scholarly journals Common variants at 21q22.3 locus influence MX1 gene expression and susceptibility to severe COVID-19

2020 ◽  
Author(s):  
Immacolata Andolfo ◽  
Roberta Russo ◽  
Alessandro Vito Lasorsa ◽  
Sueva Cantalupo ◽  
Barbara Eleni Rosato ◽  
...  
Keyword(s):  
Risk Factors ◽  
Genetic Factors ◽  
Genome Wide Association Study ◽  
Wide Spectrum ◽  
Clinical Manifestations ◽  
Study Data ◽  
Chromosome 21 ◽  
Type I ◽  
Nucleotide Polymorphisms ◽  
Common Variants

AbstractThe COVID-19 disease, caused by the SARS-Cov-2, presents a heterogeneous clinical spectrum. The risk factors do not fully explain the wide spectrum of disease manifestations, so it is possible that genetic factors could account for novel insights into its pathogenesis.In our previous study, we hypothesized that common variants on chromosome 21, near TMPRSS2 and MX1 genes, may be genetic risk factors associated to the different clinical manifestations of COVID-19. Here, we performed an in-depth genetic analysis of chromosome 21 exploiting the genome-wide association study data including 6,406 individuals hospitalized for COVID-19 and 902,088 controls with European genetic ancestry from COVID-19 Host Genetics Initiative. We found that five single nucleotide polymorphisms (SNPs) within TMPRSS2 and near MX1 gene show suggestive associations (P≤1×10−5) with severe COVID-19. All five SNPs replicated the association in two independent cohorts of Asian subjects while two and one out of the 5 SNPs replicated in African and Italian populations, respectively (P≤0.05). The minor alleles of these five SNPs correlated with a reduced risk of developing severe COVID-19 and increased level of MX1 expression in blood.Our findings provide further evidence that host genetic factors can contribute to determine the different clinical presentations of COVID-19 and that MX1, an antiviral effector of type I and III interferon pathway, may be a potential therapeutic target.

Genetic aspects of intervertebral disc degeneration

2015 ◽  
Vol 26 (5) ◽  
pp. 581-606 ◽  
Author(s):  
Sara Hanaei ◽  
Sina Abdollahzade ◽  
Alireza Khoshnevisan ◽  
Christopher K. Kepler ◽  
Nima Rezaei
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Genetic Factors ◽  
Wide Spectrum ◽  
Nucleotide Polymorphisms ◽  
Disc Disease ◽  
Multifactorial Diseases ◽  
Common Causes

AbstractIntervertebral disc degeneration (IVDD) is one of the common causes of low back pain. Similar to many other multifactorial diseases, it is affected by environmental and genetic factors. Although not completely understood, genetic factors include a wide spectrum of variations, such as single nucleotide polymorphisms, which could play a significant role in the etiology of this disease. Besides, the interactions with environmental factors could make the role of genetic factors more complicated. Genetic variations in disc components could participate in developing degenerative disc disease through altering the normal homeostasis of discs. Gene polymorphisms in disc proteins (collagens I, II, III, IX, and XI), proteoglycans (aggrecan), cytokines (interleukins I, VI, and X), enzymes (matrix metalloproteinases II, III, and IX), and vitamin D receptor seem to play considerable roles in the pathology of this disease. There are also many other investigated genes that could somehow take part in the process. However, it seems that more studies are needed to clarify the exact role of genetics in IVDD.

scholarly journals Assessing causality in associations between cannabis use and schizophrenia risk: a two-sample Mendelian randomization study

2016 ◽  
Vol 47 (5) ◽  
pp. 971-980 ◽  
Author(s):  
S. H. Gage ◽  
H. J. Jones ◽  
S. Burgess ◽  
J. Bowden ◽  
G. Davey Smith ◽  
...  
Keyword(s):  
Fixed Effects ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Positive Control ◽  
Negative Control ◽  
Study Data ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Genome Wide Data

