scholarly journals Human genetics of tuberculosis: a long and winding road

2014 ◽  
Vol 369 (1645) ◽  
pp. 20130428 ◽  
Author(s):  
Laurent Abel ◽  
Jamila El-Baghdadi ◽  
Ahmed Aziz Bousfiha ◽  
Jean-Laurent Casanova ◽  
Erwin Schurr
Keyword(s):  
Human Genetics ◽  
Association Studies ◽  
Single Gene ◽  
Genetic Association Studies ◽  
Epidemiological Studies ◽  
Interferon Γ ◽  
Past Century ◽  
Inborn Errors ◽  
Novel Treatments ◽  
The Past

Only a small fraction of individuals exposed to Mycobacterium tuberculosis develop clinical tuberculosis (TB). Over the past century, epidemiological studies have shown that human genetic factors contribute significantly to this interindividual variability, and molecular progress has been made over the past decade for at least two of the three key TB-related phenotypes: (i) a major locus controlling resistance to infection with M. tuberculosis has been identified, and (ii) proof of principle that severe TB of childhood can result from single-gene inborn errors of interferon-γ immunity has been provided; genetic association studies with pulmonary TB in adulthood have met with more limited success. Future genetic studies of these three phenotypes could consider subgroups of subjects defined on the basis of individual (e.g. age at TB onset) or environmental (e.g. pathogen strain) factors. Progress may also be facilitated by further methodological advances in human genetics. Identification of the human genetic variants controlling the various stages and forms of TB is critical for understanding TB pathogenesis. These findings should have major implications for TB control, in the definition of improved prevention strategies, the optimization of vaccines and clinical trials and the development of novel treatments aiming to restore deficient immune responses.

scholarly journals Genetics and genomics of human ageing

2011 ◽  
Vol 366 (1561) ◽  
pp. 43-50 ◽  
Author(s):  
Heather E. Wheeler ◽  
Stuart K. Kim
Keyword(s):  
Human Genetics ◽  
Association Studies ◽  
Transcriptional Profiling ◽  
Genetic Association Studies ◽  
Human Kidney ◽  
Age Related ◽  
Quantitative Trait Mapping ◽  
Human Ageing ◽  
Probability Of Death ◽  
Genomic Convergence

Ageing in humans is typified by the decline of physiological functions in various organs and tissues leading to an increased probability of death. Some individuals delay, escape or survive much of this age-related decline and live past age 100. Studies comparing centenarians to average-aged individuals have found polymorphisms in genes that are associated with long life, including APOE and FOXOA3 , which have been replicated many times. However, the associations found in humans account for small percentages of the variance in lifespan and many other gene associations have not been replicated in additional populations. Therefore, ageing is probably a highly polygenic trait. In humans, it is important to also consider differences in age-related decline that occur within and among tissues. Longitudinal data of age-related traits can be used in association studies to test for polymorphisms that predict how an individual will change over time. Transcriptional and genetic association studies of different tissues have revealed common and unique pathways involved in human ageing. Genomic convergence is a method that combines multiple types of functional genomic information such as transcriptional profiling, expression quantitative trait mapping and gene association. The genomic convergence approach has been used to implicate the gene MMP20 in human kidney ageing. New human genetics technologies are continually in development and may lead to additional breakthroughs in human ageing in the near future.

scholarly journals Why is type 1 diabetes increasing?

2013 ◽  
Vol 51 (1) ◽  
pp. R1-R13 ◽  
Author(s):  
Francesco Maria Egro
Keyword(s):  
Type 1 Diabetes ◽  
Epidemiological Studies ◽  
Past Century ◽  
Β Cell ◽  
The Past ◽  
Immunological Mechanisms ◽  
Triggering Factor ◽  
A Cell ◽  
Shift Model

A series of studies have reported a constant global rise in the incidence of type 1 diabetes. Epidemiological and immunological studies have demonstrated that environmental factors may influence the pathogenesis, leading to a cell-mediated pancreatic β-cell destruction associated with humoral immunity. The search for the triggering factor(s) has been going on for the past century, and yet they are still unknown. This review provides an overview of some of the most well-known theories found in the literature: hygiene, viral, vitamin D deficiency, breast milk and cow's milk hypotheses. Although the hygiene hypothesis appears to be the most promising, positive evidence from animal, human and epidemiological studies precludes us from completely discarding any of the other hypotheses. Moreover, due to contrasting evidence in the literature, a single factor is unlikely to cause an increase in the incidence of diabetes all over the world, which suggests that a multifactorial process might be involved. Although the immunological mechanisms are still unclear, there seems to be some overlap between the various hypotheses. It is thought that the emphasis should be shifted from a single to a multifactorial process and that perhaps the ‘balance shift’ model should be considered as a possible explanation for the rise in the incidence of type 1 diabetes.

