scholarly journals Phenomic Impact of Genetically-Determined Euthyroid Function and Molecular Differences between Thyroid Disorders

2018 ◽  
Vol 7 (10) ◽  
pp. 296 ◽  
Author(s):  
Silvia Ravera ◽  
Nancy Carrasco ◽  
Joel Gelernter ◽  
Renato Polimanti
Keyword(s):  
Multiple Testing ◽  
Molecular Mechanisms ◽  
Causal Effect ◽  
Individual Variability ◽  
Whole Body ◽  
Phenotypic Traits ◽  
Thyroid Disorders ◽  
Nucleotide Exchange ◽  
Multiple Testing Correction ◽  
Genetically Determined

Background: The thyroid plays a key role in development and homeostasis, but it has been difficult to establish causality with diseases and phenotypic traits because of several potential confounders. Methods: To determine the causal effect of euthyroid function, we conducted a two-sample Mendelian randomization study of euthyroid thyrotropin (TSH) and free thyroxine (FT4) levels with respect to 2419 traits assessed in 337,199 individuals from UK Biobank. Additionally, we investigated the molecular differences between hypothyroidism and hyperthyroidism using genome-wide data. Results: After multiple testing correction, sixteen traits appear to be affected by genetically-determined euthyroid TSH, including multiple thyroid-related traits, e.g., hypothyroidism (p = 2.39 × 10−17), height (p = 2.76 × 10−10), body fat distribution (impedance of whole body, p = 4.43 × 10−8), pulse rate (p = 2.84 × 10−8), female infertility (p = 4.91 × 10−6), and hearing aid use (p = 7.10 × 10−5). Moreover, we found a consistent genetic correlation between hypothyroidism and hyperthyroidism (rg = 0.45, p = 5.45 × 10−6) with several immune pathways shared between these diseases. Two molecular pathways survived multiple testing correction for specificity to hyperthyroidism, JAK/STAT signaling (p = 1.02 × 10−6) and Rac guanyl-nucleotide exchange factor activity (p = 4.39 × 10−6). Conclusion: Our data shed new light on the inter-individual variability of euthyroid function and the molecular mechanisms of the two thyroid disorders investigated.

scholarly journals Phenome-wide association study of TTR and RBP4 genes in 361,194 individuals reveals novel insights in the genetics of hereditary and senile systemic amyloidoses

2019 ◽  
Author(s):  
Antonella De Lillo ◽  
Flavio De Angelis ◽  
Marco Di Girolamo ◽  
Marco Luigetti ◽  
Sabrina Frusconi ◽  
...  
Keyword(s):  
Association Study ◽  
Multiple Testing ◽  
Large Scale ◽  
Phenotypic Traits ◽  
Multiple Testing Correction ◽  
Gene Variation ◽  
Senile Systemic Amyloidosis ◽  
Phenotypic Spectrum ◽  
Tunnel Syndrome ◽  
Coding Variants

ABSTRACTTransthyretin (TTR) gene has a causal role in a hereditary form of amyloidosis (ATTRm) and is potentially involved in the risk of senile systemic amyloidosis (SSA). To understand the genetics of ATTRm and SSA, we conducted a phenome-wide association study of TTR gene in 361,194 participants of European descent testing coding and non-coding variants. Among the 382 clinically-relevant phenotypes tested, TTR non-coding variants were associated with 26 phenotypic traits after multiple testing correction. These included signs related to both ATTRm and SSA such as chronic ischaemic heart disease (rs140226130, p=2.00×10−6), heart failure (rs73956431, p=2.74×10−6), atrial fibrillation (rs10163755, p=4.63×10−6), dysphagia (rs2949506, p=3.95×10−6), intestine diseases (rs970866, p=7.14×10−6) and anxiety (rs554521234, p=8.85×10−6). Consistent results were observed for TTR disease-causing mutation Val122Ile (rs76992529) with respect to carpal tunnel syndrome (p=6.41×10−6) and mononeuropathies of upper limbs (p=1.22×10−5). Sex differences were also observed in line with ATTRm and SSA epidemiology. Additionally, we explored possible modifier genes related to TTR function, observing convergent associations of RBP4 variants with the clinical phenotypes associated with TTR locus. In conclusion, we provide novel insights regarding the molecular basis of ATTRm and SSA based on large-scale cohort, expanding our understanding of the phenotypic spectrum associated with TTR gene variation.

