PRS), respectively. The hazard ratio (HR) and 95% confidence interval (CI) of PhenoAge and combined PRS for Crohn’s disease (CD) and ulcerative colitis (UC) were evaluated by Cox proportional hazards models. Additive interactions were examined to evaluate the joint effect. C statistic was employed to assess the predictive ability. Results: During the follow-up period of 5,320,311 person-years of 401,013 participants, 2467 patients with UC and 1262 patients with CD were observed. PhenoAge showed a significant association with an increased risk of incident IBD. Each standard deviation of PhenoAge acceleration correlated with a 38% (95% CI: 34%–41%), 35% (95% CI: 30%–38%), and 46% (95% CI: 41%–51%) increased risk of IBD, UC, and CD, respectively. Joint effects and additive interactions were noted between PhenoAge and the PRS. Individuals with a high PRS and the highest PhenoAge acceleration had the highest risk for UC (HR: 9.16, 95% CI: 7.08–11.85) and CD (7.72, 6.05–9.86), respectively. Incorporating PhenoAge and the PRS could enhance the accuracy of predicting IBD, with a highest C statistic of 0.71 for UC and 0.72 for CD. Conclusion: Accelerated biological aging is associated with an increased risk of IBD, particularly in individuals with high genetic predisposition. Identifying individuals with accelerated biological aging has significant implications for reducing IBD risk.

Background: Juvenile Idiopathic Arthritis (JIA) is a complex autoimmune disease and the most common chronic rheumatological disease affecting children under the age of 16. The etiology of JIA remains poorly understood, but evidence suggests a significant genetic predisposition. Methods: We analyzed a Swedish cohort of 329 JIA patients and 728 healthy adult controls using the Illumina OmniExpress array for genotyping. HLA alleles were imputed from GWAS data using the SNP2HLA algorithm. Results: Case–control analysis yielded 12 SNPs with genome-wide significant association to JIA, all located on chromosome 6 within the MHC class II gene region. Notably, the top SNP (rs28421666) was located adjacent to HLA-DQA1 and HLA-DRB1. HLA-DRB1*08:01, HLA-DQA1*04:01, and HLA-DQB1*04:02 were the haplotypes most strongly associated with an increased risk of JIA in the overall cohort. When analyzing disease specific subtypes, these alleles were associated with oligoarthritis and RF-negative polyarthritis. Within the complex linkage disequilibrium of the HLA-DRB1-DQA1-DQB1 haplotype, our analysis suggests that HLA-DRB1*08 might be the primary allele linked to JIA susceptibility. The HLA-DRB1*11 allele group was also independently associated with JIA and specifically enriched in the oligoarthritis patient group. Additionally, our study revealed a significant correlation between antinuclear antibody (ANA) positivity and specific HLA alleles. The ANA-positive JIA group showed stronger associations with the HLA-DRB1-DQA1-DQB1 haplotype, HLA-DRB1*11, and HLA-DPB1*02, suggesting a potential connection between genetic factors and ANA production in JIA. Furthermore, logistic regression analysis reaffirmed the effects of HLA alleles, female sex, and lower age at onset on ANA positivity. Conclusions: This study identified distinct genetic associations between HLA alleles and JIA subtypes, particularly in ANA-positive patients. These findings contribute to a better understanding of the genetic basis of JIA and provide insights into the genetic control of autoantibody production in ANA-positive JIA patients. This may inform future classification and personalized treatment approaches for JIA, ultimately improving patient outcomes and management of this disease. [ABSTRACT FROM AUTHOR]

Background: Epidemiological evidence on weight change and atrial fibrillation (AF) remains limited and inconsistent. Previous studies on body mass index (BMI) in youth and AF rarely considered subsequent BMI. This study aimed to assess the associations of AF with weight change and BMI in youth, as well as modified effect by genetic susceptibility of AF. Methods: The study included 21,761 individuals (mean age 57.8 years) from the Malmö Diet and Cancer cohort. Weight information was obtained at three time points, including recalled weight at age 20 years, measured weight at baseline (middle adulthood), and reported weight at 5-year follow-up examination (late middle adulthood). A weighted genetic risk score of AF was created using 134 variants. Results: During a median follow-up of 23.2 years, a total of 4038 participants developed AF. The association between weight change from early to middle adulthood and AF risk was modified by sex (Pinteraction = 0.004); weight loss was associated with a lower AF risk in females, but not in males. Conversely, weight gain was positively associated with AF risk in a linear manner in females, whereas increased AF risk appeared only when weight gain exceeded a threshold in males. Participants with weight gain of > 5 kg from middle to late middle adulthood had a 19% higher risk of AF relative to those with stable weight, whereas weight loss showed a null association. Compared to individuals with a lower BMI at age 20 years, those with a BMI above 25 kg/m2 had an increased risk of AF (HR = 1.14; 95% CI: 1.02–1.28), after controlling for baseline BMI; this association was more pronounced in males or those with a lower genetic risk of AF. Conclusions: Weight gain in middle adulthood was associated with higher AF risk. Weight loss from early to middle adulthood, but not from middle to late middle adulthood, was associated with a lower risk of AF only in females. Higher BMI in youth was associated with an increased risk of AF, particularly among males or those with a lower genetic risk of AF. [ABSTRACT FROM AUTHOR]

