Genetic variations and human health

IL28B single nucleotide polymorphisms in the treatment of hepatitis C

Interspecific phenotypic variation in plant secondary metabolites (PSM) is often explained by biotic and abiotic factors. However, patterns of variation within species do not clearly fit the theoretical predictions. Exploring how genetics, environment and demographic processes shape such variation among and within populations is crucial for understanding evolution of PSM, particularly in long‐lived plants such as forest trees. Here, we quantified genetic variation in PSM among and within populations, and explored drivers of local adaptation by studying the role of climate as a source of population differentiation in PSM of maritime pine. Constitutive profile and concentrations of 63 PSM and their herbivory‐associated inducibility were determined in the bark of 130 clonally replicated genotypes with known familial structure from 10 populations covering the distribution range of the species. We compared neutral and quantitative population genetic differentiation of PSM (FST and QST). Also, we accounted for population genetic structure and kinship among individuals when exploring climate–trait relationships. We found large population differentiation and additive genetic variation in constitutive PSM. Many PSM were inducible, although very low genetic variation was observed with respect to their inducibility. QST–FST comparisons suggest that differentiation of most diterpenes, monoterpenes, and phenolics can be explained by neutral demographic processes. Spatially heterogeneous selection across populations leading to local adaptation was only found for total constitutive sesquiterpenes and a few individual PSM. After accounting for population genetic structure, only the constitutive concentration of two sesquiterpenes showing signs of diversifying selection was predicted by climate, with decreasing concentrations along a growth‐prone climatic gradient. Synthesis. Evolutionary patterns of plant secondary metabolites depended on their chemical nature, with neutral differentiation governing most plant secondary metabolites. Evidence of local adaptation was only found for total constitutive sesquiterpenes and a few individual plant secondary metabolites. The low genetic variation in the inducibility of plant secondary metabolites suggests a conserved model of defensive induction in this species. Since population differentiation linked to past demographic history could lead to false positives of adaptive differentiation signals, accounting for the genetic relatedness among populations is required to infer the environmental determinants of intraspecific genetic variation in putatively adaptive traits such as plant defences.

The content of the 13th Mutation Detection meeting (Leiden, April 2015) is summarized in this report. Topics discussed at the meeting included current challenges of clinical NGS, advances in bioinformatics, data quality control, single cell analysis and RNA sequencing, among others. Social, ethical and regulatory challenges of genomic data handling and data sharing were the focus of an expert panel debate. The 14th International Symposium on Variants in the Genome will take place in Santiago de Compostela, June 5-8, 2017. http://isv.variome.org.

The acquired and congenital forms of long QT syndrome represent 2 distinct but clinically and genetically intertwined disorders of cardiac repolarization characterized by the shared final common pathway of QT interval prolongation and risk of potentially life-threatening arrhythmias. Over the past 2 decades, our understanding of the spectrum of genetic variation that (1) perturbs the function of cardiac ion channel macromolecular complexes and intracellular calcium-handling proteins, (2) underlies acquired/congenital long QT syndrome susceptibility, and (3) serves as a determinant of QT interval duration in the general population has grown exponentially. In turn, these molecular insights led to the development and increased utilization of clinically impactful genetic testing for congenital long QT syndrome. However, the widespread adoption and potential misinterpretation of the 2015 American College of Medical Genetics and Genomics variant classification and reporting guidelines may have contributed unintentionally to the reduced reporting of common genetic variants, with compelling epidemiological and functional evidence to support a potentially proarrhythmic role in patients with congenital and acquired long QT syndrome. As a result, some genetic testing reports may fail to convey the full extent of a patient's genetic susceptibility for a potentially life-threatening arrhythmia to the ordering healthcare professional. In this white paper, we examine the current classification and reporting (or lack thereof) of potentially proarrhythmic common genetic variants and investigate potential mechanisms to facilitate the reporting of these genetic variants without increasing the risk of diagnostic miscues.

Human genetic variation influences all aspects of our biology, including the oral cavity1-3, through which nutrients and microbes enter the body. Yet it is largely unknown which human genetic variants shape a person's oral microbiome and potentially promote its dysbiosis3-5. We characterized the oral microbiomes of 12,519 people by re-analysing whole-genome sequencing reads from previously sequenced saliva-derived DNA. Human genetic variation at 11 loci (10 new) associated with variation in oral microbiome composition. Several of these related to carbohydrate availability; the strongest association (P = 3.0 × 10-188) involved the common FUT2 W154X loss-of-function variant, which associated with the abundances of 58 bacterial species. Human host genetics also seemed to powerfully shape genetic variation in oral bacterial species: these 11 host genetic variants also associated with variation of gene dosages in 68 regions of bacterial genomes. Common, multi-allelic copy number variation of AMY1, which encodes salivary amylase, associated with oral microbiome composition (P = 1.5 × 10-53) and with dentures use in UK Biobank (P = 5.9 × 10-35, n = 418,039) but not with body mass index (P = 0.85), suggesting that salivaryamylase abundance impacts health by influencing the oral microbiome. Two other microbiome composition-associated loci, FUT2 and PITX1, also significantly associated with dentures risk, collectively nominating numerous host-microbial interactions that contribute to tooth decay.