scholarly journals Smoking, DNA Methylation, and Breast Cancer: A Mendelian Randomization Study

2021 ◽  
Vol 11 ◽  
Author(s):  
Haibo Tang ◽  
Desong Yang ◽  
Chaofei Han ◽  
Ping Mu
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Multiple Testing ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Cancer Tissue ◽  
Nucleotide Polymorphisms ◽  
Multiple Testing Correction ◽  
Cpg Sites ◽  
Meta Analyses

BackgroundSmoking was strongly associated with breast cancer in previous studies. Whether smoking promotes breast cancer through DNA methylation remains unknown.MethodsTwo-sample Mendelian randomization (MR) analyses were conducted to assess the causal effect of smoking-related DNA methylation on breast cancer risk. We used 436 smoking-related CpG sites extracted from 846 middle-aged women in the ARIES project as exposure data. We collected summary data of breast cancer from one of the largest meta-analyses, including 69,501 cases for ER+ breast cancer and 21,468 cases for ER− breast cancer. A total of 485 single-nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) for smoking-related DNA methylation. We further performed an MR Steiger test to estimate the likely direction of causal estimate between DNA methylation and breast cancer. We also conducted colocalization analysis to evaluate whether smoking-related CpG sites shared a common genetic causal SNP with breast cancer in a given region.ResultsWe established four significant associations after multiple testing correction: the CpG sites of cg2583948 [OR = 0.94, 95% CI (0.91–0.97)], cg0760265 [OR = 1.07, 95% CI (1.03–1.11)], cg0420946 [OR = 0.95, 95% CI (0.93–0.98)], and cg2037583 [OR =1.09, 95% CI (1.04–1.15)] were associated with the risk of ER+ breast cancer. All the four smoking-related CpG sites had a larger variance than that in ER+ breast cancer (all p < 1.83 × 10−11) in the MR Steiger test. Further colocalization analysis showed that there was strong evidence (based on PPH4 > 0.8) supporting a common genetic causal SNP between the CpG site of cg2583948 [with IMP3 expression (PPH4 = 0.958)] and ER+ breast cancer. There were no causal associations between smoking-related DNA methylation and ER− breast cancer.ConclusionsThese findings highlight potential targets for the prevention of ER+ breast cancer. Tissue-specific epigenetic data are required to confirm these results.

scholarly journals MR-PheWAS: exploring the causal effect of SUA level on multiple disease outcomes by using genetic instruments in UK Biobank

2018 ◽  
Vol 77 (7) ◽  
pp. 1039-1047 ◽  
Author(s):  
Xue Li ◽  
Xiangrui Meng ◽  
Athina Spiliopoulou ◽  
Maria Timofeeva ◽  
Wei-Qi Wei ◽  
...  
Keyword(s):  
Genetic Risk ◽  
Multiple Testing ◽  
Causal Effect ◽  
Uk Biobank ◽  
Disease Group ◽  
Multiple Testing Correction ◽  
Disease Outcomes ◽  
Multiple Disease Outcomes ◽  
Using Data

ObjectivesWe aimed to investigate the role of serum uric acid (SUA) level in a broad spectrum of disease outcomes using data for 120 091 individuals from UK Biobank.MethodsWe performed a phenome-wide association study (PheWAS) to identify disease outcomes associated with SUA genetic risk loci. We then implemented conventional Mendelianrandomisation (MR) analysis to investigate the causal relevance between SUA level and disease outcomes identified from PheWAS. We next applied MR Egger analysis to detect and account for potential pleiotropy, which conventional MR analysis might mistake for causality, and used the HEIDI (heterogeneity in dependent instruments) test to remove cross-phenotype associations that were likely due to genetic linkage.ResultsOur PheWAS identified 25 disease groups/outcomes associated with SUA genetic risk loci after multiple testing correction (P<8.57e-05). Our conventional MR analysis implicated a causal role of SUA level in three disease groups: inflammatory polyarthropathies (OR=1.22, 95% CI 1.11 to 1.34), hypertensive disease (OR=1.08, 95% CI 1.03 to 1.14) and disorders of metabolism (OR=1.07, 95% CI 1.01 to 1.14); and four disease outcomes: gout (OR=4.88, 95% CI 3.91 to 6.09), essential hypertension (OR=1.08, 95% CI 1.03 to 1.14), myocardial infarction (OR=1.16, 95% CI 1.03 to 1.30) and coeliac disease (OR=1.41, 95% CI 1.05 to 1.89). After balancing pleiotropic effects in MR Egger analysis, only gout and its encompassing disease group of inflammatory polyarthropathies were considered to be causally associated with SUA level. Our analysis highlighted a locus (ATXN2/S2HB3) that may influence SUA level and multiple cardiovascular and autoimmune diseases via pleiotropy.ConclusionsElevated SUA level is convincing to cause gout and inflammatory polyarthropathies, and might act as a marker for the wider range of diseases with which it associates. Our findings support further investigation on the clinical relevance of SUA level with cardiovascular, metabolic, autoimmune and respiratory diseases.

