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Background: The purpose of this study is to investigate the genotype and allele distribution of MTHFR rs1801133 in the Chinese population, and to analyze the relationship between gene polymorphism of MTHFR rs1801133 and risk of childhood leukemia. Methods: Blood samples and clinical data of childhood leukemia cases (n=1132) and age-matched healthy controls (n=1053) were collected. Genotypes and allele distribution of MTHFR rs1801133 were detected by PCR-RFLP. Logistic regression model was generated to analyze the relation between MTHFR rs1801133 and susceptibility to childhood leukemia and the chemotherapy response. Results: Age, sex, BMI and family history of tumor were comparable between childhood leukemia cases and healthy controls. Genotypes and allele distribution of MTHFR rs1801133 were remarkably correlated to the risk of childhood leukemia. Genotype risk of MTHFR rs1801133 was parallel to the susceptibility to childhood leukemia. Specifically, compared with people carrying AA allele of MTHFR rs1801133, higher risk of childhood leukemia may occur in people carrying AG+GG allele of MTHFR rs1801133 with a younger age (

Molecular testing, including apolipoprotein L1 (APOL1) sequencing, has recently become more accessible for use in the clinical setting. Although there is a strong association between APOL1 and kidney disease, only a small minority of African American kidney disease patients are estimated to have an APOL1 high-risk genotype. In addition, the lifetime risk for developing kidney disease among individuals with two risk alleles is estimated to be very low. The low prevalence suggests that it follows a two-hit model, where a secondary factor, such as environmental or genomic modifiers, is required to develop kidney disease. We still have a limited appreciation of factors that can act as a “second hit,” and it is unclear whether the hyperfiltration that follows donor nephrectomy constitutes as a “second hit” for the disease. One does not yet know the burden of APOL1 risk alleles among prospective living donors. Now that APOL1 genetic testing is available, and in the absence of prospective data, the role of APOL1 genotyping in live kidney donor candidate selection remains uncertain. There are several ethical issues concerning the use of genetic testing to determine donor eligibility, which can impact the development of policy around APOL1 genetic testing, release of results, and counseling.

Background: The relationship of air pollutants and residential exposure to greenspace with severe liver disease remains inconclusive. Objective: Our objective was to assess the relationship of joint exposure to air pollutants, residential exposure to greenspaces with new-onset severe liver disease. Methods: We included 427,697 participants without prior liver diseases from UK Biobank. A weighted air pollution score was calculated based on PM2.5, PM10, PM2.5–10, NO2, and NOX. The percentage of land coverage by residential greenspaces was estimated using land use data. The primary outcome was new-onset severe liver disease, defined as a composite outcome including hospitalization or death due to compensated or decompensated liver cirrhosis, liver failure, and hepatocellular carcinoma. Results: During a median follow-up of 12.0 years, 4572 participants developed severe liver disease. A higher air pollution score was significantly associated with an increased risk of new-onset severe liver disease (per SD increment; adjusted hazard ratio [HR],1.07; 95% confidence interval [CI],1.04–1.10). Moreover, residential greenspace coverage was inversely associated with new-onset severe liver disease (per SD increment; adjusted HR, 0.95; 95% CI,0.92–0.98). Genetic risks of liver cirrhosis did not significantly modify the associations (both P-interactions >0.05). However, we observed a stronger positive association between air pollution scores and new-onset severe liver disease in individuals with higher fibrosis-4 (FIB-4) scores, lower residential greenspaces, hypertension, and smokers (all P-interactions

We aimed to investigate the prospective association of individual and combined sleep behaviors and mental health (psychological distress and neuroticism) with incident irritable bowel syndrome (IBS). A total of 302,839 participants without prior IBS in the UK Biobank were enrolled. A healthy sleep score was created according to five sleep factors and defined the low-risk groups as follows: sleep 7–8 h/day, early chronotype, never/rarely insomnia, no snoring, and no frequent excessive daytime sleepiness. Psychological distress and neuroticism were ascertained using the Patient Health Questionnaire and the Eysenck Personality Questionnaire-Revised Short Form, respectively. The primary outcome was incident IBS, based on self-report or linkage to death register and/or primary care and/or hospital admission data. During a median follow-up of 12.0 years, 5574 participants developed IBS. Overall, low-risk sleep behaviors and a healthy sleep score (per one point increment, HR, 0.81, 95%CI, 0.79–0.83) were associated with a lower risk of incident IBS, 29.4 %–32.4 % of which was mediated by mental health. Psychological distress (per one point increment, HR, 1.16, 95%CI, 1.14–1.17) and neuroticism (HR, 1.11, 95%CI, 1.10–1.12) were positively associated with incident IBS, and healthy sleep scores mediated 8.3 %–9.7 % of the association. Moreover, participants with lowest healthy sleep score/highest mental health score and higher genetic risk of IBS showed the highest risk of incident IBS. Sleep behaviors and mental health were assessed by self-reported questionnaires. Healthy sleep scores and low psychological distress/neuroticism were associated with a lower risk of IBS, regardless of genetic predisposition. • Healthy sleep was associated with a lower risk of incident IBS. • Mental health mediated 29.4 %–32.4 % of the association between sleep and IBS. • Psychological distress and neuroticism were related to a higher risk of incident IBS. • Sleep mediated 8.3 %–9.7 % of the association between mental health and IBS. • Participants with poor sleep/mental health and high IBS genetic risk had highest IBS risk. [ABSTRACT FROM AUTHOR]

The aim of this pilot study was to investigate whether single nucleotide polymorphisms (SNP) in the gene encoding the catalytic subunit of glutamate cysteine ligase (GCLC) are associated with the risk and clinical features of psoriasis. A total of 944 unrelated individuals, including 474 patients with a diagnosis of psoriasis and 470 healthy controls, were recruited for the study. Six common SNPs in the GCLC gene were genotyped using the MassArray-4 system. Polymorphisms rs648595 (OR = 0.56, 95% CI 0.35–0.90; Pperm = 0.017) and rs2397147 (OR = 0.54, 95% CI 0.30–0.98; Pperm = 0.05) were associated with susceptibility to psoriasis in males. In the male group, diplotype rs2397147-C/C × rs17883901-G/G was associated with a decreased risk of psoriasis (FDR-adjusted p = 0.014), whereas diplotype rs6933870-G/G × rs17883901-G/G (FDR-adjusted p = 0.045) showed an association with an increased disease risk in females. The joint effects of SNPs with tobacco smoking (rs648595 and rs17883901) and alcohol abuse (rs648595 and rs542914) on psoriasis risk were observed (Pperm ≤ 0.05). We also found multiple sex-independent associations between GCLC gene polymorphisms and various clinical features such as earlier disease onset, the psoriatic triad, and specific localizations of skin lesions. The present study is the first to show that polymorphisms of the GCLC gene are significantly associated with the risk of psoriasis and related to its clinical features. [ABSTRACT FROM AUTHOR]

