scholarly journals Human genetic evidence supports MAP3K15 inhibition as a therapeutic strategy for diabetes

2021 ◽  
Author(s):  
Abhishek Nag ◽  
Ryan Dhindsa ◽  
Andrew R. Harper ◽  
Dimitrios Vitsios ◽  
Andrea Ahnmark ◽  
...  
Keyword(s):  
Adult Population ◽  
Tissue Expression ◽  
Chronic Health Condition ◽  
Genetic Evidence ◽  
Uk Biobank ◽  
Genetic Associations ◽  
Pancreatic Islet Cell ◽  
Resistance Pathway ◽  
Increased Risk ◽  
Reduced Risk

Diabetes mellitus is a chronic health condition that can result in significant end-organ complications and is estimated to impact at least 8.5% of the global adult population. Here, we performed gene-level collapsing analysis on exome sequences from 454,796 multi-ancestry UK Biobank participants to detect genetic associations with diabetes. Rare nonsynonymous variations in GCK, GIGYF1, HNF1A, and HNF4A were significantly associated (P<1x10-8) with increased risk of diabetes, whereas rare nonsynonymous variations in MAP3K15 were significantly associated with reduced risk of diabetes. Recessive carriers of rare non-synonymous variants in the X chromosome gene MAP3K15 had a 30% reduced risk of diabetes (OR=0.70, 95% CI: [0.62,0.79], P=5.7x10-10), along with reduced blood glucose (beta=-0.13, 95% CI: [-0.15,-0.10], P=5.5x10-18) and reduced glycosylated haemoglobin levels (beta=-0.14, 95% CI: [-0.16,-0.11], P=1.1x10-24). Hemizygous males carrying protein-truncating variants (PTVs) in MAP3K15 demonstrated a 40% reduced risk of diabetes (OR=0.60, 95% CI: [0.45,0.81], P=0.0007). These findings were independently replicated in FinnGen, with a MAP3K15 PTV associating with decreased risk of both type 1 diabetes (T1DM) and type 2 diabetes (T2DM) (p<0.05). The effect of MAP3K15 loss on diabetes was independent of body mass index, suggesting its protective effect is unlikely to be mediated via the insulin resistance pathway. Tissue expression profile of MAP3K15 indicates a possible involvement of pancreatic islet cell or stress response pathways. No safety concerns were identified among heterozygous or recessive MAP3K15 PTV carriers across over 15,719 studied endpoints in the UK Biobank. Human population genetic evidence supports MAP3K15 inhibition as a novel therapeutic target for diabetes.

scholarly journals Pleiotropic associations of heterozygosity for the SERPINA1 Z allele in the UK Biobank

2021 ◽  
pp. 00049-2021
Author(s):  
Katherine A. Fawcett ◽  
Kijoung Song ◽  
Guoqing Qian ◽  
Aliki-Eleni Farmaki ◽  
Richard Packer ◽  
...  
Keyword(s):  
Lung Function ◽  
Disease Risk ◽  
Large Population ◽  
Rare Condition ◽  
Forced Expiratory Volume ◽  
Uk Biobank ◽  
Mineral Density ◽  
Increased Risk ◽  
The Uk ◽  
Reduced Risk

Homozygosity for the SERPINA1 Z allele causes alpha-1 antitrypsin deficiency, a rare condition that can cause lung and liver disease. However, the effects of Z allele heterozygosity on non-respiratory phenotypes, and on lung function in the general population, remain unclear.We conducted a large population-based study to determine Z allele effects on >2400 phenotypes in UK Biobank (N>303 353).Z allele heterozygosity was strongly associated with increased height (β=1.02 cm, p=3.91×10−68), and with other non-respiratory phenotypes including increased risk of gall bladder disease, reduced risk of heart disease and lower blood pressure, reduced risk of osteoarthritis and reduced bone mineral density, increased risk of headache and enlarged prostate, as well as with blood biomarkers of liver function. Heterozygosity was associated with higher height-adjusted forced expiratory volume in 1 s (FEV1) (β=19.36 mL, p=9.21×10−4) and FEV1/forced vital capacity (FEV1/FVC) (β=0.0031, p=1.22×10−5) in non-smokers, whereas in smokers this protective effect was abolished. Furthermore, we show for the first time that sex modifies the association of the Z allele on lung function.We conclude that Z allele heterozygosity and homozygosity exhibit opposing effects on lung function in the UK population, and that these associations are modified by smoking and sex. In exploratory analyses, heterozygosity for the Z allele also showed pleiotropic associations with non-respiratory health-related traits and disease risk.