scholarly journals Genetic biomarkers in the VEGF pathway predicting response to anti-VEGF therapy in age-related macular degeneration

2019 ◽  
Vol 4 (1) ◽  
pp. e000273
Author(s):  
Irina Balikova ◽  
Laurence Postelmans ◽  
Brigitte Pasteels ◽  
Pascale Coquelet ◽  
Janet Catherine ◽  
...  
Keyword(s):  
Visual Acuity ◽  
Macular Degeneration ◽  
Treatment Response ◽  
Multiple Testing ◽  
Age Related Macular Degeneration ◽  
Patient Specific ◽  
Multiple Testing Correction ◽  
Anti Vegf ◽  
Age Related ◽  
Vegf Pathway

ObjectiveAge-related macular degeneration (ARMD) is a leading cause of visual impairment. Intravitreal injections of anti-vascular endothelial growth factor (VEGF) are the standard treatment for wet ARMD. There is however, variability in patient responses, suggesting patient-specific factors influencing drug efficacy. We tested whether single nucleotide polymorphisms (SNPs) in genes encoding VEGF pathway members contribute to therapy response.Methods and analysisA retrospective cohort of 281 European wet ARMD patients treated with anti-VEGF was genotyped for 138 tagging SNPs in the VEGF pathway. Per patient, we collected best corrected visual acuity at baseline, after three loading injections and at 12 months. We also registered the injection number and changes in retinal morphology after three loading injections (central foveal thickness (CFT), intraretinal cysts and serous neuroepithelium detachment). Changes in CFT after 3 months were our primary outcome measure. Association of SNPs to response was assessed by binomial logistic regression. Replication was attempted by associating visual acuity changes to genotypes in an independent Japanese cohort.ResultsAssociation with treatment response was detected for seven SNPs, including in FLT4 (rs55667289: OR=0.746, 95% CI 0.63 to 0.88, p=0.0005) and KDR (rs7691507: OR=1.056, 95% CI 1.02 to 1.10, p=0.005; and rs2305945: OR=0.963, 95% CI 0.93 to 1.00, p=0.0472). Only association with rs55667289 in FLT4 survived multiple testing correction. This SNP was unavailable for testing in the replication cohort. Of six SNPs tested for replication, one was significant although not after multiple testing correction.ConclusionIdentifying genetic variants that define treatment response can help to develop individualised therapeutic approaches for wet ARMD patients and may point towards new targets in non-responders.

scholarly journals 2dFDR: a new approach to confounder adjustment substantially increases detection power in omics association studies

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Sangyoon Yi ◽  
Xianyang Zhang ◽  
Lu Yang ◽  
Jinyan Huang ◽  
Yuanhang Liu ◽  
...  
Keyword(s):  
Multiple Testing ◽  
Statistical Power ◽  
Association Studies ◽  
Control Procedure ◽  
Multiple Testing Correction ◽  
New Approach ◽  
False Discovery ◽  
Traditional Procedure ◽  
Extensive Evaluation ◽  
Confounder Adjustment

AbstractOne challenge facing omics association studies is the loss of statistical power when adjusting for confounders and multiple testing. The traditional statistical procedure involves fitting a confounder-adjusted regression model for each omics feature, followed by multiple testing correction. Here we show that the traditional procedure is not optimal and present a new approach, 2dFDR, a two-dimensional false discovery rate control procedure, for powerful confounder adjustment in multiple testing. Through extensive evaluation, we demonstrate that 2dFDR is more powerful than the traditional procedure, and in the presence of strong confounding and weak signals, the power improvement could be more than 100%.