Background & Aims: Physical activity, sedentary behaviour, and genetic variants have been associated with the nonalcoholic fatty liver disease (NAFLD). However, whether and how the degree of healthy activity patterns may modify the impact of genetic susceptibility on NAFLD remains unknown. Methods: Behaviour activity factors were determined according to total physical activity (TPA) and sedentary time. The polygenic risk score (PRS) was calculated by variants in PNPLA3, TM6SF2, MBOAT7, and GCKR. Cox regression was used to analyse the associations of genetic and behaviour activity factors with incident NAFLD in the UK Biobank (N = 338 087). Results: During a median follow‐up of 12.4 years, 3201 incident NAFLD cases were ascertained. Analyses of TPA and sedentary time simultaneously showed a dose–response association with the risk of NAFLD (ptrend <.001). The association of behaviour activity patterns with NAFLD varied by genetic variants. Of the subjects with high genetic risk, we observed a null protective effect of moderate or high TPA on NAFLD risk, while sitting less than three hours a day significantly decreased the risk of NAFLD (p = 3.50 × 10−4). The high genetic risk of NAFLD can also be offset by the combination of moderate physical activity and shorter sedentary time. Moreover, the high genetic risk group has the greatest reduction of 10‐year absolute risk (6.95 per 1000 person‐years) if reaching both healthy activities. Conclusions: Moderate‐to‐high physical activity and favourable sedentary behaviour may be lifestyle modifications in preventing NAFLD, which could offset the harmful effect of predisposing genetic factors. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of death due to a single bacterial agent, with approximately 10.6 million people developing active disease and 1.6 million deaths reported globally in 2021. After exposure, some, but not all individuals, will become infected with the bacillus. However, only a small fraction (approximately 5 to 15%) of these individuals will progress to clinical disease, while in the remainder, infection is seemingly contained, and no signs of clinical disease are shown. Numerous observations have advocated for the role of host genetics in the display of these inter-individual variabilities in infection and disease phenotypes. In this review, we will provide an overview of the approaches, findings and limitations of the very first studies investigating TB genetic susceptibility to more recent studies. Lastly, we highlight several approaches, namely, linkage analyses and association studies, proposed to discover genetic markers associated with TB susceptibility. This review also explored the concept of polygenic risk scores (PRS) for prediction of tuberculosis susceptibility. The identification of host genetic factors influencing TB susceptibility/resistance is paramount to not only better understand the physiopathology of the disease but also explore more effective approaches for the development of both optimal preventive measures (i.e. better vaccines) and treatments of TB disease. [ABSTRACT FROM AUTHOR]

Simple Summary: We investigated the influence of autophagy-related variants in modulating Multiple Myeloma (MM) risk through a meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined the functional mechanisms behind the observed associations. We identified SNPs within the six CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A loci associated with MM risk and observed that their effect on disease risk was mediated by specific subsets of immune cells, as well as vitamin D3-, MCP-2-, and IL20-dependent mechanisms. Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10−9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10−4−5.79 × 10−14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10−4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10−4) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10−4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3− B cells, CD5+IgD− cells, IgM− cells, IgD−IgM− cells, and CD4−CD8− PBMCs (p = 4.9 × 10−4−8.6 × 10−4) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27− cells (p = 9.3 × 10−4). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3−, MCP-2−, and IL20-dependent pathways. [ABSTRACT FROM AUTHOR]

Pancreatic cancer usually results in poor survival with limited options for treatment, as most affected individuals present with advanced disease. Early detection of preinvasive pancreatic neoplasia and identifying molecular therapeutic targets provide opportunities for extending survival. Although screening for pancreatic cancer is currently not recommended for the general population, emerging evidence indicates that pancreatic surveillance can improve outcomes for individuals in certain high-risk groups. Changes in the epidemiology of pancreatic cancer, experience from pancreatic surveillance, and discovery of novel biomarkers provide a roadmap for new strategies for pancreatic cancer risk assessment, early detection, and prevention. [ABSTRACT FROM AUTHOR]

Background: Sudden unexpected cardiac arrest is one of the life-threatening interventions of the pre hospital emergency medicine teams. Globally sudden cardiac death (SCD) accounts for 4-5 million deaths per year and is in most cases linked to coronary artery disease. Other causes include cardiomyopathies and channelopathies, but these are not always clear to the physician. Case Presentation: We present two unconscious patients with life-threatening cardiac arrests who were unsuccessfully resuscitated by the emergency team. As the cause of the sudden cardiac arrest was unclear an autopsy was performed. Conclusion: SCD can be the final stage of several pathologies. In acute myocardial infarction due to coronary artery disease, the underlying cause is clear. The situation is however more complex in drug abuse where the physician should be aware that underlying pathologies can be masked. If the cause of sudden cardiac arrest is unclear, a "molecular" autopsy is recommended to detect genetic susceptibility to dysrhythmias (long QT syndrome, Brugada syndrome), cardiomyopathies, thoracic aortic aneurysm, and dissection. Correlating significant clinical information, postmortem findings and genetic analysis can be used to detect underlying pathologies and to decide whether genetic screening and clinical follow up of relatives should be carried out. [ABSTRACT FROM AUTHOR]

The genetic variants of HLAs (human leukocyte antigens) play a crucial role in the virus–host interaction and pathology of COVID-19. The genetic variants of HLAs not only influence T cell immune responses but also B cell immune responses by presenting a variety of peptide fragments of invading pathogens. Peptide cocktail vaccines produced by using various conserved HLA-A2 epitopes provoke substantial specific CD8+ T cell responses in experimental animals. The HLA profiles vary among individuals and trigger different T cell-mediated immune responses in COVID-19 infections. Those with HLA-C*01 and HLA-B*44 are highly susceptible to the disease. However, HLA-A*02:01, HLA-DR*03:01, and HLA-Cw*15:02 alleles show resistance to SARS infection. Understanding the genetic association of HLA with COVID-19 susceptibility and severity is important because it can help in studying the transmission of COVID-19 and its physiopathogenesis. The HLA-C*01 and B*44 allele pathways can be studied to gain insight into disease transmission and physiopathogenesis. Therefore, integrating HLA testing is suggested in the ongoing pandemic, which will help in the rapid identification of highly susceptible populations worldwide and possibly acclimate vaccine development. Therefore, understanding the correlation between HLA and SARS-CoV-2 is critical in opening new insights into COVID-19 therapeutics, based on previous studies conducted. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia (BPD) is a common chronic respiratory disease in preterm infants caused by multifactorial etiology. Genetic factors are involved in the occurrence of BPD, but studies have found that candidate genes have poor reproducibility and are influenced by ethnic heterogeneity; therefore, more exploration is still needed. We performed whole-exon sequencing in 34 preterm infants with BPD and 32 non-BPD control neonates. The data were analyzed and interpreted by Fisher difference comparison, PLINK and eQTL association analysis, KEGG and GO enrichment analysis, STRING tool, Cytoscape software, ProtParam tool, HOPE online software, and GEOR2 analysis on NCBI GEO dataset. BPD has a highly heterogeneity in different populations, and we found 35 genes overlapped with previous whole-exon sequencing studies, such as APOB gene. Arterial and epithelial cell development and energy metabolism pathways affect BPD. In this study, 24 key genes were identified, and BIVM rs3825519 mutation leads to prolonged assisted ventilation in patients with BPD. A novel DDAH1 mutation site (NM_012137: exon1: c.89 T > G: p.L30R) was found in 9 BPD patients. Conclusion: BIVM gene rs3825519 mutation may play a role in the pathogenesis of BPD by affecting cilia movement, and the DDAH1 and APOB genes mutations may have a pathogenic role in BPD. What is Known: • Genetic factors are involved in the occurrence of bronchopulmonary dysplasia. • The candidate genes have poor reproducibility and are influenced by ethnic heterogeneity, therefore, more exploration is still needed. What is New: • We identified the role of susceptible SNPs in BPD in Shenzhen, China, and identified 24 key genes that influence the pathogenesis of BPD, and also found 35 genes overlapped with previous whole exon sequencing studies, such as APOB gene. • We found that BIVM and DDAH1 genes may play a pathogenic role in the pathogenesis of BPD. [ABSTRACT FROM AUTHOR]

