Untangling the immune basis of disease susceptibility

© 2020 Copyright Ribeiro and Graca. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are creditedInteractions between immune cell receptors and proteins that determine disease susceptibility shed light on how different arms of the immune system are involved in three viral infections and Crohn's disease.info:eu-repo/semantics/publishedVersio

Understanding the effect of adaptive mutations on the three-dimensional structure of RNA

Single-nucleotide polymorphisms (SNPs) are variations in the genome where one base pair can differ between individuals.1 SNPs occur throughout the genome and can correlate to a disease-state if they occur in a functional region of DNA.1According to the central dogma of molecular biology, any variation in the DNA sequence will have a direct effect on the RNA sequence and will potentially alter the identity or conformation of a protein product. A single RNA molecule, due to intramolecular base pairing, can acquire a plethora of 3-D conformations that are described by its structural ensemble. One SNP, rs12477830, which was previously shown to harbor signatures of positive selection by Sugden et. al,3 was passed through multiple RNA folding algorithms. The results of SNPfold 2 demonstrate that the SNP significantly alters the structural ensemble, and the significance of this change offers a potential explanation of SWIF(r)’s result.3 Furthermore, the RNAfold Webserver 4-6reveals that the mutant RNA molecule is more stable than the wild-type with a more negative free energy and a higher frequency. These loci of variation should be studied in order to understand the potentially induced conformational changes that could significantly alter the functional capacity of an RNA molecule. Future work aims to assess conformational changes elicited by SNPs previously shown to harbor signatures of positive selection using ancestry-specific reference genomes to better understand motivations behind a locus experiencing positive selective pressure

Lifestyle, heart rate and cardiovascular disease:novel insights from genomics and big data

Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, despite declining mortality rates due to improved treatment. Preventive strategies could be essential to reduce CVD burden, but will require a better understanding of the pathophysiological mechanisms underlying CVD development. Studying the genetic architecture of CVD and its risk factors might aid in this endeavor. Genome-wide association studies can increase our understanding of the underlying biological architecture of CVD and its risk factors by identifying associated genetic variants. These genetic variants can then be used to obtain generally unconfounded genetic associations between a risk factor and CVD. This thesis identifies novel genetic variants associated with prevalent lifestyle behaviors and several heart rate traits. We provide evidence that television watching might causally increase risk of coronary artery disease development. A genetic association between caffeine intake and CVD was not established. We find that heart rate at rest, its variability, its increase during exercise, and its recovery after exercise, are not likely on the causal pathway to mortality. We do find that higher genetically predicted resting heart rate decreases risk of atrial fibrillation, ischemic stroke and cardio-embolic stroke. The genetic association of resting heart rate with ischemic and cardio-embolic stroke is unlikely caused by resting heart rate itself, but is probably driven by the effect of resting heart rate associated variants on respectively pulse pressure and atrial fibrillation. The findings described in this thesis increase our insights in the pathophysiological mechanisms leading to CVD and may improve risk stratification and prevention strategies

Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia.

Refractive errors, in particular myopia, are a leading cause of morbidity and disability worldwide. Genetic investigation can improve understanding of the molecular mechanisms that underlie abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies (GWAS) that involved 542,934 European participants and identified 336 novel genetic loci associated with refractive error. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (area under the curve (AUC) = 0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes that participate in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may enable the prediction of refractive error and the development of personalized myopia prevention strategies in the future

Chronic Obstructive Pulmonary Disease (COPD): Making Sense of Existing GWAS Findings in Indian Context

To date, more than 1456 associations have been identified for Chronic Obstructive Pulmonary Disease (COPD) risk through Genome-Wide Association Studies (GWAS). However, target genes for COPD susceptibility in the Indian population and the mechanism underlying remains largely unexplored and no GWAS studies on COPD are available on the Indian population till now. This study was conducted using the existing public data on GWAS of different parts of the world, and the genetic polymorphisms to understand the possible mechanisms of these polymorphisms using available data from the Genotype-Tissue Expression (GTEx) project. We jotted down 16 important genes and 28 Single Nucleotide Polymorphisms (SNPs) in the Indian population from 1456 variants. Pathway analysis showed that these relevant genes are mostly associated with immune responses and activation, which is a key factor in COPD development. Our investigation revealed possible target genes associated with COPD in the context of the Indian population

The impact of adjusting for baseline in pharmacogenomic genome-wide association studies of quantitative change.

In pharmacogenomic studies of quantitative change, any association between genetic variants and the pretreatment (baseline) measurement can bias the estimate of effect between those variants and drug response. A putative solution is to adjust for baseline. We conducted a series of genome-wide association studies (GWASs) for low-density lipoprotein cholesterol (LDL-C) response to statin therapy in 34,874 participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort as a case study to investigate the impact of baseline adjustment on results generated from pharmacogenomic studies of quantitative change. Across phenotypes of statin-induced LDL-C change, baseline adjustment identified variants from six loci meeting genome-wide significance (SORT/CELSR2/PSRC1, LPA, SLCO1B1, APOE, APOB, and SMARCA4/LDLR). In contrast, baseline-unadjusted analyses yielded variants from three loci meeting the criteria for genome-wide significance (LPA, APOE, and SLCO1B1). A genome-wide heterogeneity test of baseline versus statin on-treatment LDL-C levels was performed as the definitive test for the true effect of genetic variants on statin-induced LDL-C change. These findings were generally consistent with the models not adjusting for baseline signifying that genome-wide significant hits generated only from baseline-adjusted analyses (SORT/CELSR2/PSRC1, APOB, SMARCA4/LDLR) were likely biased. We then comprehensively reviewed published GWASs of drug-induced quantitative change and discovered that more than half (59%) inappropriately adjusted for baseline. Altogether, we demonstrate that (1) baseline adjustment introduces bias in pharmacogenomic studies of quantitative change and (2) this erroneous methodology is highly prevalent. We conclude that it is critical to avoid this common statistical approach in future pharmacogenomic studies of quantitative change