scholarly journals Bemisia tabaci Vesicle-Associated Membrane Protein 2 Interacts with Begomoviruses and Plays a Role in Virus Acquisition

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1700
Author(s):  
Yun-Yun Fan ◽  
Yu-Wei Zhong ◽  
Jing Zhao ◽  
Yao Chi ◽  
Sophie Bouvaine ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Bemisia Tabaci ◽  
Species Complex ◽  
Molecular Mechanisms ◽  
Whole Body ◽  
Sri Lankan ◽  
Tomato Production ◽  
Virus Acquisition ◽  
Leaf Curl Virus ◽  
Whitefly Vector

Begomoviruses cause substantial losses to agricultural production, especially in tropical and subtropical regions, and are exclusively transmitted by members of the whitefly Bemisia tabaci species complex. However, the molecular mechanisms underlying the transmission of begomoviruses by their whitefly vector are not clear. In this study, we found that B. tabaci vesicle-associated membrane protein 2 (BtVAMP2) interacts with the coat protein (CP) of tomato yellow leaf curl virus (TYLCV), an emergent begomovirus that seriously impacts tomato production globally. After infection with TYLCV, the transcription of BtVAMP2 was increased. When the BtVAMP2 protein was blocked by feeding with a specific BtVAMP2 antibody, the quantity of TYLCV in B. tabaci whole body was significantly reduced. BtVAMP2 was found to be conserved among the B. tabaci species complex and also interacts with the CP of Sri Lankan cassava mosaic virus (SLCMV). When feeding with BtVAMP2 antibody, the acquisition quantity of SLCMV in whitefly whole body was also decreased significantly. Overall, our results demonstrate that BtVAMP2 interacts with the CP of begomoviruses and promotes their acquisition by whitefly.

scholarly journals Insulin-mediated muscle microvascular perfusion and its phenotypic predictors in humans

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kaitlin M. Love ◽  
Linda A. Jahn ◽  
Lee M. Hartline ◽  
James T. Patrie ◽  
Eugene J. Barrett ◽  
...  
Keyword(s):  
Body Mass ◽  
Hdl Cholesterol ◽  
Total Body Weight ◽  
Microvascular Perfusion ◽  
Whole Body ◽  
Glucose Disposal ◽  
Phenotypic Traits ◽  
Predictive Information ◽  
Class 1 ◽  
Insulin Responses

AbstractInsulin increases muscle microvascular perfusion and enhances tissue insulin and nutrient delivery. Our aim was to determine phenotypic traits that foretell human muscle microvascular insulin responses. Hyperinsulinemic euglycemic clamps were performed in 97 adult humans who were lean and healthy, had class 1 obesity without comorbidities, or controlled type 1 diabetes without complications. Insulin-mediated whole-body glucose disposal rates (M-value) and insulin-induced changes in muscle microvascular blood volume (ΔMBV) were determined. Univariate and multivariate analyses were conducted to examine bivariate and multivariate relationships between outcomes, ΔMBV and M-value, and predictor variables, body mass index (BMI), total body weight (WT), percent body fat (BF), lean body mass, blood pressure, maximum consumption of oxygen (VO2max), plasma LDL (LDL-C) and HDL cholesterol, triglycerides (TG), and fasting insulin (INS) levels. Among all factors, only M-value (r = 0.23, p = 0.02) and VO2max (r = 0.20, p = 0.047) correlated with ΔMBV. Conversely, INS (r = − 0.48, p ≤ 0.0001), BF (r = − 0.54, p ≤ 0.001), VO2max (r = 0.5, p ≤ 0.001), BMI (r = − 0.40, p < 0.001), WT (r = − 0.33, p = 0.001), LDL-C (r = − 0.26, p = 0.009), TG (r = − 0.25, p = 0.012) correlated with M-value. While both ΔMBV (p = 0.045) and TG (p = 0.03) provided significant predictive information about M-value in the multivariate regression model, only M-value was uniquely predictive of ΔMBV (p = 0.045). Thus, both M-value and VO2max correlated with ΔMBV but only M-value provided unique predictive information about ΔMBV. This suggests that metabolic and microvascular insulin responses are important predictors of one another, but most metabolic insulin resistance predictors do not predict microvascular insulin responses.