BackgroundObservational associations between cannabis and schizophrenia are well documented, but ascertaining causation is more challenging. We used Mendelian randomization (MR), utilizing publicly available data as a method for ascertaining causation from observational data.MethodWe performed bi-directional two-sample MR using summary-level genome-wide data from the International Cannabis Consortium (ICC) and the Psychiatric Genomics Consortium (PGC2). Single nucleotide polymorphisms (SNPs) associated with cannabis initiation (p < 10−5) and schizophrenia (p < 5 × 10−8) were combined using an inverse-variance-weighted fixed-effects approach. We also used height and education genome-wide association study data, representing negative and positive control analyses.ResultsThere was some evidence consistent with a causal effect of cannabis initiation on risk of schizophrenia [odds ratio (OR) 1.04 per doubling odds of cannabis initiation, 95% confidence interval (CI) 1.01–1.07, p = 0.019]. There was strong evidence consistent with a causal effect of schizophrenia risk on likelihood of cannabis initiation (OR 1.10 per doubling of the odds of schizophrenia, 95% CI 1.05–1.14, p = 2.64 × 10−5). Findings were as predicted for the negative control (height: OR 1.00, 95% CI 0.99–1.01, p = 0.90) but weaker than predicted for the positive control (years in education: OR 0.99, 95% CI 0.97–1.00, p = 0.066) analyses.ConclusionsOur results provide some that cannabis initiation increases the risk of schizophrenia, although the size of the causal estimate is small. We find stronger evidence that schizophrenia risk predicts cannabis initiation, possibly as genetic instruments for schizophrenia are stronger than for cannabis initiation.

scholarly journals MMP2 Polymorphism Affects Plasma Matrix Metalloproteinase (MMP)-2 Levels, and Correlates with the Decline in Lung Function in Hypersensitivity Pneumonitis Positive to Autoantibodies Patients.

Biomolecules ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 574 ◽  
Author(s):  
Santiago-Ruiz ◽  
Buendía-Roldán ◽  
Pérez-Rubio ◽  
Ambrocio-Ortiz ◽  
Mejía ◽  
...  
Keyword(s):  
Hypersensitivity Pneumonitis ◽  
Vital Capacity ◽  
Genetic Factors ◽  
Genetic Model ◽  
Linear Regression Analysis ◽  
Clinical Manifestations ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Dominant Genetic Model ◽  
Pulmonary Remodeling

Among hypersensitivity pneumonitis (HP) patients have been identified who develop autoantibodies with and without clinical manifestations of autoimmune disease. Genetic factors involved in this process and the effect of these autoantibodies on the clinical phenotype are unknown. Matrix metalloproteinases (MMPs) have an important role in architecture and pulmonary remodeling. The aim of our study was to identify polymorphisms in the MMP1, MMP2, MMP9 and MMP12 genes associated with susceptibility to HP with the presence of autoantibodies (HPAbs+). Using the dominant model of genetic association, comparisons were made between three groups. For rs7125062 in MMP1 (CC vs. CT+TT), we found an association when comparing groups of patients with healthy controls: HPAbs+ vs. HC (p < 0.001, OR = 10.62, CI 95% = 4.34 − 25.96); HP vs. HC (p < 0.001, OR = 7.85, 95% CI 95% = 4.54 − 13.57). This rs11646643 in MMP2 shows a difference in the HPAbs+ group by the dominant genetic model GG vs. GA+AA, (p = 0.001, OR = 8.11, CI 95% = 1.83 − 35.84). In the linear regression analysis, rs11646643 was associated with a difference in basal forced vital capacity (FVC)/12 months (p = 0.013, = 0.228, 95% CI95% = 1.97 − 16.72). We identified single-nucleotide polymorphisms (SNPs) associated with the risk of developing HP, and with the evolution towards the phenotype with the presence of autoantibodies. Also, to the decrease in plasma MMP-2 levels.

scholarly journals Clinical and Genetic Risk Factors for Acute Pancreatitis in Patients With Acute Lymphoblastic Leukemia

2016 ◽  
Vol 34 (18) ◽  
pp. 2133-2140 ◽  
Author(s):  
Chengcheng Liu ◽  
Wenjian Yang ◽  
Meenakshi Devidas ◽  
Cheng Cheng ◽  
Deqing Pei ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Pancreatitis ◽  
Native American ◽  
Acute Lymphoblastic Leukemia ◽  
Genetic Risk ◽  
Genome Wide Association Study ◽  
Lymphoblastic Leukemia ◽  
Genome Wide Association ◽  
Common Variants ◽  
Genome Wide