Men at a high genetic risk adhering to a healthy lifestyle had a reduced risk of lethal prostate cancer compared with men at a high genetic risk not adhering to a healthy lifestyle. The genetic risk of prostate cancer may be modifiable. Prostate cancer is the most heritable cancer. There is a need to identify possible modifiable factors for men at an increased risk of prostate cancer due to genetic factors. To examine whether men at an increased genetic risk of prostate cancer can offset their risk of disease or disease progression by adhering to a healthy lifestyle. We prospectively followed 12 411 genotyped men in the Health Professionals Follow-up Study (1993–2019) and the Physicians' Health Study (1983–2010). Genetic risk of prostate cancer was quantified using a polygenic risk score (PRS). A healthy lifestyle was defined by healthy weight, vigorous physical activity, not smoking, and a healthy diet. Overall and lethal prostate cancer events (metastatic disease/prostate cancer–specific death) were analyzed using time-to-event analyses estimating hazard ratios (HRs) and lifetime risks. During 27 yr of follow-up, 3005 overall prostate cancer and 435 lethal prostate cancer events were observed. The PRS enabled risk stratification not only for overall prostate cancer, but also for lethal disease with a four-fold difference between men in the highest and lowest quartiles (HR, 4.32; 95% confidence interval [CI], 3.16–5.89). Among men in the highest PRS quartile, adhering to a healthy lifestyle was associated with a decreased rate of lethal prostate cancer (HR, 0.55; 95% CI, 0.36–0.86) compared with having an unhealthy lifestyle, translating to a lifetime risk of 1.6% (95% CI, 0.8–3.1%) among the healthy and 5.3% (95% CI, 3.6–7.8%) among the unhealthy. Adhering to a healthy lifestyle was not associated with a decreased risk of overall prostate cancer. Our findings suggest that a genetic predisposition for prostate cancer is not deterministic for a poor cancer outcome. Maintaining a healthy lifestyle may provide a way to offset the genetic risk of lethal prostate cancer. This study examined whether the genetic risk of prostate cancer can be attenuated by a healthy lifestyle including a healthy weight, regular exercise, not smoking, and a healthy diet. We observed that adherence to a healthy lifestyle reduced the risk of metastatic disease and prostate cancer death among men at the highest genetic risk. We conclude that men at a high genetic risk of prostate cancer may benefit from adhering to a healthy lifestyle. [ABSTRACT FROM AUTHOR]

The present study investigated whether an unhealthy diet and other lifestyle behaviors may modify the genetic susceptibility to impulsivity. A total of 33,047 participants (mean age = 42.1 years, 59.8% females) from the Dutch Lifelines cohort were included. Each diet index and other lifestyle behaviors were tested for their interactions on the effect on the attention-deficit/hyperactivity disorder (ADHD) polygenic risk score (PRS) on impulsivity using a linear regression model with adjustment for covariates. The ADHD PRS was significantly associated with impulsivity (B = 0.03 (95% CI: 0.02, 0.04); p = 2.61 × 10−9). A poorer diet, a higher intake of energy, and a higher intake of fat were all associated with higher impulsivity, and a high intake of energy amplified the effect of ADHD PRS on impulsivity (e.g., for the interaction term of ADHD PRS and highest tertile on intake of energy, B = 0.038 (95% CI: 0.014, 0.062); p = 0.002. The other lifestyle factors, namely short and long sleep duration, current and past smoking, higher alcohol intake, and more time spent on moderate-to-vigorous physical activity were associated with higher impulsivity, but no interaction effect was observed. In conclusion, we found that a high intake of energy exacerbated the genetic susceptibility to impulsivity. Our study helps to improve our understanding of the role of diet and genetic factors on impulsivity. [ABSTRACT FROM AUTHOR]

Abstract Background Single nucleotide polymorphisms (SNPs) located in microRNA (miRNA) binding sites can affect the interactions between miRNAs and target genes, which is related to cancer susceptibility and tumorigenesis. However, the association between SNPs located in miR-17-92 cluster binding sites and ESCC risk remains unclear. Therefore, we aimed to explore the relationship between polymorphisms in miR-17-92 cluster binding sites and ESCC susceptibility. Methods Six SNPs in the binding sites of miR-17-92 cluster were selected using bioinformatics databases, and their association with ESCC risk was investigated in a case-control study (including 488 cases and 512 controls) based on the population from high incidence areas of ESCC in China. We evaluated the SNP-SNP and SNP-smoking interactions using generalized multifactor dimensionality reduction (GMDR). Moreover, the expression of the miR-17-92 cluster and its target genes was determined in ESCC and adjacent normal tissues by quantitative real-time polymerase chain reaction (qRT-PCR). The dual-luciferase reporter assay was conducted to verify the effect of SNPs on the binding affinity between miRNAs and target genes. Results We found that the SNP rs1804506 C > T had a significant association with the decreased ESCC risk. The SNP rs1804506 T allele was associated with a significantly decreased risk of ESCC in the additive model (OR = 0.817, 95% CI = 0.681–0.981, P = 0.030). The rs1804506 T allele had more striking effects on reducing ESCC risk in older individuals, female or non-smoker subgroups. We also found a significant interaction effect between rs1366600 and smoking by GMDR methods (P = 0.011). Additionally, the expression levels of miR-19a-3p and TGFBR3 were significantly downregulated in ESCC tissues compared with normal tissues, and the carriers of rs1804506 TT genotype had lower expression level of TGFBR3 than those of rs1804506 CC/CT genotype. Following dual-luciferase reporter assay showed that the rs1804506 T allele reduced the binding of miR-19a-3p and TGFBR3 3′-UTR. Conclusions Our findings suggest that the rs1804506 polymorphism in miR-17-92 cluster binding sites contributes to the susceptibility of ESCC, which might provide new clues and scientific evidence for the etiology and biomarkers for the prevention and treatment of ESCC.