Human genetic variation can modulate pathophysiologic processes that alter susceptibility to complex disease. Recent genomic analyses have sought to identify how common genetic variation alters susceptibility to coronary artery disease (CAD). From genome-wide association studies (GWAS), common genetic variants in several novel chromosomal loci have been associated with CAD. GWAS identified the 9p21 locus as the strongest independent genetic CAD risk factor, along with 11 additional loci that harbor common genetic variants associated with increased CAD risk. A thorough understanding of human genetic variation and genomic analyses will be crucial to understand how GWAS-identified loci increase susceptibility to CAD. This article outlines the relevance of genetic variation in the elucidation of novel CAD risk factors and the clinical utility of genetic variants in the management and treatment of CAD.

The 1000 Genomes Project: paving the way for personalized genomic medicine.

Hordeum brevisubulatum (Trin) Link, a perennial wild grass, shows high tolerance to salinity- and/or alkaline-eroded soil, and is an important forage grass. Nonetheless, the genetic variation within and among natural populations of this species has not been investigated. In this study, four PCR-based dominant nuclear DNA markers, i.e., amplified fragment length polymorphism (AFLP), inter-simple sequence repeat (ISSR), retrotransposon-microsatellite-amplifiedpolymorphism (REMAP), and random amplified polymor phic DNA (RAPD) were used to investigate the genetic variation of a total of 80 plants with an average of 20 individual plants randomly collected from each of the four natural populations of H. brevisubulatum distributed in the Songnen Prairie in northeastern China. Results indicated that all four markers detected a surprisingly high level of genetic variation among the individual genotypes both within and among populations. Specifically, (i) of the 708 bands produced by 10 AFLP primer pairs, 223 (32%) were polymorphic, corresponding to a genetic similarity coefficient (Dice) range of 0.703 to 0.895 with a mean of 0.793; (ii) of the 174 bands produced by 12 ISSR primers, 149 (85%) were polymorphic, corresponding to a genetic similarity coefficient range of 0.524 to 0.826 with a mean of 0.676; (iii) of the 104 bands produced by REMAP (one retrotransopon-specific primer in combination with each of 8 ISSR primers), 89 (85%) were polymorphic, leading to an average similarity coefficient range of 0.494–0.840 with a mean of 0.688, and; (iv) of the 150 bands produced by 17 RAPD primers, 117 (77%) were polymorphic, giving a similarity coefficient range of 0.526–0.909 with a mean of 0.713. Thus, all four markers are highly informative in detecting genetic variations among the individual genotypes in natural populations of H. brevisubulatum. Nevertheless, no correlation was detected among the markers, suggesting that they likely targeted to different genomic regions of H. brevisubulatum. Whereas ISSR, REMAP and RAPD showed significantly higher levels of polymorphism than AFLP, only the latter was capable of grouping some of the plants largely in accordance with their geographic localities, suggesting population differentiation probably occurred preferentially at genomic regions targeted to by AFLP primers. Key words: Genetic diversity, Hordeum brevisubulatum, Molecular markers, Population differentiation

Atherosclerosis and Vascular Biology

Gene expression and genetic variation in human atria.

Rasd2 Modulates Psychotomimetic Drug Effects in Mice and Schizophrenia-related Phenotypes in Humans

Genetic variation in targets of antihyperglycemic drugs and inflammatory bowel disease' risk: A mendelian randomization study.

Gastrointestinal cancers account for 20% of all cancer incidences worldwide. Colorectal cancer is the second most common cause of all cancer-related mortality and is increasing in Western societies. Infection and inflammation contribute to 15-20% of all malignancies, and are predisposing risk factors for gastrointestinal cancers. Helicobacter pylori infection is commonly associated with gastric cancers, and chronic inflammation increases the risk of colorectal cancer by 1% per year. Micronutrient status and common genetic variations in human populations modify risk for gastrointestinal cancer. Chronic inflammation promotes carcinogenesis by inducing gene mutations, inhibiting apoptosis, and stimulating angiogenesis and cell proliferation. Inflammation also induces epigenetic alterations that are associated with cancer development. Two key genes in the inflammatory process, cyclooxygenase-2 (COX-2) and nuclear factor-kappa B (NF-kappaB), provide a mechanistic link between inflammation and cancer and are targets for chemoprevention. Dietary components, and human genetic variation that affects nutrient utilization, can directly modify inflammatory processes and/or suppress genomic alterations that are the molecular antecedents of cancers. The present report focuses on the convergence of genetic, nutritional, and inflammatory factors in the initiation and progression of gastrointestinal cancers, and the emerging dietary strategies for cancer prevention.