Purpose Acute pancreatitis is one of the common causes of asparaginase intolerance. The mechanism is unknown, and genetic predisposition to asparaginase-induced pancreatitis has not been previously identified. Methods To determine clinical risk factors for asparaginase-induced pancreatitis, we studied a cohort of 5,185 children and young adults with acute lymphoblastic leukemia, including 117 (2.3%) who were diagnosed with at least one episode of acute pancreatitis during therapy. A genome-wide association study was performed in the cohort and in an independent case-control group of 213 patients to identify genetic risk factors. Results Risk factors associated with pancreatitis included genetically defined Native American ancestry (P < .001), older age (P < .001), and higher cumulative dose of asparaginase (P < .001). No common variants reached genome-wide significance in the genome-wide association study, but a rare nonsense variant rs199695765 in CPA2, encoding carboxypeptidase A2, was highly associated with pancreatitis (hazard ratio, 587; 95% CI, 66.8 to 5166; P = 9.0 × 10−9). A gene-level analysis showed an excess of additional CPA2 variants in patients who did versus those who did not develop pancreatitis (P = .001). Sixteen CPA2 single-nucleotide polymorphisms were associated (P < .05) with pancreatitis, and 13 of 24 patients who carried at least one of these variants developed pancreatitis. Biologic functions that were overrepresented by common variants modestly associated with pancreatitis included purine metabolism and cytoskeleton regulation. Conclusion Older age, higher exposure to asparaginase, and higher Native American ancestry were independent risk factors for pancreatitis in patients with acute lymphoblastic leukemia. Those who inherit a nonsense rare variant in the CPA2 gene had a markedly increased risk of asparaginase-induced pancreatitis.

scholarly journals Risk factors and molecular entities of the etiopathogenesis of the knee osteoarthritis (literature review)

2021 ◽  
Vol 27 (1) ◽  
pp. 112-120
Author(s):  
V.B. Novakov ◽  
◽  
O.N. Novakova ◽  
M.I. Churnosov ◽  
◽  
...  
Keyword(s):  
Risk Factors ◽  
Literature Review ◽  
Knee Osteoarthritis ◽  
Subchondral Bone ◽  
Molecular Mechanisms ◽  
Wide Spectrum ◽  
Clinical Manifestations ◽  
Bibliographic Databases ◽  
Joint Involvement ◽  
Knee Oa

Introduction Osteoarthritis (OA) is a heterogenic group of disorders of different etiology with similar biological, morphological and clinical manifestations and outcomes. OA is now considered a disease of the whole joint, including alterations in the articular cartilage, subchondral bone, synovial membrane, ligaments, capsule and periarticular muscles. OA of the knee as the most commonly affected joint accounts for the great medical, medical, social and economic impact. Material and methods A literature review assessing Russian and foreign studies on molecular mechanisms of etiology and pathogenesis of knee OA identified a set of factors for which there was consistent evidence for their association with onset of knee OA. A search of studies published in Russian and in English for the last ten years was conducted using bibliographic databases, including PubMed, PubMedCentral, GoogleScholar, eLIBRARY. Search terms included 'knee osteoarthritis', 'etiology', 'pathogenesis', 'risk factors'. Results Review of the literature showed that patients with knee OA are characterized by changes in cartilage, subchondral bone, synovium, suggesting common mechanisms of joint degeneration during OA development. Osteoarthritis (OA) is multifactorial in origin and closely associated with a wide spectrum of local (previous injury, muscle weakness, knee malalignment, knee surgeries, abnormal mechanical loading, excessive high impact sports, occupational physical activities) and systemic risk factors (advanced age, female sex, height, greater body mass index and obesity, hormone status, family history, mineral bone density, vitamin D deficiency, ethnicity). The prevalence of the knee OA and patterns of joint involvement vary among different racial and ethnic groups. Conclusion The literature review allowed us to identify the molecular mechanisms of etiopathogenesis of knee OA and the major risk factors for the pathology.