scholarly journals Structural basis for activation of trimeric Gi proteins by multiple growth factor receptors via GIV/Girdin

2014 ◽  
Vol 25 (22) ◽  
pp. 3654-3671 ◽  
Author(s):  
Changsheng Lin ◽  
Jason Ear ◽  
Krishna Midde ◽  
Inmaculada Lopez-Sanchez ◽  
Nicolas Aznar ◽  
...  
Keyword(s):  
Growth Factor ◽  
G Proteins ◽  
Protein Interaction ◽  
Cross Talk ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Growth Factor Receptors ◽  
Structural Basis ◽  
Nucleotide Exchange ◽  
Protein Protein Interaction

A long-standing issue in the field of signal transduction is to understand the cross-talk between receptor tyrosine kinases (RTKs) and heterotrimeric G proteins, two major and distinct signaling hubs that control eukaryotic cell behavior. Although stimulation of many RTKs leads to activation of trimeric G proteins, the molecular mechanisms behind this phenomenon remain elusive. We discovered a unifying mechanism that allows GIV/Girdin, a bona fide metastasis-related protein and a guanine-nucleotide exchange factor (GEF) for Gαi, to serve as a direct platform for multiple RTKs to activate Gαi proteins. Using a combination of homology modeling, protein–protein interaction, and kinase assays, we demonstrate that a stretch of ∼110 amino acids within GIV C-terminus displays structural plasticity that allows folding into a SH2-like domain in the presence of phosphotyrosine ligands. Using protein–protein interaction assays, we demonstrated that both SH2 and GEF domains of GIV are required for the formation of a ligand-activated ternary complex between GIV, Gαi, and growth factor receptors and for activation of Gαi after growth factor stimulation. Expression of a SH2-deficient GIV mutant (Arg 1745→Leu) that cannot bind RTKs impaired all previously demonstrated functions of GIV—Akt enhancement, actin remodeling, and cell migration. The mechanistic and structural insights gained here shed light on the long-standing questions surrounding RTK/G protein cross-talk, set a novel paradigm, and characterize a unique pharmacological target for uncoupling GIV-dependent signaling downstream of multiple oncogenic RTKs.

scholarly journals Baicalin Attenuates High Fat Diet-Induced Obesity and Liver Dysfunction: Dose-Response and Potential Role of CaMKKβ/AMPK/ACC Pathway

2015 ◽  
Vol 35 (6) ◽  
pp. 2349-2359 ◽  
Author(s):  
Youli Xi ◽  
Miaozong Wu ◽  
Hongxia Li ◽  
Siqi Dong ◽  
Erfei Luo ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Fatty Liver ◽  
High Fat Diet ◽  
Molecular Mechanisms ◽  
Liver Steatosis ◽  
Serum Levels ◽  
Whole Body ◽  
Therapeutic Effects ◽  
High Fat ◽  
Dependent Protein

Background/Aims: Obesity-associated fatty liver disease affects millions of individuals. This study aimed to evaluate the therapeutic effects of baicalin to treat obesity and fatty liver in high fat diet-induced obese mice, and to study the potential molecular mechanisms. Methods: High fat diet-induced obese animals were treated with different doses of baicalin (100, 200 and 400 mg/kg/d). Whole body, fat pad and liver were weighed. Hyperlipidemia, liver steatosis, liver function, and hepatic Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ) / AMP-activated protein kinase (AMPK) / acetyl-CoA carboxylase (ACC) were further evaluated. Results: Baicalin significantly decreased liver, epididymal fat and body weights in high fat diet-fed mice, which were associated with decreased serum levels of triglycerides, total cholesterol, LDL, alanine transaminase and aspartate transaminase, but increased serum HDL level. Pathological analysis revealed baicalin dose-dependently decreased the degree of hepatic steatosis, with predominantly diminished macrovesicular steatosis at lower dose but both macrovesicular and microvesicular steatoses at higher dose of baicalin. Baicalin dose-dependently inhibited hepatic CaMKKβ/AMPK/ACC pathway. Conclusion: These data suggest that baicalin up to 400 mg/kg/d is safe and able to decrease the degree of obesity and fatty liver diseases. Hepatic CaMKKβ/AMPK/ACC pathway may mediate the therapeutic effects of baicalin in high fat diet animal model.

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