Background: Offspring consistently exhibit similar imaging features as their parents in cases of degenerative lumbar scoliosis (DLS). Nevertheless, the role of genetic factors in the pathogenesis of DLS remains uncertain. Methods: A prospective analysis was conducted on 35 patients with DLS and their 36 offspring. Genomic DNA was extracted from 71 blood samples for gene mutation analysis using whole exome sequencin. Various demographic and imaging parameters were compared. Results: In 11 pedigrees of the 35 family members with DLS, 13 suspected pathogenic genes were identified. Among the 35 DLS patients, 11/35(31.5%) exhibited susceptibility gene mutations (mutant group), while 24/35(68.5%) had no pathogenic gene mutations (non-mutant group). AVR was more severe in mutant group than that in no-mutant group (p < 0.05). Among the 36 offspring, 11/36(30.6%) cohorts presented susceptibility genes (mutant group), 25/36(69.4%) cohorts presented no pathogenic genes (no-mutant group). More cohorts in the mutant group presented vertebral rotation (72.8%) and scoliosis (45.5%) than those (24%), (12%) in the no-mutant group, respectively (p < 0.05). Among the 36 offspring, 8/36(22.2%) presented scoliosis (study group), they all presented the same scoliosis orientation and apex vertebrae/disc location to their parents, the other 28/36(77.8%) cohorts without scoliosis were enrolled as control group, the mutation rate (62.5%) was higher in study group than that (21.4%) in control group. Conclusions: Genetic influences are significant in the onset of DLS, with affected families showing similar scoliosis patterns and identical apex vertebrae. Moreover, individuals with genetic mutations tend to have more pronounced vertebral rotation and at a higher risk of developing scoliosis. [ABSTRACT FROM AUTHOR]

The greater muscle fiber cross-sectional area (CSA) is associated with greater skeletal muscle mass and strength, whereas muscle fiber atrophy is considered a major feature of sarcopenia. Muscle fiber size is a polygenic trait influenced by both environmental and genetic factors. However, the genetic variants underlying inter-individual differences in muscle fiber size remain largely unknown. The aim of our study was to determine whether 1535 genetic variants previously identified in a genome-wide association study of appendicular lean mass are associated with the CSA of fast-twitch muscle fibers (which better predict muscle strength) in the m. vastus lateralis of 148 physically active individuals (19 power-trained and 28 endurance-trained females, age 28.0 ± 1.1; 28 power-trained and 73 endurance-trained males, age 31.1 ± 0.8). Fifty-seven single-nucleotide polymorphisms (SNPs) were identified as having an association with muscle fiber size (p < 0.05). Of these 57 SNPs, 31 variants were also associated with handgrip strength in the UK Biobank cohort (n = 359,729). Furthermore, using East Asian and East European athletic (n = 731) and non-athletic (n = 515) cohorts, we identified 16 SNPs associated with athlete statuses (sprinter, wrestler, strength, and speed–strength athlete) and weightlifting performance. All SNPs had the same direction of association, i.e., the lean mass-increasing allele was positively associated with the CSA of muscle fibers, handgrip strength, weightlifting performance, and power athlete status. In conclusion, we identified 57 genetic variants associated with both appendicular lean mass and fast-twitch muscle fiber size of m. vastus lateralis that may, in part, contribute to a greater predisposition to power sports. [ABSTRACT FROM AUTHOR]

