Mitochondrial mutations associated with aminoglycoside ototoxicity and hearing loss susceptibility identified by meta-analysis.

BACKGROUND: Genetic variations, including mitochondrial mutations, are important contributors to hearing loss, especially in children, and newborn genetic screens for hearing loss mutations are becoming increasingly common. Mitochondrial mutations have been linked with ototoxic responses to common antibiotics, therefore understanding the association of these mutations with hearing loss is of special importance. To address the usefulness of screening for these mutations in a clinical setting, we formed a collaboration of clinicians and geneticists to analyse the association of mitochondrial mutations with non-syndromic hearing loss, including the effect of ethnicity, audiological test methods and aminoglycoside exposure. METHODS: This survey identified 122 variants in 43 studies that have been assessed for an association with hearing loss, and meta-analysis was performed on clinically relevant subsets. RNA folding and conservation analysis further explored possible relevance of these variants. RESULTS: Among all studies, eight variants were found to have significant associations with hearing loss. A partially overlapping set of six variants had significant association with hearing loss when aminoglycoside exposure was assessed. Five of these variants predictive of sensitivity to aminoglycoside spatially co-localise in an RNA folding model. There was little effect of the audiological test method used to assess hearing loss on the association with the variants. CONCLUSIONS: Our results found a small set of studied variants had reproducible association with hearing loss, which will help clarify mutations useful in genetic screens for hearing loss. Several of the aminoglycoside exposure-associated mutations may co-localise on folded 12S rRNA, suggesting a functional association between these loci and aminoglycoside-induced hearing loss.

Recommendations of the 2006 Human Variome Project meeting.

Lists of variations in genomic DNA and their effects have been kept for some time and have been used in diagnostics and research. Although these lists have been carefully gathered and curated, there has been little standardization and coordination, complicating their use. Given the myriad possible variations in the estimated 24,000 genes in the human genome, it would be useful to have standard criteria for databases of variation. Incomplete collection and ascertainment of variants demonstrates a need for a universally accessible system. These and other problems led to the World Heath Organization-cosponsored meeting on June 20-23, 2006 in Melbourne, Australia, which launched the Human Variome Project. This meeting addressed all areas of human genetics relevant to collection of information on variation and its effects. Members of each of eight sessions (the clinic and phenotype, the diagnostic laboratory, the research laboratory, curation and collection, informatics, relevance to the emerging world, integration and federation and funding and sustainability) developed a number of recommendations that were then organized into a total of 96 recommendations to act as a foundation for future work worldwide. Here we summarize the background of the project, the meeting and its recommendations.

Situation, Education, Innovation, and Recommendation: A Large-Scale Systematic Review of Advance Care Planning in the Age of COVID-19.

The COVID-19 pandemic highlighted the need for advance care planning (ACP) as a way to help mitigate the various care concerns that accompanied the healthcare crisis. However, unique obstacles to typical ACP practice necessitated the need for guidance and innovation to help facilitate these vital conversations. The aim of this systematic review was to identify the various ACP barriers and facilitators that arose during the pandemic and determine how ACP practice was affected across different contexts and among different populations. This systematic review (PROSPERO registration number: CRD42022359092), which adheres to the PRISMA guidelines for reporting systematic reviews, examined studies on ACP in the context of the COVID-19 pandemic. The review involved searches of five databases, including MEDLINE and Embase. Of the 843 identified studies, 115 met the inclusion criteria. The extracted ACP barriers and facilitators were codified and quantified. The most frequently occurring ACP barrier codes were: Social distancing measures and visitation restrictions, Uncertainty surrounding the COVID-19 prognosis, and Technological/Telehealth barriers. The most frequently occurring ACP facilitator codes were the following: Telehealth/virtual ACP platforms, Training for clinicians, and Care team collaboration. Identifying the ACP barriers and facilitators is essential for developing effective, resilient ACP promotion strategies and improving its delivery, accessibility, and acceptability.