scholarly journals Pleiotropic effects of heterozygosity for the SERPINA1 Z allele in the UK Biobank

2020 ◽  
Author(s):  
Katherine A Fawcett ◽  
Kijoung Song ◽  
Guoqing Qian ◽  
Aliki-Eleni Farmaki ◽  
Richard Packer ◽  
...  
Keyword(s):  
Lung Function ◽  
Rare Condition ◽  
Population Based ◽  
Uk Biobank ◽  
Mineral Density ◽  
Increased Risk ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin ◽  
The Uk ◽  
Reduced Risk

Homozygosity for the SERPINA1 Z allele causes alpha-1 antitrypsin deficiency, a rare condition that can cause lung and liver disease. However, the effects of Z allele heterozygosity on non-respiratory phenotypes, and on lung function in the general population, remain unclear. We conducted the largest population-based study to date to determine Z allele effects on >2,400 phenotypes using the UK Biobank study (N>303,353). We detected strong associations between heterozygosity and non-respiratory phenotypes including increased height, increased risk of gall bladder disease, reduced risk of heart disease and lower blood pressure, reduced risk of osteoarthritis and reduced bone mineral density, increased risk of headache and enlarged prostate, as well as with blood biomarkers of liver function. Heterozygosity was associated with higher lung function in non-smokers, but smoking appears to abolish this protective effect. Individuals heterozygous for the Z allele may therefore have altered risk of smoking-induced lung disease and other, non-respiratory conditions.

scholarly journals A Network-Based Analysis of Disease Complication Associations for Obstetric Disorders in the UK Biobank

2021 ◽  
Vol 11 (12) ◽  
pp. 1382
Author(s):  
Vivek Sriram ◽  
Yonghyun Nam ◽  
Manu Shivakumar ◽  
Anurag Verma ◽  
Sang-Hyuk Jung ◽  
...  
Keyword(s):  
Characteristic Curve ◽  
Risk Scores ◽  
Uk Biobank ◽  
Genetic Associations ◽  
Clinical Tool ◽  
Related Disorder ◽  
Related Disease ◽  
Complication Risk ◽  
Increased Risk ◽  
The Uk

Background: Recent studies have found that women with obstetric disorders are at increased risk for a variety of long-term complications. However, the underlying pathophysiology of these connections remains undetermined. A network-based view incorporating knowledge of other diseases and genetic associations will aid our understanding of the role of genetics in pregnancy-related disease complications. Methods: We built a disease–disease network (DDN) using UK Biobank (UKBB) summary data from a phenome-wide association study (PheWAS) to elaborate multiple disease associations. We also constructed egocentric DDNs, where each network focuses on a pregnancy-related disorder and its neighboring diseases. We then applied graph-based semi-supervised learning (GSSL) to translate the connections in the egocentric DDNs to pathologic knowledge. Results: A total of 26 egocentric DDNs were constructed for each pregnancy-related phenotype in the UKBB. Applying GSSL to each DDN, we obtained complication risk scores for additional phenotypes given the pregnancy-related disease of interest. Predictions were validated using co-occurrences derived from UKBB electronic health records. Our proposed method achieved an increase in average area under the receiver operating characteristic curve (AUC) by a factor of 1.35 from 55.0% to 74.4% compared to the use of the full DDN. Conclusion: Egocentric DDNs hold promise as a clinical tool for the network-based identification of potential disease complications for a variety of phenotypes.

scholarly journals The overlap of genetic susceptibility to schizophrenia and cardiometabolic disease can be used to identify metabolically different groups of individuals

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rona J. Strawbridge ◽  
Keira J. A. Johnston ◽  
Mark E. S. Bailey ◽  
Damiano Baldassarre ◽  
Breda Cullen ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
European Ancestry ◽  
Cardiometabolic Disease ◽  
Metabolic Profiles ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Major Depressive ◽  
Increased Risk