Purpose: Our study’s primary objective is to assess the knowledge and attitudes regarding non-invasive prenatal testing (NIPT) to screen for 22q11.2 deletion syndrome in healthcare providers caring for obstetrical patients. Introduction: 22q11.2 deletion syndrome is a clinically significant microdeletion syndrome associated with substantial morbidity and mortality. Non-invasive prenatal testing (NIPT) has revolutionized prenatal screening, offering a non-invasive method to detect various genetic abnormalities, including 22q11.2 deletion. Despite its potential benefits, the integration of NIPT for 22q11.2 deletion into clinical practice remains inconsistent. This study aims to assess the knowledge and attitudes of healthcare providers towards NIPT for 22q11.2 deletion, shedding light on current practices and identifying gaps in provider education and confidence in patient counseling. By understanding these factors, we can better inform future clinical guidelines and educational initiatives to enhance the utilization of NIPT in prenatal care. Methods: A cross-sectional survey using an online multiple-choice format was conducted among healthcare providers in OB/GYN departments and Maternal-Fetal Medicine divisions at an academic medical center and a large referral center-community hospital system in Northwest Ohio. Participants included trainees, staff, and faculty members, who accessed the anonymous survey via a link or QR code. The survey, administered using QuestionPro software, is comprised of 18 multiple-choice questions covering demographics, clinical use of carrier and NIPT screening, and knowledge and attitudes towards NIPT for 22q11.2 deletion syndrome. The Delphi method was employed to achieve consensus on the final question list. Data collection began on April 23, 2024 and was completed on June 5, 2024. Results: Thirteen physicians completed the survey: five OB/GYN residents, six OB/GYN generalists, and two Maternal-Fetal Medicine specialists. All non-trainee respondents had at least five years of practice experience. All physicians reported using NIPT for fetal aneuploidies (Trisomies 21, 18, and 13), and 92% offered carrier screening. The initial data indicated variability in the use of NIPT based on years in practice. None of the residents reported using NIPT for sex chromosome aneuploidies or microdeletion syndromes, including 22q11.2 deletion. Conversely, all experienced physicians used expanded NIPT panels, with 50% selecting 22q11.2 screening as an add-on. 63% of experienced physicians screened all obstetric patients for 22q11.2 deletion, whereas the other physicians in our sample selected screening only for patients who presented with a detected fetal congenital anomaly or family history of aneuploidy or other genetic disorder. Additionally, 88% of experienced physicians offered multiple NIPT options, compared to 100% of residents who offered a single option which excludes 22q11.2 screening. Regarding provider knowledge, 15% (two experienced OB/GYN physicians) incorrectly equated screening sensitivities for 22q11.2 deletion and common Trisomies. Only 46% of respondents, including both Maternal-Fetal Medicine specialists, felt adequately informed to counsel patients on 22q11.2 deletion screening. However, 77% indicated confidence in managing positive screening results. Conclusions: Given the significant morbidity and mortality associated with 22q11.2 deletion syndrome, early intervention via expanded NIPT is clinically beneficial. However, the performance of NIPT for 22q11.2 deletion lags behind that of the common Trisomies, with an 83% sensitivity reported. Insufficient research exists on how clinicians utilize this information for patient counseling. Our study highlights that only trained physicians use NIPT for 22q11.2 deletion, with limited confidence in counseling. These findings underscore the need for enhanced education during residency to ensure comprehensive patient counseling. Continued recruitment aims to expand these initial findings to inform future clinical recommendations and standardize counseling guidelines.

The theory of evolution via natural selection predicts that the genetic composition of wild populations changes over time in response to the environment. Different genotypes should exhibit different demographic patterns, but genetic variation in demography is often impossible to separate from environmental variation. Here, we asked if genetic variation is important in determining demographic patterns. We answer this question using a long-term field experiment combined with general linear modeling of deterministic population growth rates (lambda), deterministic life table response experiment (LTRE) analysis, and stochastic simulation of demography by paternal lineage in a short-lived perennial plant, Plantago lanceolata, in which we replicated genotypes across four cohorts using a standard breeding design. General linear modeling showed that growth rate varied significantly with year, spatial block, and sire. In LTRE analysis of all cohorts, the strongest influences on growth rate were from year x spatial block, and cohort x year x spatial block interactions. In analysis of genetics vs. temporal environmental variation, the strongest impacts on growth rate were from year and year x sire. Finally, stochastic simulation suggested different genetic composition among cohorts after 100 years, and different population growth rates when genetic differences were accounted for than when they were not. We argue that genetic variation, genotype x environment interactions, natural selection, and cohort effects should be better integrated into population ecological studies, as these processes should result in deviations from projected deterministic and stochastic population parameters.