Complex relationship between TAS2 receptor variations, bitterness perception, and alcohol consumption observed in a population of wine consumers.

Our ability to taste bitterness affects our food choices and alcohol consumption. Alleles in the taste 2 receptor member TAS2R38 have been linked to the ability to perceive bitterness in bitter-tasting compounds and in many foods, and people with these bitterness sensitivity alleles have been shown to be less likely to consume alcohol, presumably because of alcohol's bitter taste. In a survey of 519 participants, almost all of whom regularly consumed alcohol, we observed that genetic variants in TAS2R38 were significantly associated with both increased alcohol consumption and the ability to perceive bitterness in several foods and a bitter chemical. In total, we assayed 39 variants in 25 genes that have been implicated in the genetics of taste perception, and no other variants predicted alcohol consumption. Perception of bitterness in broccoli and a preference for black coffee were also positively associated with alcohol consumption. As the consumption of alcohol is a social activity there may be incentive to appreciate its bitter aspects, and increased perception of bitterness could therefore be associated with consumption of some bitter beverages. As this study's respondents were predominantly frequent consumers of alcohol, these findings may be consistent with previous studies that have seen that increased experience in the consumption of wine is associated with an increased perception of PROP bitterness. Further work elucidating the complex relationship between the genetics of bitter perception and alcohol consumption will better describe these connections.

Large scale newborn deafness genetic screening of 142,417 neonates in Wuhan, China.

Almost one third of the three million people in China suffering severe deafness are children, and 50% of these cases are believed to have genetic components to their etiology. Newborn hearing genetic screening can complement Universal Neonatal Hearing Screening for the diagnosis of congenital hearing loss as well as identifying children at risk for late-onset and progressive hearing impairment. The aim of this joint academic and Ministry of Health project was to prototype a cost effective newborn genetic screen in a community health setting on a city-wide level, and to ascertain the prevalence of variation at loci that have been associated with non-syndromic hearing loss. With the participation of 143 local hospitals in the city of Wuhan, China we screened 142,417 neonates born between May 2014 and Dec. 2015. The variants GJB2 c.235delC, SLC26A4 c.919-2A>G, and mitochondrial variants m.1555A>G and m.1494C>T were assayed using real time PCR. Newborns found to carry a variant were re-assayed by sequencing in duplicate. Within a subset of 707 newborns we assayed using real-time PCR and ARMS-PCR to compare cost, sensitivity and operating procedure. The most frequent hearing loss associated allele detected in this population was the 235delC variant in GJB2 gene. In total, 4289 (3.01%) newborns were found to carry at least one allele of either GJB2 c.235delC, SLC26A4 c.919-2A>G or two assayed MT-RNR1 variants. There was complete accordance between the real-time PCR and the ARMS PCR, though the real-time PCR had a much lower failure rate. Real-time PCR had a lower cost and operating time than ARMS PCR. Ongoing collaboration with the participating hospitals will determine the specificity and sensitivity of the association of the variants with hearing loss at birth and arising in early childhood, allowing an estimation of the benefits of newborn hearing genetic screening in a large-scale community setting.

Joint effect of dopaminergic genes on likelihood of smoking following treatment with bupropion SR.

OBJECTIVE: To determine the relationship between joint variation in 2 dopaminergic genes and the likelihood of nonsmoking following treatment with bupropion sustained release (SR). DESIGN: Three hundred twenty-three participants in a bupropion SR smoking cessation effectiveness trial with 12-month follow-up were genotyped for variants of dopamine receptor gene DRD2 and dopamine transporter SLC6A3. MAIN OUTCOME MEASURES: Self-reported 7-day point prevalence of nonsmoking. RESULTS: Neither genotype alone was associated with 7-day point-prevalent nonsmoking at the 12-month follow-up. However, in the presence of the DRD2 A1 allele, SLC6A3 status was significantly associated with the likelihood of nonsmoking at the 12-month follow-up (individuals with DRD2 A1+ and SLC6A3 9- were more likely to be smoking). In the absence of the DRD2 A1 allele, the association between SLC6A3 status and nonsmoking was nonsignificant. CONCLUSION: Although these results are suggestive, a more compelling test is needed of the hypothesis that dopaminergic gene interaction underlies, in part, the likelihood of smoking following treatment with bupropion SR. Most likely this will come from larger studies involving prospective randomization to treatment based on genotype.