AbstractUnderstanding why individuals with severe mental illness (Schizophrenia, Bipolar Disorder and Major Depressive Disorder) have increased risk of cardiometabolic disease (including obesity, type 2 diabetes and cardiovascular disease), and identifying those at highest risk of cardiometabolic disease are important priority areas for researchers. For individuals with European ancestry we explored whether genetic variation could identify sub-groups with different metabolic profiles. Loci associated with schizophrenia, bipolar disorder and major depressive disorder from previous genome-wide association studies and loci that were also implicated in cardiometabolic processes and diseases were selected. In the IMPROVE study (a high cardiovascular risk sample) and UK Biobank (general population sample) multidimensional scaling was applied to genetic variants implicated in both psychiatric and cardiometabolic disorders. Visual inspection of the resulting plots used to identify distinct clusters. Differences between these clusters were assessed using chi-squared and Kruskall-Wallis tests. In IMPROVE, genetic loci associated with both schizophrenia and cardiometabolic disease (but not bipolar disorder or major depressive disorder) identified three groups of individuals with distinct metabolic profiles. This grouping was replicated within UK Biobank, with somewhat less distinction between metabolic profiles. This work focused on individuals of European ancestry and is unlikely to apply to more genetically diverse populations. Overall, this study provides proof of concept that common biology underlying mental and physical illness may help to stratify subsets of individuals with different cardiometabolic profiles.

Association Between Potentially Inappropriate Medications and 30-Day Post–Hospital Discharge Outcomes in US Veterans

2021 ◽  
pp. 106002802110320
Author(s):  
Heather G. Allore ◽  
Danijela Gnjidic ◽  
Melissa Skanderson ◽  
Ling Han
Keyword(s):  
Hospital Discharge ◽  
Adverse Drug Events ◽  
Primary Care Clinic ◽  
Care Utilization ◽  
Potentially Inappropriate Medications ◽  
Care Hospital ◽  
Care Clinic ◽  
Risk Of Mortality ◽  
Increased Risk ◽  
Reduced Risk

Background Potentially inappropriate medication (PIMs) use is common in older inpatients and it may lead to increased risk of adverse drug events. Objectives To examine prevalence of PIMs at hospital discharge and its contribution to health care utilization and mortality within 30-days of hospital discharge. Methods This was a prospective cohort of 117 570 veterans aged ≥65 years and hospitalized in 2013. PIMs at discharge were categorized into central nervous system acting (CNS) and non-CNS. Outcomes within 30-days of hospital discharge were: (1) time to first acute care hospital readmission, and all-cause mortality, (2) an emergency room visit, and (3) ≥3 primary care clinic visits. Results The cohort’s mean age was 74.3 years (SD 8.1), with 51.3% exposed to CNS and 62.8% to non-CNS PIMs. Use of CNS and non-CNS PIMs, respectively, was associated with a reduced risk of readmission, with an adjusted hazard ratio (aHR) of 0.93 (95% CI = 0.89-0.96) for ≥2 (vs 0) CNS PIMs and an aHR of 0.85 (95% CI = 0.82-0.88) for ≥2 (vs 0) non-CNS PIMs. Use of CNS PIMs (≥2 vs 0) was associated with increased risk of mortality (aHR = 1.37 [95% CI = 1.25-1.51]), whereas non-CNS PIMs use was associated with a reduced risk of mortality (aHR = 0.75 [95% CI = 0.69-0.82]). Conclusion and Relevance PIMs were highly common in this veteran cohort, and the association with outcomes differed by PIMs. Thus, it is important to consider whether PIMs are CNS acting to optimize short-term posthospitalization outcomes.

scholarly journals Socioeconomic Inequalities and Ethnicity Are Associated with a Positive COVID-19 Test among Cancer Patients in the UK Biobank Cohort

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1514
Author(s):  
Shing Fung Lee ◽  
Maja Nikšić ◽  
Bernard Rachet ◽  
Maria-Jose Sanchez ◽  
Miguel Angel Luque-Fernandez
Keyword(s):  
Cancer Patients ◽  
Socioeconomic Inequalities ◽  
Uk Biobank ◽  
Incident Cancer ◽  
Increased Risk ◽  
Exposure Variable ◽  
Independent Risk Factors ◽  
The Uk ◽  
Deprived Areas