Abstract Background Bladder cancer (BC) is the 10th most frequent tumor worldwide. Evidence shows an association between elevated risk of BC and various single nucleotide polymorphisms (SNP). BC incidence was the highest in Lebanon according to Globocan 2018 report, but little is known about the genetic susceptibility of Lebanese people to this disease. We aim to evaluate whether this prominent incidence of BC in Lebanon is attributable to known coding genetic variants. Methods A case-control study was conducted at Hotel-Dieu de France Hospital, Beirut. A cohort of 51 Lebanese patients with BC were recruited between 2017 and 2020. Whole Exome Sequencing (WES) was performed on peripheral blood samples to detect coding genetic variants in the patients. An in-house database including WES data from 472 Lebanese individuals served as control. Literature review of the genetic predisposition to BC was conducted to establish a database of variants known to influence the risk of BC. In-common SNPs were identified between cases and the aforecited database, and their allelic frequencies was quantified in the former and in controls. Comparative analysis of the allelic frequencies of each in-common SNP was carried out between cases, controls, and the genome aggregation database (gnomAD). Analysis was performed by applying the binomial law and setting the p-value to 10− 10. Results 484 polymorphisms associated with BC were extracted from the literature review ;151 of which were in-common with the 206 939 variations detected by WES in our cases. Statistically significant differences (p-value

Pancreatitis is one of the most common inflammatory diseases of the pancreas caused by autodigestion induced by excessive premature protease activation. However, recognition of novel pathophysiological mechanisms remains a still challenge. Both genetic and environmental factors contribute to the pathogenesis of pancreatitis, and the gut microbiota is a potential source of an environmental effect. In recent years, several new frontiers in gut microbiota and genetic risk assessment research have emerged and improved the understanding of the disease. These investigations showed that the disease progression of pancreatitis could be regulated by the gut microbiome, either through a translocation influence or in a host immune response manner. Meanwhile, the onset of the disease is also associated with the heritage of a pathogenic mutation, and the disease progression could be modified by genetic risk factors. In this review, we focused on the recent advances in the role of gut microbiota in the pathogenesis of pancreatitis, and the genetic susceptibility in pancreatitis.

Abstract Background The association between body mass index (BMI) and Alzheimer's disease (AD) remains controversial. Genetic and environmental factors are now considered contributors to AD risk. However, little is known about the potential interaction between genetic risk and BMI on AD risk. Objective To study the causal relationship between BMI and AD, and the potential interaction between AD genetic risk and BMI on AD risk. Methods and Results Using the UK Biobank database, 475,813 participants were selected for an average follow-up time of more than 10 years. Main findings: 1) there was a nonlinear relationship between BMI and AD risk in participants aged 60 years or older (p for non-linear 30 kg/m2) group was associated with a lower AD risk (HR = 0.741; 95% CI 0.618–0.888, p

Abstract Background Alzheimer's disease (AD) is the most frequently occurring type of dementia. Concurrently, inadequate sleep has been recognized as a public health epidemic. Notably, genetic and environmental factors are now considered contributors to AD progression. Objective To assess the association between sleep duration, genetic susceptibility, and AD. Methods and results Based on 483,507 participants from the UK Biobank (UKB) with an average follow-up of 11.3 years, there was a non-linear relationship between AD incidence and sleep duration (P for non-linear 9 h/night). No statistically significant interaction was identified between sleep duration and the AD-GRS (Alzheimer's disease genetic risk score, P for interaction = 0.45) using Cox proportional risk model. Compared with the participants who had a low AD-GRS and normal sleep duration, there was associated with a higher risk of AD in participants with a low AD-GRS and long sleep duration (HR = 3.4806; 95% CI 2.0011–6.054, p 9 h/night) was significantly associated with a higher risk of AD, regardless of high, intermediate or low AD-GRS. Prolonged sleep duration may be one of the clinical predictors of a higher risk of AD.

Abstract Ependymoma is the second most common malignant brain tumor in children. The etiology is largely unknown and germline DNA sequencing studies focusing on childhood ependymoma are limited. We therefore performed germline whole-genome sequencing on a population-based cohort of children diagnosed with ependymoma in Denmark over the past 20 years (n = 43). Single nucleotide and structural germline variants in 457 cancer related genes and 2986 highly evolutionarily constrained genes were assessed in 37 children with normal tissue available for sequencing. Molecular ependymoma classification was performed using DNA methylation profiling for 39 children with available tumor tissue. Pathogenic germline variants in known cancer predisposition genes were detected in 11% (4/37; NF2, LZTR1, NF1 & TP53). However, DNA methylation profiling resulted in revision of the histopathological ependymoma diagnosis to non-ependymoma tumor types in 8% (3/39). This included the two children with pathogenic germline variants in TP53 and NF1 whose tumors were reclassified to a diffuse midline glioma and a rosette-forming glioneuronal tumor, respectively. Consequently, 50% (2/4) of children with pathogenic germline variants in fact had other tumor types. A meta-analysis combining our findings with pediatric pan-cancer germline sequencing studies showed an overall frequency of pathogenic germline variants of 3.4% (7/207) in children with ependymoma. In summary, less than 4% of childhood ependymoma is explained by genetic predisposition, virtually restricted to pathogenic variants in NF2 and NF1. For children with other cancer predisposition syndromes, diagnostic reconsideration is recommended for ependymomas without molecular classification. Additionally, LZTR1 is suggested as a novel putative ependymoma predisposition gene.

Background: Oral cancer is alarming disease in the developing countries like India. DNA repair capacity may affect by genetic polymorphisms in DNA repair genes and thus may cause to cancer. XRCC3 involves in homologous recombination repair pathway and repair DNA damage and crosslinks while, NBS1 participate in repair of double strand DNA break and starts the cell-cycle checkpoint signaling. Aims and Objectives: This study was to conducted to find the association of XRCC3, NBS1 polymorphisms with oral disease. Materials and Methods: This study included 230 patients of precancerous oral lesions (Leukoplakia 70, Oral Sub mucous fibrosis 90, Lichen Planus 70), 72 oral cancer and 300 healthy control samples and genotyping was done by PCR-RFLP methods. Chi-square test was used for calculation of genotype and allele frequencies. Odds ratio and P values were calculated with Epi-Info programme (http://wwwn.cdc.gov/epiinfo/). Results: TT genotype of XRCC3 was associated with high risk of precancerous lesions and oral cancerous lesions (P value=0.0001, OR=9.68, 95% CI=2.82-33.21; and P value=0.0001, OR=13.10, 95% CI=3.38-50.73 respectively). We did not observe any interactions of XRCC3 polymorphism with demographic parameters in influencing the risk of oral diseases. Variant allele genotypes (CG, GG) of NBS1 (C>G) polymorphism showed protective association with Oral submucous fibrosis (OSMF), lichen planus as well as oral cancer (OR=0.31, OR=0.01; OR=0.39, OR=0.03; OR=0.43, OR=0.31 respectively). Particularly, tobacco chewer with CG & GG genotypes were at decrease risk of oral diseases (P value=0.02, OR=0.32, 95% CI=0.12-0.80). Compared to CC/CC combined genotype CG/CC, CG/CT, GG/CC and CG/CT genotypes decreased the risk of oral disease (OR=0.05, 0.47, 0.26 & 0.14 respectively). Conclusion: This study concludes that SNP in XRCC3, NBS1 affects susceptibility to oral disease. [ABSTRACT FROM AUTHOR]