Differences in pharmacogenetics of nicotine and alcohol metabolism: review and recommendations for future research.

Genetic variations in the enzymes involved in alcohol and nicotine metabolism can profoundly affect the rates of metabolism of these drugs, which in turn can influence drug-taking behaviors. The frequency of these genetic variants differs substantially among ethnic groups, resulting in differing genetic influences, or degrees of risk, among different populations. For many of these enzymatic pathways, the genetic variations that affect the rates of metabolism are very different in Asians and Caucasians and may contribute to population differences in alcohol- and tobacco-related behaviors and diseases. Understanding how variations in alcohol- and nicotine-metabolizing enzymes alter these drug responses and behaviors, with special focus on genetic variations, is the subject of this review. Each section describes genetic variations in a particular enzymatic pathway and reviews what is known about population variation and the resulting impact on alcohol- and/or nicotine-related disorders. Each section concludes with some thoughts on future research priorities. Sections 1 and 2 review the primary alcohol- and acetaldehyde-metabolizing enzymes and provide a working model for how the genetic variations in these enzymes may affect alcohol consumption and related disorders. Section 1 focuses on the alcohol and acetaldehyde dehydrogenases, while section 2 focuses on CYP2E1 and its possible role in alcohol and tobacco dependence. Sections 3 and 4 describe enzymes involved in nicotine metabolism, with section 3 focusing on the major nicotine-to-cotinine metabolizing enzyme, CYP2A6, and how genetically differing rates of metabolic inactivation of nicotine alter smoking. Section 4 describes data on the many additional enzymes involved in the metabolism of nicotine and its metabolites and summarizes our current understanding of the influence these enzymes may have on metabolism and addiction in this relatively new research area.

Pharmacogenomics: challenges and opportunities.

The outcome of drug therapy is often unpredictable, ranging from beneficial effects to lack of efficacy to serious adverse effects. Variations in single genes are 1 well-recognized cause of such unpredictability, defining the field of pharmacogenetics (see Glossary). Such variations may involve genes controlling drug metabolism, drug transport, disease susceptibility, or drug targets. The sequencing of the human genome and the cataloguing of variants across human genomes are the enabling resources for the nascent field of pharmacogenomics (see Glossary), which tests the idea that genomic variability underlies variability in drug responses. However, there are many challenges that must be overcome to apply rapidly accumulating genomic information to understand variable drug responses, including defining candidate genes and pathways; relating disease genes to drug response genes; precisely defining drug response phenotypes; and addressing analytic, ethical, and technological issues involved in generation and management of large drug response data sets. Overcoming these challenges holds the promise of improving new drug development and ultimately individualizing the selection of appropriate drugs and dosages for individual patients.

Molecular Classification of Lobular Carcinoma of the Breast.

The morphology of breast tumors is complicated and diagnosis can be difficult. We present here a novel diagnostic model which we validate on both array-based and RNA sequencing platforms which reliably distinguishes this tumor type across multiple cohorts. We also examine how this molecular classification predicts sensitivity to common chemotherapeutics in cell-line based assays. A total of 1845 invasive breast cancer cases in six cohorts were collected, split into discovery and validation cohorts, and a classifier was created and compared to pathological diagnosis, grade and survival. In the validation cohorts the concordance of predicted diagnosis with a pathological diagnosis was 92%, and 97% when inconclusively classified cases were excluded. Tumor-derived cell lines were classified with the model as having predominantly ductal or lobular-like molecular physiologies, and sensitivity of these lines to relevant compounds was analyzed. A diagnostic tool can be created that reliably distinguishes lobular from ductal carcinoma and allows the classification of cell lines on the basis of molecular profiles associated with these tumor types. This tool may assist in improved diagnosis and aid in explorations of the response of lobular type breast tumor models to different compounds.