We explored the role of socioeconomic inequalities in COVID-19 incidence among cancer patients during the first wave of the pandemic. We conducted a case-control study within the UK Biobank cohort linked to the COVID-19 tests results available from 16 March 2020 until 23 August 2020. The main exposure variable was socioeconomic status, assessed using the Townsend Deprivation Index. Among 18,917 participants with an incident malignancy in the UK Biobank cohort, 89 tested positive for COVID-19. The overall COVID-19 incidence was 4.7 cases per 1000 incident cancer patients (95%CI 3.8–5.8). Compared with the least deprived cancer patients, those living in the most deprived areas had an almost three times higher risk of testing positive (RR 2.6, 95%CI 1.1–5.8). Other independent risk factors were ethnic minority background, obesity, unemployment, smoking, and being diagnosed with a haematological cancer for less than five years. A consistent pattern of socioeconomic inequalities in COVID-19 among incident cancer patients in the UK highlights the need to prioritise the cancer patients living in the most deprived areas in vaccination planning. This socio-demographic profiling of vulnerable cancer patients at increased risk of infection can inform prevention strategies and policy improvements for the coming pandemic waves.

scholarly journals Causal effect of renal function on venous thromboembolism: a two-sample Mendelian randomization investigation

2021 ◽  
Author(s):  
Shuai Yuan ◽  
Maria Bruzelius ◽  
Susanna C. Larsson
Keyword(s):  
Renal Function ◽  
Venous Thromboembolism ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Meta Analysis ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Genome Wide ◽  
Increased Risk ◽  
Mr Study

AbstractWhether renal function is causally associated with venous thromboembolism (VTE) is not yet fully elucidated. We conducted a two-sample Mendelian randomization (MR) study to determine the causal effect of renal function, measured as estimated glomerular filtration rate (eGFR), on VTE. Single-nucleotide polymorphisms associated with eGFR were selected as instrumental variables at the genome-wide significance level (p < 5 × 10−8) from a meta-analysis of 122 genome-wide association studies including up to 1,046,070 individuals. Summary-level data for VTE were obtained from the FinnGen consortium (6913 VTE cases and 169,986 non-cases) and UK Biobank study (4620 VTE cases and 356,574 non-cases). MR estimates were calculated using the random-effects inverse-variance weighted method and combined using fixed-effects meta-analysis. Genetically predicted decreased eGFR was significantly associated with an increased risk of VTE in both FinnGen and UK Biobank. For one-unit decrease in log-transformed eGFR, the odds ratios of VTE were 2.93 (95% confidence interval (CI) 1.25, 6.84) and 4.46 (95% CI 1.59, 12.5) when using data from FinnGen and UK Biobank, respectively. The combined odds ratio was 3.47 (95% CI 1.80, 6.68). Results were consistent in all sensitivity analyses and no horizontal pleiotropy was detected. This MR-study supported a casual role of impaired renal function in VTE.

scholarly journals DR15-DQ6 remains dominantly protective against type 1 diabetes throughout the first five decades of life

Diabetologia ◽  
2021 ◽  
Author(s):  
Nicholas J. Thomas ◽  
John M. Dennis ◽  
Seth A. Sharp ◽  
Akaal Kaur ◽  
Shivani Misra ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Major Type ◽  
Diabetes Incidence ◽  
Diabetes Diagnosis ◽  
Risk Haplotype ◽  
Adult Onset ◽  
Uk Biobank ◽  
Onset Type ◽  
Increased Risk

Abstract Aims/hypothesis Among white European children developing type 1 diabetes, the otherwise common HLA haplotype DR15-DQ6 is rare, and highly protective. Adult-onset type 1 diabetes is now known to represent more overall cases than childhood onset, but it is not known whether DR15-DQ6 is protective in older-adult-onset type 1 diabetes. We sought to quantify DR15-DQ6 protection against type 1 diabetes as age of onset increased. Methods In two independent cohorts we assessed the proportion of type 1 diabetes cases presenting through the first 50 years of life with DR15-DQ6, compared with population controls. In the After Diabetes Diagnosis Research Support System-2 (ADDRESS-2) cohort (n = 1458) clinician-diagnosed type 1 diabetes was confirmed by positivity for one or more islet-specific autoantibodies. In UK Biobank (n = 2502), we estimated type 1 diabetes incidence rates relative to baseline HLA risk for each HLA group using Poisson regression. Analyses were restricted to white Europeans and were performed in three groups according to age at type 1 diabetes onset: 0–18 years, 19–30 years and 31–50 years. Results DR15-DQ6 was protective against type 1 diabetes through to age 50 years (OR < 1 for each age group, all p < 0.001). The following ORs for type 1 diabetes, relative to a neutral HLA genotype, were observed in ADDRESS-2: age 5–18 years OR 0.16 (95% CI 0.08, 0.31); age 19–30 years OR 0.10 (0.04, 0.23); and age 31–50 years OR 0.37 (0.21, 0.68). DR15-DQ6 also remained highly protective at all ages in UK Biobank. Without DR15-DQ6, the presence of major type 1 diabetes high-risk haplotype (either DR3-DQ2 or DR4-DQ8) was associated with increased risk of type 1 diabetes. Conclusions/interpretation HLA DR15-DQ6 confers dominant protection from type 1 diabetes across the first five decades of life. Graphical abstract

scholarly journals IFN-λ4 is associated with increased risk and earlier occurrence of several common infections in African children