Background: Oral cancer is known as one of the most common cancers, with a poor prognosis, related to delayed clinical diagnosis, either due to the lack of particular biomarkers related to the disease or costly therapeutic alternatives. Aims and Objectives: In this study association of single nucleotide polymorphism (Taq1, T>C) in Vitamin D receptor gene with oral cancer and pre oral cancer was studied. Materials and Methods: Total 230 patients of precancerous oral lesions (Leukoplakia 70, Oral Sub mucous fibrosis 90, Lichen Planus 70), 72 oral cancer patients and 300 healthy control subjects were genotyped by PCR-RFLP methods. Chi-square test was used for calculation of genotype and allele frequencies. Results: Mutant genotype CC as well as C allele were found to significantly decrease the risk of oral disease (P value=0.04, OR=0.60 and P value=0.02, OR=0.75 respectively). In particular, compared to non smokers, smokers with TC & CC genotypes were at decrease risk of oral diseases (P value=0.0001, OR=0.04). The mutant allele genotype CC as well as the mutant allele C showed protective association with leukoplakia (P value=0.01, OR=0.39 & P value=0.009, OR=0.59 respectively). However, individual with CC genotype had developed high cell differentiated grade at diagnosis (OR= 3.78, P value= 0.008). Conclusions: This study concludes that VDR (Taq1) polymorphism is associated with oral cancer and pre oral cancer susceptibility in North Indian population. [ABSTRACT FROM AUTHOR]

Simple Summary: The occurrence of second primary cancers (SPCs) in patients with pleural mesothelioma (PM) included in the Lombardy Mesothelioma Registry (Italy) was investigated, with the aim of assessing its prognostic implications. The results of our study showed that the presence of an SPC in a patient's history did not significantly impact survival in the overall PM population; however, patients with non-epithelioid PM had a worse prognosis when an SPC was diagnosed. Further studies, including next-generation sequencing of cancer susceptibility genes on germline DNA, are needed to clarify the role of SPCs as markers of genetic susceptibility in mesothelioma. Background: The presence of a second primary cancer (SPC) in patients with pleural mesothelioma (PM) may impact overall survival and suggest a common mechanism of carcinogenesis or an underlying germline genetic alteration. Methods: We evaluated the occurrence of SPCs within PM cases collected from 2000 to 2018 by the Lombardy Mesothelioma Registry and their prognostic implications. Kaplan–Meier analysis was performed to estimate median survival times, together with univariate and multivariate Cox regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) of death. Results: The median overall survival (OS) of the entire study population (N = 6646) was 10.9 months (95% CI: 10.4–11.2); patient age and histotype were the strongest prognostic factors. No substantial survival difference was observed by the presence of an SPC (10.5 months in 1000 patients with an SPC vs. 10.9 months in 5646 patients in the non-SPC group, HR 1.03, p = 0.40). Shorter OS in the SPC group was only observed in 150 patients with the non-epithelioid subtype (median OS of 5.4 vs. 7.1 months, HR 1.21, p = 0.03). Conclusions: The diagnosis of an SPC did not influence the outcome of PM patients in the overall study population but was associated with shorter OS in non-epithelioid cases. Further studies are needed to clarify the role of SPCs as markers of genetic susceptibility in mesothelioma. [ABSTRACT FROM AUTHOR]

Human rotaviruses attach to histo-blood group antigens glycans and null alleles of the ABO, FUT2 and FUT3 genes seem to confer diminished risk of gastroenteritis. Yet, the true extent of this protection remains poorly quantified. Here, we conducted a prospective study to evaluate the risk of consulting at the hospital in non-vaccinated pediatric patients according to the ABO, FUT2 (secretor) and FUT3 (Lewis) polymorphisms, in Metropolitan France and French Guiana. At both locations, P genotypes were largely dominated by P [8]-3, with P [6] cases exclusively found in French Guiana. The FUT2 null (nonsecretor) and FUT3 null (Lewis negative) phenotypes conferred near full protection against severe gastroenteritis due to P [8]-3 strains (OR 0.03, 95% CI [0.00-0.21] and 0.1, 95% CI [0.01-0.43], respectively in Metropolitan France; OR 0.08, 95% CI [0.01-0.52] and 0.14, 95%CI [0.01-0.99], respectively in French Guiana). Blood group O also appeared protective in Metropolitan France (OR 0.38, 95% CI [0.23-0.62]), but not in French Guiana. The discrepancy between the two locations was explained by a recruitment at the hospital of less severe cases in French Guiana than in Metropolitan France. Considering the frequencies of the null ABO, Secretor and Lewis phenotypes, the data indicate that in a Western European population, 34% (95% CI [29%; 39%]) of infants are genetically protected against rotavirus gastroenteritis of sufficient severity to lead to hospital visit. [ABSTRACT FROM AUTHOR]

Increasing interest regarding neurodevelopmental disorders and democratization of chromosomal microarray analysis have led to growing identification of neuro‐susceptibility copy number variations (CNVs). These CNVs have incomplete penetrance and variable expressivity (PIEV), which makes phenotypic features hard to predict. The French Consortium "AchroPuce" has provided a list of 17 CNVs that should be considered as PIEV CNVs. This list led to consensual French practices of healthcare professionals in postnatal diagnosis. However, no consensus was established in prenatal diagnosis and fetal pathology. 121 French health professionals were surveyed their opinions and practices regarding reporting of PIEV CNVs to patients, in order to identify key points so as to establish French recommendations. The survey showed that professionals in favor of reporting PIEV CNVs to patients in prenatal diagnosis and fetal pathology (respectively, 76% and 84% of respondents) considered highlighted that multidisciplinary consultation is the main point‐of‐care management before family survey. This statement is close to recommendations published worldwide. As a consequence, multidisciplinary expertise should be the basis of French recommendations concerning the reporting of PIEV CNVs and genetic counseling in prenatal diagnosis and fetal pathology. [ABSTRACT FROM AUTHOR]