Heritability of plasma sex hormones and hormone binding globulin in adult male twins.

Plasma sex hormone concentrations have been used as biomarkers in epidemiological studies of many conditions including cancer, obesity, bone density, and coronary heart disease. The objective of this analysis was to estimate genetic and nongenetic influences on endogenous sex hormones (testosterone, estradiol, estrone, and SHBG) in a large sample of 532 adult white male twins (134 monozygotic and 132 dizygotic twin pairs) from the National Heart, Lung, and Blood Institute Twin Study. Participants were aged 59-70 yr at the time of plasma collection, and hormone concentrations were determined with RIA. Genetic models were fitted by the method of maximum likelihood. Testosterone and SHBG concentrations have substantial genetic variation, with additive genetic factors accounting for 57 and 68% of the total phenotypic variation, respectively. In contrast, variation in estrone (37% shared environmental and 63% individual specific environmental effects) and estradiol concentrations (25% genetic effect, 44% shared environmental effects, and 31% individual specific environmental effects) were largely influenced by nongenetic factors. Assessment of the relative contribution of genetic and nongenetic influences on hormone concentrations may help in the search for genes underlying variation and covariation in complex traits affected by plasma sex hormone concentrations.

Analysis of Social and Genetic Factors Influencing Heterosexual Transmission of HIV within Serodiscordant Couples in the Henan Cohort.

There is considerable variability between individuals in susceptibility to infection by human immunodeficiency virus (HIV). Many social, clinical and genetic factors are known to contribute to the likelihood of HIV transmission, but there is little consensus on the relative importance and potential interaction of these factors. Additionally, recent studies of several variants in chemokine receptors have identified alleles that may be predictive of HIV transmission and disease progression; however the strengths and directions of the associations of these genetic markers with HIV transmission have markedly varied between studies. To better identify factors that predict HIV transmission in a Chinese population, 180 cohabiting serodiscordant couples were enrolled for study by the Henan Center for Disease Prevention and Control, and transmission and progression of HIV infection were regularly measured. We found that anti-retroviral therapy, education level, and condom use were the most significant factors in determining likelihood of HIV transmission in this study. We also assessed ten variants in three genes (CXCL12, CCR2, and CCR5) that have been shown to influence HIV transmission. We found two tightly linked variants in CCR2 and CCR5, rs1799864 and rs1800024, have a significant positive association with transmission as recessive models (OR>10, P value=0.011). Mixed effects models showed that these genetic variants both retained significance when assessed with either treatment or condom use. These markers of transmission susceptibility may therefore serve to help stratify individuals by risk for HIV transmission.

Environmental and genetic determinants of tobacco use: methodology for a multidisciplinary, longitudinal family-based investigation.

This article describes the ongoing collaborative effort of six research teams to operationalize and execute an integrative approach to the study of gene x environment interactions in the development of tobacco dependence. At the core of the project is a longitudinal investigation of social and behavioral risk factors for tobacco use in individuals who were, on average, 13 years of age at intake and for whom smoking outcomes extending from early adolescence to young adulthood have been characterized previously (current average age of the cohort is 29 years). The conceptual framework for the integrative approach and the longitudinal investigation on which the study is based is presented. A description is also provided of the methods used to: (a) recruit participants and families to provide DNA samples and information on tobacco use; (b) assess participants for relevant tobacco-related phenotypes including smoking history, current use of tobacco, and nicotine metabolism; (c) assess the quality of the DNA samples collected from participants for genome-wide scanning and candidate gene analysis; (d) examine several research questions concerning the role of genetic and environmental factors in the onset and maintenance of tobacco use; and (e) ensure adherence to local and federal guidelines for ethical and legal investigations of genotypic associations with tobacco-related phenotypes in families. This investigation is unique among ongoing studies of the genetics of tobacco dependence in the extent to which equal importance has been assigned to both phenotypic and genotypic measurements.