2021 ◽  
Author(s):  
Ludmila Prokunina-Olsson ◽  
Robert D. Morrison ◽  
Adeola Obajemu ◽  
Almahamoudou Mahamar ◽  
Sungduk Kim ◽  
...  
Keyword(s):  
Respiratory Infections ◽  
Genomic Region ◽  
First Episode ◽  
Genetic Associations ◽  
Gastrointestinal Infections ◽  
Type Iii ◽  
Functional Variants ◽  
Younger Age ◽  
Increased Risk ◽  
Pediatric Infections

AbstractGenetic polymorphisms within the IFNL3/IFNL4 genomic region, which encodes type III interferons, have been strongly associated with clearance of hepatitis C virus. We hypothesized that type III interferons might be important for the immune response to other pathogens as well. In a cohort of 914 Malian children, we genotyped functional variants IFNL4-rs368234815, IFNL4-rs117648444, and IFNL3-rs4803217 and analyzed episodes of malaria, gastrointestinal, and respiratory infections recorded at 30,626 clinic visits from birth up to 5 years of age. Compared to children with the rs368234815-TT/TT genotype (IFN-λ4-Null), rs368234815-dG allele was most strongly associated with an earlier time-to-first episode of gastrointestinal infections (p = 0.003). The risk of experiencing an infection episode during the follow-up was also significantly increased with rs368234815-dG allele, with OR = 1.53, 95%CI (1.13–2.07), p = 0.005 for gastrointestinal infections and OR = 1.30, 95%CI (1.02–1.65), p = 0.033 for malaria. All the associations for the moderately linked rs4803217 (r2 = 0.78 in this set) were weaker and lost significance after adjusting for rs368234815. We also analyzed all outcomes in relation to IFN-λ4-P70S groups. Our results implicate IFN-λ4 and not IFN-λ3 as the primary functional cause of genetic associations with increased overall risk and younger age at first clinical episodes but not with recurrence or intensity of several common pediatric infections.

scholarly journals In Silico Exploration of the Potential Role of Acetaminophen and Pesticides in the Etiology of Autism Spectrum Disorder

Toxics ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 97
Author(s):  
Tristan Furnary ◽  
Rolando Garcia-Milian ◽  
Zeyan Liew ◽  
Shannon Whirledge ◽  
Vasilis Vasiliou
Keyword(s):  
Autism Spectrum Disorder ◽  
Prenatal Exposure ◽  
Pesticide Exposure ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Biomedical Literature ◽  
Spectrum Disorder ◽  
Biological Processes ◽  
Genetic Associations ◽  
Increased Risk

Recent epidemiological studies suggest that prenatal exposure to acetaminophen (APAP) is associated with increased risk of Autism Spectrum Disorder (ASD), a neurodevelopmental disorder affecting 1 in 59 children in the US. Maternal and prenatal exposure to pesticides from food and environmental sources have also been implicated to affect fetal neurodevelopment. However, the underlying mechanisms for ASD are so far unknown, likely with complex and multifactorial etiology. The aim of this study was to explore the potential effects of APAP and pesticide exposure on development with regards to the etiology of ASD by highlighting common genes and biological pathways. Genes associated with APAP, pesticides, and ASD through human research were retrieved from molecular and biomedical literature databases. The interaction network of overlapping genetic associations was subjected to network topology analysis and functional annotation of the resulting clusters. These genes were over-represented in pathways and biological processes (FDR p < 0.05) related to apoptosis, metabolism of reactive oxygen species (ROS), and carbohydrate metabolism. Since these three biological processes are frequently implicated in ASD, our findings support the hypothesis that cell death processes and specific metabolic pathways, both of which appear to be targeted by APAP and pesticide exposure, may be involved in the etiology of ASD. This novel exposures-gene-disease database mining might inspire future work on understanding the biological underpinnings of various ASD risk factors.

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