Inclusion body myositis (IBM) belongs to the group of idiopathic inflammatory myopathies and is characterized by a slowly progressive disease course with asymmetric muscle weakness of predominantly the finger flexors and knee extensors. The disease leads to severe disability and most patients lose ambulation due to lack of curative or disease-modifying treatment options. Despite some genes reported to be associated with hereditary IBM (a distinct group of conditions), data on the genetic susceptibility of sporadic IBM are very limited. This review gives an overview of the disease and focuses on the current genetic knowledge and potential therapeutic implications. [ABSTRACT FROM AUTHOR]

Background: Systemic sclerosis (SSc) is a connective tissue disease with ethnic differences. Single-nucleotide polymorphisms (SNPs) in the ARID3A, CXCR5, and TNFSF8 genes have been reported to be associated with various autoimmune diseases. The aim of this study was to investigate the association between these SNPs and susceptibility to SSc in a Chinese Han population. Methods: A case–control study was conducted in 342 patients with SSc and 694 ethnically matched healthy controls. SNPs in ARID3A, CXCR5, and TNFSF8 were genotyped using a Sequenom MassArray iPLEX system, and allele association analyses were performed using the PLINK v1.90 software. Results: Our study demonstrated that the ARID3A rs10415976 G and CXCR5 rs77871618 T alleles were suggestively associated with patients with SSc (P = 0.049 and P = 0.024, respectively) and TNFSF8 rs1555457 T allele was strongly associated with SSc (P = 0.003). Patients carrying the ARID3A rs350146 TT and TNFSF8 rs1555457 TT genotypes had a significant increased risk of SSc (P = 0.03 and P = 0.004, respectively). Moreover, rs10415976, rs77871618, and rs1555457 were associated with SSc in an additive genetic model (P < 0.05). rs62132345 and rs1555457 were associated with SSc in the dominant genetic model (P < 0.05). rs350146 was associated with SSc in the recessive genetic model (P = 0.029). Conclusions: ARID3A rs10415976, ARID3A rs350146, and CXCR5 rs77871618 were suggestively associated with SSc and TNFSF8 rs1555457 was strongly associated with SSc in the Chinese Han population in this study. Key Points • This case-control study determined that ARID3A rs10415976, ARID3A rs350146 and CXCR5 rs77871618 were suggestively associated with SSc and TNFSF8 rs1555457 was strongly associated with SSc in the Chinese Han population. • The differences in these results compared with previous studies may be a result of ethnic and racial differences. [ABSTRACT FROM AUTHOR]

Numerous studies have shown that oxidative stress resulting from an imbalance between the production of free radicals and their neutralization by antioxidant enzymes is one of the major pathological disorders underlying the development and progression of type 2 diabetes (T2D). The present review summarizes the current state of the art advances in understanding the role of abnormal redox homeostasis in the molecular mechanisms of T2D and provides comprehensive information on the characteristics and biological functions of antioxidant and oxidative enzymes, as well as discusses genetic studies conducted so far in order to investigate the contribution of polymorphisms in genes encoding redox state-regulating enzymes to the disease pathogenesis. [ABSTRACT FROM AUTHOR]

Transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative diseases with a chronic and fatal course, which are caused by a misfolded form of the cellular prion protein that is encoded by the host. The purpose of this work was to evaluate the resistance and genetic susceptibility to prion diseases in Pelibuey sheep from Mexico. The sequences of 99 Pelibuey sheep from the central and southwestern regions of Mexico were analyzed to determine the polymorphisms related to resistance and genetic susceptibility to scrapie, the Hardy-Weinberg equilibrium test and the D-Tajima test was used to identify the effect of evolutionary forces on the PRNP gene. Twelve non-synonymous polymorphisms Q101R, M112T, A116P, G127A, A136V, M137T, L141F, H143R, R154H, Q171R, Q171H, N176K were detected, in addition two synonymous substitutions 231R (agg/cgg) and 237L (ctc/ctg) were found. As a result of the sequence analysis, the ARR allele was not under the Hardy-Weinberg equilibrium, indicating that there is an evolutionary force at work, and the D-Tajima suggest the existence of purifying genetic selection. In conclusion, Pelibuey sheep exhibit genotypes for the PRNP gene that make them resistant to developing classic scrapie; at least 98% of the population is a carrier of an allele related to scrapie resistance; while for atypical scrapie there is a very high probability that an outbreak occurred in the herds, since the ARQ allele in combination with the L substitution at codon 141 confers susceptibility to carrier sheep. [ABSTRACT FROM AUTHOR]

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Background: Evidence linking air pollution to major depressive disorder (MDD) remains sparse and results are heterogeneous. In addition, the evidence about the interaction and joint associations of genetic risk and lifestyle with air pollution on incident MDD risk remains unclear. We aimed to examine the association of various air pollutants with the risk of incident MDD and assessed whether genetic susceptibility and lifestyle influence the associations. Methods: This population-based prospective cohort study analyzed data collected between March 2006 and October 2010 from 354,897 participants aged 37 to 73 years from the UK Biobank. Annual average concentrations of PM2.5, PM10, NO2, and NOx were estimated using a Land Use Regression model. A lifestyle score was determined based on a combination of smoking, alcohol drinking, physical activity, television viewing time, sleep duration, and diet. A polygenic risk score (PRS) was defined using 17 MDD-associated genetic loci. Results: During a median follow-up of 9.7 years (3,427,084 person-years), 14,710 incident MDD events were ascertained. PM2.5 (HR: 1.16, 95% CI: 1.07–1.26; per 5 μg/m3) and NOx (HR: 1.02, 95% CI: 1.01–1.05; per 20 μg/m3) were associated with increased risk of MDD. There was a significant interaction between the genetic susceptibility and air pollution for MDD (P-interaction < 0.05). Compared with participants with low genetic risk and low air pollution, those with high genetic risk and high PM2.5 exposure had the highest risk of incident MDD (PM2.5: HR: 1.34, 95% CI: 1.23–1.46). We also observed an interaction between PM2.5 exposure and unhealthy lifestyle (P-interaction < 0.05). Participants with the least healthy lifestyle and high air pollution exposures had the highest MDD risk when compared to those with the most healthy lifestyle and low air pollution (PM2.5: HR: 2.22, 95% CI: 1.92–2.58; PM10: HR: 2.09, 95% CI: 1.78–2.45; NO2: HR: 2.11, 95% CI: 1.82–2.46; NOx: HR: 2.28, 95% CI: 1.97–2.64). Conclusions: Long-term exposure to air pollution is associated with MDD risk. Identifying individuals with high genetic risk and developing healthy lifestyle for reducing the harm of air pollution to public mental health. [ABSTRACT FROM AUTHOR]