ACE Gene Mutations (rs577350502) in Early-Onset and Recurrent Myocardial Infarction: A Case Report and Review

Xiaoxi Deng,1,* Xiaofei Guo,1,* Xiaojie Chen,2 Xinyu Zeng,1 Jiamin Guo,1 Xin Bai,1 Ping Zhang,1 Yuan Wang1 1Department of Pathology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, 100102, People’s Republic of China; 2Department of Emergency, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, 100102, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuan Wang, Ping Zhang, Department of Pathology, Wangjing Hospital, China Academy of Chinese Medical Sciences, 6 Wangjing Zhonghuan South Road, Chaoyang District, Beijing, 100102, People’s Republic of China, Tel +86 010-84739040, Email [email protected]; [email protected]: Acute myocardial infarction (AMI) is a severe acute coronary syndrome, demonstrating a trend toward affecting younger individuals in recent years. The association between early-onset myocardial infarction and single nucleotide polymorphism necessitates further exploration and evaluation.Case description: We present a case of a patient experiencing early-onset and recurrent myocardial infarction. The patient underwent stent implantation for myocardial infarction at the age of 53 and subsequently encountered two more myocardial infarctions within a span of 16 years. Following interventional therapy, genetic testing was conducted to assess the efficacy of subsequent anti-heart failure medications, with the aim to preemptively address heart failure risks. Genetic testing revealed a mutation in the angiotensin-converting enzyme (ACE) gene (rs577350502, g.63488533C>A), characterized by an intron-deletion single nucleotide variant.Conclusion: While this variant has not been previously reported to be associated with any specific disease, we hypothesize that it may contribute to the susceptibility and risk of myocardial infarction and coronary heart disease in the patient under consideration. This observation underscores the significance of investigating the insertion/deletion polymorphisms of the ACE gene in the context of AMI and emphasizes the necessity for further validation of this variant and other genetic markers associated with AMI in related diseases.Keywords: ACE, case reports, gene mutations, myocardial infarction, SN

Hyperthyroidism, and bone mineral density : dissecting the causal association with Mendelian randomization analysis

IntroductionUntreated hyperthyroidism is associated with accelerated bone turnover, low bone mineral density (BMD) and increased susceptibility to fragility fractures. Although treatment appears to improve or even reverse some of these adverse skeletal effects, there is limited guidance on routine BMD assessment in hyperthyroid patients following treatment. By using Mendelian randomization (MR) analysis, we aimed to assess the causal association of hyperthyroid thyroid states with BMD and fractures using the UK Biobank.MethodsThis MR analysis included data from 473,818 participants (women: 54% of the total sample, the median age of 58.0 years (IQR=50‐63 years), median body mass index (BMI) of 26.70 (IQR+24.11‐29.82 kg/m2) as part of the UK biobank study. The study outcomes were heel BMD assessed by quantitative ultrasound of the heel and self‐reported fractures. Beta‐weighted genetic risk score analysis was performed using 19 Single Nucleotide Polymorphisms (SNPs) for Graves' disease, 9 SNPs for hyperthyroidism and 11 SNPs for autoimmune thyroiditis. Since the unadjusted risk score, MR is equivalent to the inverse‐variance weighted method; the genetic risk score analysis was adjusted for age, gender, and BMI. Sensitivity analyses were conducted using the Mendelian randomization‐Egger (MR‐Egger) and the inverse‐variance weighted estimate methods. Replication analysis was performed using the GEnetic Factors for Osteoporosis (GEFOS) consortium data.ResultsMR analysis using beta‐weighted genetic risk score showed no association of genetic risk for Graves’ disease (Beta = ‐0.01, P‐value=0.10), autoimmune thyroiditis (Beta = ‐0.006 P‐value=0.25) and hyperthyroidism (Beta = ‐0.009, P‐value=0.18) with heel ultrasound BMD. MR Egger and inverse‐variance MR methods in UK Biobank and GEFOS consortium confirmed these findings. The genetic risk for these hyperthyroid conditions was not associated with an increased risk of fractures.ConclusionOur study shows that excess genetic risk for Graves' autoimmune thyroiditis and hyperthyroidism does not increase the risk for low BMD and is not associated fractures in the Caucasian population. Our findings do not support routine screening for osteoporosis following definitive treatment of hyperthyroid states

Finding all maximal perfect haplotype blocks in linear time

Recent large-scale community sequencing efforts allow at an unprecedented level of detail the identification of genomic regions that show signatures of natural selection. Traditional methods for identifying such regions from individuals' haplotype data, however, require excessive computing times and therefore are not applicable to current datasets. In 2019, Cunha et al. (Advances in bioinformatics and computational biology: 11th Brazilian symposium on bioinformatics, BSB 2018, Niteroi, Brazil, October 30 - November 1, 2018, Proceedings, 2018. 10.1007/978-3-030-01722-4_3) suggested the maximal perfect haplotype block as a very simple combinatorial pattern, forming the basis of a new method to perform rapid genome-wide selection scans. The algorithm they presented for identifying these blocks, however, had a worst-case running time quadratic in the genome length. It was posed as an open problem whether an optimal, linear-time algorithm exists. In this paper we give two algorithms that achieve this time bound, one conceptually very simple one using suffix trees and a second one using the positional Burrows-Wheeler Transform, that is very efficient also in practice.Peer reviewe