scholarly journals REAP: A platform to identify autoantibodies that target the human exoproteome

2021 ◽  
Author(s):  
Eric Y. Wang ◽  
Yile Dai ◽  
Connor E. Rosen ◽  
Monica M. Schmitt ◽  
Mei X. Dong ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Wide Spectrum ◽  
Intrinsic Factor ◽  
Clinical Manifestations ◽  
Type I Interferons ◽  
Type I ◽  
Glycoprotein Hormone ◽  
Binding Event ◽  
Extracellular Matrix Components ◽  
Autoimmune Polyendocrinopathy

AbstractAutoantibodies that recognize extracellular protein epitopes (the “exoproteome”) exert potent functional effects that underlie numerous disease processes. Identifying these antibodies can thus provide insights into the pathophysiology of a wide spectrum of illnesses and therapeutic strategies to treat them. Here, we developed Rapid Extracellular Antigen Profiling (REAP) as a technique for comprehensive and high-throughput discovery of exoproteome-targeting autoantibodies. With REAP, patient samples are applied to a genetically-barcoded library containing 2,688 unique members of the human exoproteome displayed on the surface of yeast. Antibody-coated cells are isolated by magnetic selection and deep sequencing of their barcodes is used to identify the displayed antigens, thereby converting an antibody:antigen binding event into a digital sequencing readout. To benchmark the performance of REAP, we screened 77 patients with the rare monogenic autoimmune disease autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). REAP sensitively and specifically detected known autoantibody reactivities in APECED, including responses against type I interferons, IL-17, IL-22, and gastric intrinsic factor. REAP also identified highly prevalent reactivities that had not been previously described such as those against the glycoprotein hormone GPHB5. We additionally screened 106 patients with systemic lupus erythematosus (SLE) and identified novel autoantibody reactivities against a diverse set of antigens including growth factors, extracellular matrix components, cytokines, and immunomodulatory proteins. Several of these responses were associated with disease severity and specific clinical manifestations of SLE, including autoantibodies that target immunoreceptors, antagonize the pro-inflammatory cytokine IL-33, and recognize endosialin (CD248) and the chemokine CCL8. In summary, these findings demonstrate the utility of REAP to atlas the expansive landscape of exoproteome-targeting autoantibodies in patients.

scholarly journals Clinical manifestations of cow milk protein intolerance in infants

2005 ◽  
Vol 133 (7-8) ◽  
pp. 348-352
Author(s):  
Marija Mladenovic ◽  
Nedeljko Radlovic ◽  
Zoran Lekovic ◽  
Dragana Ristic ◽  
Dragana Zivanovic ◽  
...  
Keyword(s):  
Milk Protein ◽  
Wide Spectrum ◽  
Clinical Signs ◽  
Clinical Manifestations ◽  
Signs And Symptoms ◽  
Cow Milk ◽  
Type I ◽  
Digestive Disorders ◽  
Clinical Signs And Symptoms ◽  
Protein Intolerance

Introduction. The disorder of cow milk protein intolerance is characterized by a wide spectrum of clinical manifestations caused by hypersensitivity of type I, II, or IV, and occurs in 2-3% of children, mostly infants. Objective. The aim of this study was to present our experiences and observations of clinical signs and symptoms of cow milk protein intolerance in infants aged below 12 months. Method. The investigation was carried out on a sample of 55 infants, aged between 1.5-9 months (x=4.2l?1.25), who had cow milk protein intolerance. Diagnosis of illness was based on characteristic anamnestic, clinical, and laboratory parameters, as well as on an adequate patient's response to antigen elimination. Results. The clinical presentation of cow milk protein intolerance was dominated by cutaneous problems, found in 40/55 (72.73%) infants, followed by digestive disorders, found in 31 (56.36%), while respiratory tract disorders were observed least frequently (14.55%). None of the patients developed anaphylactic shock. Changes involving only one system were found in 35 (63.64%) patients; of these 20 (36.36%) were cutaneous and 15 (27.27%) digestive. Twenty (36.36%) infants displayed multisystemic changes; of these 12 were cutaneus with digestive, 4 were cutaneus with respiratory, while 4 infants had cutaneous, digestive, and respiratory disorders. Of the 55 infants with cow milk protein intolerance, 26 (47.27%) had urticaria, 22 (40.00%) perioral erythema, 21 (38.18%) diarrhoea (15 haemorrhagic, 6 non-haemorrhagic), 13 (23.64%) vomiting, 12 (21.82%) Quincke's oedema, 12 (21.82%) eczema, 5 (9.09%) obstructive bronchitis, while 3 (5.45%) infants had laryngitis. In 5 (9.09%) patients we found a significant body weight deficit and in 3 (5.45%), sideropenic anaemia, while longitudinal growth retardation was not registered in any of the patients. Conclusion. Our study showed that the disorder of cow milk protein intolerance predominantly involved cutaneous disorders as well as combinations of cutaneous and digestive disorders, while respiratory system disorders proved to be relatively rare.