Background: Protein kinase C delta (PRKCD) and caspase recruitment domain family member 9 (CARD9) are genes involved in B and T cell activation, and cytokine production, which are vital mechanisms underlying autoimmune disease development. This study aimed to explore the association of the PRKCD and CARD9 genes with Vogt–Koyanagi–Harada disease (VKH) disease. The case–control study was performed to in 912 patients with VKH and 878 normal controls. MassARRAY system, SHEsis online platform, real-time PCR, and enzyme-linked immunosorbent assay were used to detect genotyping, haplotyping, mRNA expression, and cytokine levels, respectively. Results: We found that rs74437127 C allele of PRKCD, rs3812555 CC genotype, and C allele of CARD9 were associated with increased susceptibility of VKH (Pc = 0.020, OR = 1.624; Pc = 2.04 × 10–5, OR = 1.810; Pc = 2.76 × 10–5, OR = 1.698, respectively). However, the rs74437127 T allele, and rs3812555 TC genotype and T allele were linked with decreased susceptibility to VKH (Pc = 0.020, OR = 0.616; Pc = 7.85 × 10–5, OR = 0.559; Pc = 2.76 × 10–5, OR = 0.589, respectively). PRKCD ATG and CARD9 GCTTA haplotypes decreased susceptibility to VKH (Pc = 3.11 × 10–3, OR = 0.594; Pc = 5.00 × 10–3, OR = 0.639, respectively). Functional studies on rs3812555 genotyped individuals revealed that CC carriers had significantly higher CARD9 mRNA expression and tumour necrosis factor-α production than TC/TT carriers (P = 1.00 × 10–4; P = 2.00 × 10–3, respectively). Conclusions: We found an association between PRKCD rs74437127 and CARD9 rs3812555 polymorphisms and VKH susceptibility and revealed that the increased susceptibility of rs3812555 for VKH may be mediated by regulating CARD9 gene expression and the production of pro-inflammatory cytokines, such as TNF-α. [ABSTRACT FROM AUTHOR]

Background: Rotator cuff disease is one of the leading causes of musculoskeletal pain and disability, and its etiology is most likely multifactorial but remains incompletely understood. Therefore, the objective of this research was to investigate the relationship of the single-nucleotide rs820218 polymorphism of the SAP30-binding protein (SAP30BP) gene with rotator cuff tears in the Amazonian population. Methods: The case group consisted of patients who were operated on due to rotator cuff tears in a hospital in the Amazon region between 2010 and 2021, and the control group was composed of individuals who were selected after negative physical examinations for rotator cuff tears. Genomic DNA was obtained from saliva samples. For the genotyping and allelic discrimination of the selected single nucleotide polymorphism (rs820218) in the SAP30BP gene, real-time PCR was performed. Results: The frequency of the A allele in the control group was four times as high as that in the case group (AA homozygotes); an association of the genetic variant rs820218 of the SAP30BP gene with rotator cuff tears was not established (p = 0.28 and 0.20), as the A allelic frequency is ordinarily low in the general population. Conclusions: The presence of the A allele indicates protection against rotator cuff tears. [ABSTRACT FROM AUTHOR]

Three partially overlapping breast cancer polygenic risk scores (PRS) comprising 77, 179 and 313 SNPs have been proposed for European-ancestry women by the Breast Cancer Association Consortium (BCAC) for improving risk prediction in the general population. However, the effect of these SNPs may vary from one country to another and within a country because of other factors. To assess their associated risk and predictive performance in French women from (1) the CECILE population-based case-control study, (2) BRCA1 or BRCA2 (BRCA1/2) pathogenic variant (PV) carriers from the GEMO study, and (3) familial breast cancer cases with no BRCA1 /2 PV and unrelated controls from the GENESIS study. All three PRS were associated with breast cancer in all studies, with odds ratios per standard deviation varying from 1.7 to 2.0 in CECILE and GENESIS, and hazard ratios varying from 1.1 to 1.4 in GEMO. The predictive performance of PRS 313 in CECILE was similar to that reported in BCAC but lower than that in GENESIS (area under the receiver operating characteristic curve (AUC) = 0.67 and 0.75, respectively). PRS were less performant in BRCA2 and BRCA1 PV carriers (AUC = 0.58 and 0.54 respectively). Our results are in line with previous validation studies in the general population and in BRCA1/2 PV carriers. Additionally, we showed that PRS may be of clinical utility for women with a strong family history of breast cancer and no BRCA1/2 PV, and for those carrying a predicted PV in a moderate-risk gene like ATM , CHEK2 or PALB2. • Three polygenic risk scores for breast cancer assessed in 3 groups of French women. • All of them associated with breast cancer but effects varied depending on group. • Predictive ability is higher in women with no BRCA1 or BRCA2 pathogenic variant. • Opportunity to refine risk stratification in carriers of a moderate-risk variant. • Effects of SNPs in polygenic risk scores vary depending on country and population. [ABSTRACT FROM AUTHOR]

Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome‐wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10−8) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4‐rs34517439‐A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13‐1.32, P = 4.81 × 10−7). rs34517439‐A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA‐binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4‐rs34517439 as a potentially novel MM risk locus. [ABSTRACT FROM AUTHOR]

The main aim of this study was to evaluate the effects of Na intake and cardiorespiratory fitness (CRF) on body composition. The study was also intended to assess whether Na intake and/or CRF mediate the genetic susceptibility to obesity. Analyses were performed on a sample of 526 adult participants from the Quebec Family Study for whom a complete data set was available for nutrient and energy intake, CRF and body composition variables. The effects of Na, CRF and their interaction were analysed by comparing sex-specific tertiles using general linear mixed models. In both males and females, we observed a significant effect of Na intake and CRF on all body composition variables. However, in females only, we found that the effect of Na intake on body composition variables varies according to CRF level such that high Na intake was associated with increased body fatness, but only in females with low CRF. This interaction effect remained significant after statistical adjustment for total sugar, fat and energy intake. Using mediation analysis, we also found Na intake and CRF to be significant mediators of the relationship between a polygenic risk score of obesity based on > 500 000 genetic variants and BMI or waist circumference. In conclusion, the current study shows that Na intake influences body composition via mechanisms that interact with aerobic fitness, especially in females. Furthermore, both Na intake and CRF seem to be involved in the expression of the genetic susceptibility to obesity. [ABSTRACT FROM AUTHOR]

In the present study, the genetics of susceptibility to peach leaf curl, a worldwide disease that affects both crop yield and plant longevity, was investigated using a progeny 'Dofi-84.364' that is highly resistant to the agent Taphrina deformans, as well as 8 cultivars and 2 selections obtained at the University of Florence. Heritability and combining ability were estimated by comparing parent and offspring leaf curl scores of 20 families. The broad-sense heritability of the trait was high (H2Cullis = 0.65). Variance components of the general (GCA) and specific (SCA) effects showed that in the genetic determination of this trait both additive parental effects and interactive effects are important. However, the magnitude of SCA was lower than GCA possibly indicating a preponderance of additive genes controlling susceptibility to leaf curl disease. As expected, the resistant selection 'Dofi-84.364' proved to be a donor of low susceptibility to leaf curl in peach. Progeny tests are relevant to improve the chance to obtain genotypes less susceptible to leaf curl disease. In this trial, both additive and non-additive genetic effects were found to be important, with a greater contribution of additive effects to total genetic effects. Consequently, there may be a good opportunity to advance in T. deformans tolerance by crossing cultivars that have been selected for their phenotypic value and not only for their combining ability. [ABSTRACT FROM AUTHOR]