As a result of the immune system's excessive reaction to normally innocuous substances, allergies pose a serious threat to global public health. The goal of this study is to compile a comprehensive literature review on allergies, including those that manifest in childhood and those that manifest later in life. The study compares the symptoms experienced by those whose allergies develop later in life as a consequence of environmental or lifestyle factors with those experienced by individuals whose allergies are inherited. Research strongly suggests that a person's genetic makeup has a significant role in the onset of congenital allergies. Having a history of allergies in one's family and certain genetic markers greatly enhance the likelihood of developing allergies at a young age. Congenital allergies often emerge in early childhood or infancy and may cause a variety of symptoms, including food allergies, asthma, and eczema. However, there is also evidence that adults may develop allergies. Some allergies might emerge as a result of changes in immune system function or as a result of exposure to new allergens. Among the many variables that are examined are changes to the gut flora, stress, environmental exposures, and changes to the diet. To further understand this phenomenon, it is helpful to understand how these factors play a role in the slow onset of allergies after tolerance has set in. Synthesising data from genetic studies, epidemiological research, and clinical observations, the project aims to solve the knowledge gap between congenital and later-onset allergies. This makes it quite evident that different approaches to treatment and prevention are necessary based on the onset of allergy symptoms. A comprehensive grasp of these pathways is necessary for the development of targeted medicines, which in turn improve patient outcomes throughout the lifespan. [ABSTRACT FROM AUTHOR]

Background: Preeclampsia (PE) and eclampsia (E) are severe pregnancy complications with significant maternal and neonatal health impacts. This study explores the association of the rs5707 polymorphism in the renin-angiotensin system (RAS) with PE/E and related neonatal outcomes. Materials and Methods: We conducted a cross-sectional study involving 400 mother–newborn dyads at the "Pius Brinzeu" Emergency Clinical Hospital Timisoara. Participants were divided into a control group (254 normotensive women) and a PE/E group (146 women with PE/E). Genotyping for the rs5707 polymorphism was performed using real-time PCR, and statistical analyses assessed associations with maternal body mass index (BMI) and neonatal outcomes. Results: The AA genotype of rs5707 was significantly associated with a reduced risk of PE/E and more favorable neonatal outcomes, including higher Apgar scores, greater birth weights, and longer gestational ages. Conversely, the AC genotype correlated with increased maternal BMI and adverse neonatal outcomes. Odds ratios highlighted the protective effect of the AA genotype against PE/E and the increased risk associated with the AC genotype. Conclusions: This study revealed the critical role of the rs5707 polymorphism in PE/E development and neonatal health. Genetic screening for rs5707 could enhance early identification and personalized intervention strategies, improving outcomes for both mothers and neonates. Further research is needed to validate these findings across diverse populations and to uncover the underlying mechanisms. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simple Summary: Overall, this review offers a comprehensive and insightful exploration of the significance, implementation, and challenges of genomic newborn screening for pediatric cancer predisposition syndromes (CPSs). It emphasizes the importance of next-generation sequencing (NGS) in uncovering germline mutations that are responsible for CPSs in childhood malignancies. It delves into the selection criteria for screening, ethical considerations, gene panel selection, and the integration of established and emerging genes in CPS into large-scale newborn screening programs in healthcare systems. It also stresses the importance of early detection and its potential impact on pediatric care and outcomes, thus providing valuable information for healthcare professionals, researchers, and policymakers in the field of pediatric oncology and genetics. 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. [ABSTRACT FROM AUTHOR]

The catalytic subunit telomerase reverse transcriptase (hTERT) is a prerequisite for malignant transformation of human cells. Colorectal cancer (CRC) is a common malignant tumor. The genetic association of hTERT gene rs2853669 and rs2736098 polymorphisms with CRC was surveyed in the Chinese population. Two hundreds patients with CRC and 200 healthy controls were taken for blood sample collection. Sanger sequencing was applied for genotyping. Multiple logistic regression analysis was performed, and odds ratio (OR) together with confidence interval (CI) were calculated to obtain the corresponding association power. Among CRC cases (49.50%), hTERT gene rs2736098 GA genotype carriers were more prevalent compared with the control group (41.00%, P = 0.035), which increased the risk of CRC by 1.576 times (95% CI, 1.031-2.409). Distribution of the rs2736098 genotypes was significantly associated with TNM stage, tumor differentiation, tumor size and lymph node metastasis (P < 0.05). The frequencies of hTERT gene rs2853669 polymorphism were not significantly different between CRC patients and healthy controls. Logistic regression analysis indicated that both body mass index (BMI) and hTERT gene rs2736098 polymorphism remained significantly correlated with CRC susceptibility. The frequencies of hTERT gene rs2853669 polymorphism did not differ significantly between CRC patients and control group (P > 0.05). The hTERT gene rs2736098 polymorphism was correlated with CRC risk in the Chinese Han population, and the GA genotype was a risk element for the onset of CRC. [ABSTRACT FROM AUTHOR]