Candidate gene approach for pharmacogenetic studies.

Genetic diversity in the form of single nucleotide DNA polymorphisms (SNPs) contributes to variable disease susceptibility and drug response. The candidate gene approach has been widely used to identify the genetic basis for pharmacogenetic traits and becomes increasingly more powerful with the recent advances in genomic technologies. High-throughput sequencing and SNP genotyping technologies allow the study of thousands of candidate genes and the identification of those involved in drug efficacy and toxicity. Expression-based genomic technologies such as DNA microarrays and proteomics also facilitate the understanding of important biological and pharmacological pathways, thus identifying more candidate genes for SNP studies. Candidate gene-based pharmacogenetic studies will lead to improved drug development, improved clinical trial design and therapeutics tailored to individual genotypes.

ABCB1 variation and treatment response in AIDS patients: initial results of the Henan cohort.

HIV/AIDS has the highest mortality among infectious diseases in China. In ongoing efforts to alleviate this crisis, the national government has placed great emphasis on efforts in Henan province where HIV-infected former plasma donors in the 1990s contributed to AIDS becoming a public health crisis. Concomitant with a national initiative focusing the use of pharmacogenetics for the better prediction of treatment response, we studied genetic variants with known pharmacokinetic phenotypes in a set of 298 HAART-treated (highly active antiretroviral therapy) patients infected with HIV from the Henan cohort. We measured the association of response to treatment, assessed as changes in CD4+ T cell counts after antiretroviral therapy, of five polymorphisms in four genes (CYP2B6, ABCB1/MDR1, ABCG2, and ABCC4) in which variation has been suggested to affect the pharmacokinetics of drugs commonly employed to treat HIV/AIDS. We show that genotyping for ABCB1 variations (rs1045642 and rs2032582) may help predict HIV treatment response. We found variations in this gene have a significant association with outcome as measured by CD4+ T cell counts in a discovery subset (N= 197; odds ratio (OR) = 1.58; 95% CI 1.02-2.45), these results were confirmed in a validation subset of the cohort (N = 78; OR= 2.81; 95% CI 1.32-5.96). Exploratory analysis suggests that this effect may be specific to NVP (nevirapine) or 3TC (lamivudine) response. This publication represents the first genetic analysis in a continuing effort to study and assist the patients in a very large, unique, and historically significant HIV-AIDS cohort. Genotyping of AIDS patients for ABCB1 variation may help predict outcome and potentially could help guide treatment strategies.

Gene-gene interactions between CYP2B6 and CYP2A6 in nicotine metabolism.

OBJECTIVES: CYP2A6 is the major enzyme involved in nicotine metabolism, yet large interindividual variations in the rate of nicotine metabolism exist within groups of individuals having the same CYP2A6 genotype. We investigated the influence of genetic variation in another potential nicotine-metabolizing enzyme, CYP2B6, and its interaction with CYP2A6, on the metabolism of nicotine. METHODS: Two hundred and twelve healthy Caucasian adult twin volunteers underwent an intravenous infusion of stable isotope-labeled nicotine and its major metabolite, cotinine, for characterization of pharmacokinetic and metabolism phenotypes. Five CYP2B6 genetic polymorphisms causing amino acid substitutions (R22C, Q172 H, S259R, K262R, and R487C) were analyzed. RESULTS: We observed that the CYP2B6*6 haplotype (defined as having both Q172 H and K262R variants) was associated with faster nicotine and cotinine clearance, and that such associations were more prominent among individuals having decreased-activity CYP2A6 genotypes. Statistically significant interactions between CYP2B6 and CYP2A6 genotypes were observed (P<0.003 for nicotine clearance and P<0.002 for cotinine clearance). CONCLUSIONS: Our results indicate that CYP2B6 genetic variation is associated with the metabolism of nicotine and cotinine among individuals with decreased CYP2A6 activity. Further investigation of the roles of CYP2B6 and the interaction between CYP2B6 and CYP2A6 genotypes in mediating nicotine dependence and tobacco-related diseases is merited.