The associations of sleep duration and midday napping with homocysteine (Hcy) levels, and whether these sleep behaviors modify the association between genetic predisposition and Hcy levels, has yet to be investigated. We included 19,426 participants without severe health conditions at baseline from the Dongfeng–Tongji cohort. In a subgroup of 15,126 participants with genetic data, a genetic risk score (GRS) based on 18 Hcy-related loci was constructed to test the gene–sleep interactions in Hcy. Hcy levels were higher in subjects with a long sleep duration (≥9 h) and midday napping (>90 min), as compared to those who reported a moderate sleep duration (7 to <8 h) and midday napping (1–30 min) (all p values < 0.05). A long sleep duration and midday napping showed a joint effect in increasing Hcy (p for trend < 0.001). Significant interactions regarding Hcy levels were observed for a long sleep duration with GRS and MTHFR rs1801133, and long midday napping with DPEP1 rs12921383 (all p values for interaction < 0.05). Overall findings indicated that a long sleep duration and midday napping were associated with elevated serum Hcy levels, independently and jointly, and amplified the genetic susceptibility to higher Hcy. [ABSTRACT FROM AUTHOR]

Infections by the parasite E. histolytica are increasing in HIV-infected individuals. Interleukin (IL-10) plays an important role in maintaining the mucosal barrier. Therefore, the seroprevalence of E. histolytica was investigated in relation to the IL-10 serum concentration among HIV- infected patients. A total of 647 blood samples were collected from asymptomatic HIV-infected patients. The Entamoeba histolytica antigen (GALNAC lectin) and serum antibodies were assessed using specific ELISAs (TECHLAB, Virginia, USA). IL10 blood levels were measured using a commercial ELISA test, and the results were analyzed using parametric and non-parametric statistical tests. The Gal/GALNAC lectin was detected in only 0.5% (3/647) of individuals, and the antibodies against E. histolytica were detected in 65.2% (422/647) of the samples. A significant increase in IL-10 levels was found in 68.1% of patients who were sero-negative for E. histolytica antibodies compared to patients who were sero-positive. There is a high level of exposure to E. histolytica among HIV patients in South Africa, although the prevalence of amoebic liver abscesses might be low. This study revealed that elevated levels of IL-10 might be associated with a reduced risk of amebiasis. [ABSTRACT FROM AUTHOR]

IntroductionVitamin D has been known to be associated with asthma, particularly in children, while the evidence among adults is limited and inconclusive. This study aimed to investigate the association between serum, vitamin D concentrations, and the incidence of adult-onset asthma and also the modified effect caused by sleep patterns and genetic risks.MethodsA prospective cohort study with 307,872 participants aged between 37 and 73 years was conducted based on the UK Biobank, with a median follow-up of 12 years. The Cox proportional hazard model was applied to evaluate the association between vitamin D status and incident adult-onset asthma, and the modified effect was investigated by conducting stratified analysis according to sleep pattern score and genetic risk score, and subgroup analyses were performed by sex, age, BMI, and smoking status as well.ResultsIndividuals with optimal vitamin D concentration were associated with 11.1% reduced risk of incident asthma compared to those participants with deficient vitamin D (HR = 0.889; 95% CI: 0.820–0.964; p = 0.005). Moreover, stratification analysis demonstrated that the protective effect of vitamin D on asthma risk was modified by sleep patterns or genetic susceptibility, with the strongest protective effect being observed in the subpopulation with a moderate sleep pattern (HR = 0.883; 95% CI: 0.797–0.977; p = 0.016) and a moderate genetic risk (HR = 0.817; 95% CI: 0.711–0.938; p = 0.004). In subgroup analyses, the protective effect of optimal vitamin D levels was only significant among men, individuals younger than 60 years of age, overweight individuals, and current or previous smokers.ConclusionIncreased serum vitamin D levels were associated with a lower risk of incident adult-onset asthma, and this association was modified by sleep patterns and genetic predisposition to some extent.

BackgroundThe role of matrix metalloproteinase 9 (MMP-9) in the pathophysiology of chronic kidney disease (CKD), which is associated with a nearly two-fold greater risk for urinary calculi compared to people without CKD, has been demonstrated. The aim of the research is to evaluate the association between MMP-9-1562C>T polymorphism, MMP-9 serum levels and nephrolithiasis risk.MethodsA hospital-based case-control study involving 302 kidney stone patients and 408 controls without kidney stone from southern China was conducted. Sanger sequencing was used to genotype the MMP-9-1562C>T polymorphism. The serum MMP-9 was measured in 105 kidney stone patients and 77 controls by enzyme-linked immunosorbent assay.ResultsCompared to the control group, the CT genotype was more frequent in nephrolithiasis patients (adjusted OR = 1.60, 95% CI = 1.09–2.37: the risk of developing nephrolithiasis in individuals with CT genotype compared to CC genotype). Moreover, there was also a higher frequency of CT/TT genotypes among patients with nephrolithiasis (adjusted OR = 1.49, 95% CI = 1.02–2.19: the risk of developing nephrolithiasis in individuals with CT/TT genotypes compared to CC genotype). The risk remained for the subgroups of patients aged >53, smokers with pack-years of smoking >20, non-drinkers, non-diabetic patients, patients with hypertension, recurrent episodes and calcium oxalate stones (OR = 2.26, 95% CI = 1.31–3.91; OR = 5.47, 95% CI = 1.10–27.30; OR = 1.76, 95% CI = 1.14–2.72; OR = 1.54, 95% CI = 1.03–2.30; OR = 1.97, 95% CI = 1.01–3.82; OR = 1.67, 95% CI = 1.06–2.62; OR = 1.54, 95% CI = 1.02–2.32, respectively). Biochemical parameters did not differ between genotypes. Compared to controls (18.57 ± 5.80 ng/mL), nephrolithiasis patients had significantly higher serum MMP-9 levels (30.17 ± 6.78 ng/mL, p T were significantly higher than those with CC genotype (32.00 ± 6.33 vs. 29.13 ± 6.85 ng/mL, p = 0.037).ConclusionThe MMP-9-1562C>T polymorphism in association with its soluble protein increased the risk of kidney stone, thus suggesting it could be used as a susceptibility biomarker for nephrolithiasis. Further functional studies and larger studies that include environmental exposure data are needed to confirm the findings.