Modifiable risk factors for intracranial aneurysms: Evidence from genetic studies

2022 ◽  
pp. 174749302110656
Author(s):  
Xiaohui Sun ◽  
Bin Liu ◽  
Ying Chen ◽  
Linshuoshuo Lv ◽  
Ding Ye ◽  
...  
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
Educational Attainment ◽  
Genome Wide Association Study ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Health Concern ◽  
Modifiable Risk Factors ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
A Genome

Background: Intracranial aneurysm (IA) is a crucial health concern with limited strategies for prevention and treatment. Aim: To identify potentially modifiable risk factors, such as socioeconomic, behaviors, dietary, and cardiometabolic factors, for IA and its subtypes. Methods: Summary statistics for IA were derived from a genome-wide association study with an overall 79,429 participants. Single nucleotide polymorphisms associated with modifiable risk factors at genome-wide significance ( P = 5 × 10–8) were used as instrumental variables. The inverse-variance-weighted method, weighted-median method, Mendelian randomization (MR)-Egger regression, MR-Pleiotropy RESidual Sum and Outlier, and multivariable MR analyses were performed to evaluate the effect estimates. Results: Genetically predicted educational attainment, insomnia, smoking, and systolic and diastolic blood pressure (SBP and DBP) were significantly associated with the risk of IA. The odds ratios (ORs) were 0.44 (95% confidence interval (CI): 0.37–0.52) for educational attainment, 1.15 (95% CI: 1.08–1.23) for insomnia, 1.56 (95% CI: 1.38–1.75) for smoking initiation, 2.69 (95% CI: 1.77–4.07) for cigarette per day, 2.65 (95% CI: 1.72–4.08) for lifetime smoking, 1.07 (95% CI: 1.06–1.09), and 1.06 (95% CI: 1.04–1.10) for SBP and DBP, respectively. Similar effect estimates were observed for unruptured IAs and aneurysmal subarachnoid hemorrhage. Conclusions: This study provided genetic evidence that several modifiable risk factors, including blood pressure, smoking, educational attainment, and insomnia were associated with the risk of IA.

scholarly journals Genetic Factors Associated with Prostate Cancer Conversion from Active Surveillance to Treatment

2021 ◽  
Author(s):  
Yu Jiang ◽  
Travis J. Meyers ◽  
Adaeze A. Emeka, ◽  
Lauren Folgosa Cooley ◽  
Phillip R. Cooper ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Active Surveillance ◽  
Active Treatment ◽  
Genetic Factors ◽  
Genome Wide Association Study ◽  
Genetic Risk Score ◽  
Specific Antigen ◽  
Low Risk ◽  
Nucleotide Polymorphisms ◽  
Initial Management

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 6,361 PC patients who initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 single nucleotide polymorphisms (SNPs) associated with conversion, 15 of which were not previously associated with PC risk. We found two genes associated with conversion (MAST3, p = 6.9×10-7 and GAB2, p = 2.0×10-6). Moreover, increasing values of a previously validated 269-SNP genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% Confidence Interval [CI]= 0.94-1.36); whereas, decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04-1.50). These results suggest that germline genetics may help inform and individualize the decision of AS-or the intensity of monitoring on AS-versus treatment for the initial management of patients with low-risk PC.

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