Monogenic and oligogenic cardiovascular diseases: genetics of arrhythmias—short QT syndrome

ESC CardioMed ◽  
2018 ◽  
pp. 676-679
Author(s):  
Erol Tülümen ◽  
Martin Borggrefe
Keyword(s):  
Atrial Fibrillation ◽  
Genetic Basis ◽  
Association Studies ◽  
Single Gene ◽  
Epidemiological Studies ◽  
Candidate Gene Approach ◽  
Loss Of Function ◽  
Short Qt Syndrome ◽  
Qt Intervals ◽  
Qt Syndrome

Short QT syndrome (SQTS) is a very rare, sporadic or autosomal dominant inherited channelopathy characterized by abnormally short QT intervals on the electrocardiogram and increased propensity to atrial and ventricular tachyarrhythmias and/or sudden cardiac death. Since its recognition as a distinct clinical entity in 2000, significant progress has been made in defining the clinical, molecular, and genetic basis of SQTS. To date, several causative gain-of-function mutations in potassium channel genes and loss-of-function mutations in calcium channel genes have been identified. The physiological consequence of these mutations is an accelerated repolarization, thus abbreviated action potentials and shortened QT interval with an increased inhomogeneity and dispersion of repolarization. Regarding other rare monogenetic arrhythmias, a genetic basis of atrial fibrillation was considered very unlikely until very recently. However, in the last decade the heritability of atrial fibrillation in the general population has been well described in several epidemiological studies. So far, more than 30 genes have been implicated in atrial fibrillation through candidate gene approach studies, and more than 25 loci were found to be associated with atrial fibrillation through genome-wide association studies. This genetic heterogeneity and the low prevalence of mutations in any single gene restrict the clinical utility of genetic screening in atrial fibrillation.

scholarly journals Genetic Association Studies of Suicidal Behavior: A Review of the Past 10 Years, Progress, Limitations, and Future Directions

2016 ◽  
Vol 7 ◽  
Author(s):  
Bojan Mirkovic ◽  
Claudine Laurent ◽  
Marc-Antoine Podlipski ◽  
Thierry Frebourg ◽  
David Cohen ◽  
...  
Keyword(s):  
Genetic Association ◽  
Suicidal Behavior ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Future Directions ◽  
The Past

scholarly journals Integrating epidemiology and genetic association: the challenge of gene–environment interaction

2005 ◽  
Vol 360 (1460) ◽  
pp. 1609-1616 ◽  
Author(s):  
Peter Kraft ◽  
David Hunter
Keyword(s):  
Genetic Association ◽  
Association Studies ◽  
Genetic Locus ◽  
Single Gene ◽  
Genetic Association Studies ◽  
Biologically Active ◽  
Marginal Effect ◽  
Environment Interaction ◽  
Gene Environment Interaction ◽  
Gene Environment

Recent advances in human genomics have made it possible to better understand the genetic basis of disease. In addition, genetic association studies can also elucidate the mechanisms by which ‘non-genetic’ exogenous and endogenous exposures influence the risk of disease. This is true both of studies that assess the marginal effect of a single gene and studies that look at the joint effect of genes and environmental exposures. For example, gene variants that are known to alter enzyme function or level can serve as surrogates for long-term biomarker levels that are impractical or impossible to measure on many subjects. Evidence that genetic variants modify the effect of an established risk factor may help specify the risk factor's biologically active components. We illustrate these ideas with several examples and discuss design and analysis challenges, particularly for studies of gene–environment interaction. We argue that to increase the power to detect interaction effects and limit the number of false positive results, large sample sizes will be needed, which are currently only available through planned collaborative efforts. Such collaborations also ensure a common approach to measuring variation at a genetic locus, avoiding a problem that has led to difficulties when comparing results from genetic association studies.

scholarly journals Severe infectious diseases of childhood as monogenic inborn errors of immunity

2015 ◽  
Vol 112 (51) ◽  
pp. E7128-E7137 ◽  
Author(s):  
Jean-Laurent Casanova
Keyword(s):  
Infectious Diseases ◽  
Human Genetics ◽  
Single Gene ◽  
Incomplete Penetrance ◽  
Healthy Children ◽  
Genetic Theory ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity ◽  
Life Threatening ◽  
Genetically Determined

This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications.

scholarly journals dbGSRV: a manually curated database of genetic susceptibility to respiratory virus

2021 ◽  
Author(s):  
Ping Li ◽  
Yan Zhang ◽  
Wenlong Shen ◽  
Shu Shi ◽  
Zhihu Zhao
Keyword(s):  
Virus Infection ◽  
Genetic Susceptibility ◽  
Drug Targets ◽  
Respiratory Virus ◽  
Human Genetics ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Respiratory Viruses ◽  
Reference Information ◽  
Respiratory Virus Infection

Human genetics has been proposed to play an essential role in inter-individual differences in respiratory virus infection occurrence and outcomes. To systematically understand human genetic contributions to respiratory virus infection, we developed the database dbGSRV, a manually curated database that integrated the host genetic susceptibility and severity studies of respiratory viruses scattered over literatures in PubMed. At present, dbGSRV contains 1932 records of genetic association studies relating 1010 unique variants and seven respiratory viruses, manually curated from 168 published articles. Users can access the records by quick searching, batch searching, advanced searching and browsing. Reference information, infection status, population information, mutation information and disease relationship are provided for each record, as well as hyper links to public databases in convenient of users accessing more information. In addition, a visual overview of the topological network relationship between respiratory viruses and associated genes is provided. Therefore, dbGSRV offers a promising avenue to facilitate researchers to dissect human factors in respiratory virus infection, define novel drug targets, conduct risk stratification of population and develop personalized medicine approaches. Database URL: http://www.ehbio.com/dbGSRV/front/

scholarly journals A genomic region associated with protection against severe COVID-19 is inherited from Neandertals

2021 ◽  
Vol 118 (9) ◽  
pp. e2026309118 ◽  
Author(s):  
Hugo Zeberg ◽  
Svante Pääbo
Keyword(s):  
Genetic Risk ◽  
Association Studies ◽  
Severe Disease ◽  
Genetic Association Studies ◽  
Genomic Region ◽  
Risk Haplotype ◽  
The Past ◽  
Human Genomes ◽  
Using Data ◽  
Western Eurasia

It was recently shown that the major genetic risk factor associated with becoming severely ill with COVID-19 when infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is inherited from Neandertals. New, larger genetic association studies now allow additional genetic risk factors to be discovered. Using data from the Genetics of Mortality in Critical Care (GenOMICC) consortium, we show that a haplotype at a region on chromosome 12 associated with requiring intensive care when infected with the virus is inherited from Neandertals. This region encodes proteins that activate enzymes that are important during infections with RNA viruses. In contrast to the previously described Neandertal haplotype that increases the risk for severe COVID-19, this Neandertal haplotype is protective against severe disease. It also differs from the risk haplotype in that it has a more moderate effect and occurs at substantial frequencies in all regions of the world outside Africa. Among ancient human genomes in western Eurasia, the frequency of the protective Neandertal haplotype may have increased between 20,000 and 10,000 y ago and again during the past 1,000 y.

scholarly journals Human Genetics to Identify Therapeutic Targets for NAFLD: Challenges and Opportunities

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaomi Du ◽  
Natalie DeForest ◽  
Amit R. Majithia
Keyword(s):  
Human Genetics ◽  
Target Identification ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Diagnostic Methods ◽  
Genetic Associations ◽  
Alcoholic Fatty Liver ◽  
Diagnostic Measures ◽  
Challenges And Opportunities ◽  
Continuous Progression

Non-alcoholic fatty liver disease (NAFLD) is a continuous progression of pathophysiologic stages that is challenging to diagnose due to its inherent heterogeneity and poor standardization across a wide variety of diagnostic measures. NAFLD is heritable, and several loci have been robustly associated with various stages of disease. In the past few years, larger genetic association studies using new methodology have identified novel genes associated with NAFLD, some of which have shown therapeutic promise. This mini-review provides an overview of the heterogeneity in NAFLD phenotypes and diagnostic methods, discusses genetic associations in relation to the specific stages for which they were identified, and offers a perspective on the design of future genetic mapping studies to accelerate therapeutic target identification.

scholarly journals Lessons from CKD-Related Genetic Association Studies–Moving Forward

2017 ◽  
Vol 13 (1) ◽  
pp. 140-152 ◽  
Author(s):  
Sophie Limou ◽  
Nicolas Vince ◽  
Afshin Parsa
Keyword(s):  
Genetic Association ◽  
Kidney Function ◽  
Membranous Nephropathy ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Molecular Processes ◽  
Kidney Dysfunction ◽  
The Past ◽  
Based Medicine ◽  
Research Domain

Over the past decade, genetic association studies have uncovered numerous determinants of kidney function in the general, diabetic, hypertensive, CKD, ESRD, and GN-based study populations (e.g., IgA nephropathy, membranous nephropathy, FSGS). These studies have led to numerous novel and unanticipated findings, which are helping improve our understanding of factors and pathways affecting both normal and pathologic kidney function. In this review, we report on major discoveries and advances resulting from this rapidly progressing research domain. We also predict some of the next steps the nephrology community should embrace to accelerate the identification of genetic and molecular processes leading to kidney dysfunction, pathophysiologically based disease subgroups, and specific therapeutic targets, as we attempt to transition toward a more precision-based medicine approach.

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