A genome-wide screen for nicotine dependence susceptibility loci.

Genome-wide model free linkage analysis was conducted for nicotine dependence and tobacco use phenotypes in 607 members of 158 nuclear families consisting of at least two ever smokers (100 or more cigarettes smoked in lifetime). DNA from whole blood was genotyped for 739 autosomal microsatellite polymorphisms with an average inter-marker distance of 4.6 cM. A peak LOD score of 2.7 was observed on chromosome 6 for scores for the Fagerström Test for Nicotine Dependence. Exploratory analyses were conducted to determine whether sequence variation at other loci affected other measures of dependence or tobacco use. Four additional loci with LOD scores of 2.7 or more were associated with alternative measures of nicotine dependence, one with current frequency of use, and one with smoking cessation. Several of the corresponding support intervals were near putative loci reported previously (on chromosomes 6, 7, and 8) while others appear to be novel (on chromosomes 5, 16, and 19).

Support for previously identified alcoholism susceptibility Loci in a cohort selected for smoking behavior.

BACKGROUND: Alcohol consumption and alcoholism are heritable traits. Previous linkage analyses for alcoholism and related traits have identified several putative susceptibility loci. In this paper we use, for the first time, linkage analysis to search for alcoholism-related phenotypes in a family sample selected for smoking behavior. METHODS: Genome-wide model free linkage analysis was conducted for a variety of phenotypes related to alcohol consumption in 158 nuclear families ascertained for having at least two first-degree relatives who smoked 100 or more cigarettes in their lifetime. The phenotypes included dichotomous, ordinal, and continuous traits. Because the traits were typically not normally distributed the QTL score statistic as implemented in Merlin was employed to deal with deviations from normality. Simulation analysis determined that the QTL score statistic is robust to deviations from normality. RESULTS: Linkage analysis detected three loci, one on chromosome 2 and two on chromosome 4, with nominal significance (LOD score > 2.7). These loci appear to be in close proximity to loci reported in other studies. CONCLUSIONS: While these findings did not reach genome-wide significance (LOD >4.0 given multiple comparisons) we have confidence that genes in these regions affect alcohol consumption. Two of the three significant findings in this analysis have been reported previously as alcoholism susceptibility loci. Simulation analysis shows that the most widely replicated finding on chromosome 4 is strongly supported (p=0.01) even with correction for multiple comparisons. These findings suggest that previously reported linkage results are robust to the effects of different approaches to sample ascertainment and definition.

Genetics and drug use as a complex phenotype.

Drug use is a complex behavior influenced by multiple biological, family, and sociocultural factors. The concurrent use/misuse of multiple drugs is often seen and drug use also co-occurs with other psychiatric conditions. Behavior and molecular genetic studies support an important posited role of genes in drug use. This posited genetic risk does not appear to be conferred by one or two major genes manifesting large effects, but rather by a number of genes manifesting smaller effects. Genetic factors explain, on average, only about half of the total variability in drug use, with the remaining variability influenced by environmental factors. Also, genetic risk may be differentially expressed in the presence vs. absence of particular environmental conditions. Thus, investigation of environmental factors and their interaction with genetic risk is a necessary component of genetic research. While the full potential of genetic investigations for the prevention of drug misuse has yet to be realized, an example of the impact of risk factor modification under various conditions of gene-environment interaction is provided, and the implications for use of genetic information in drug-misuse prevention are discussed. The multifactorial nature of drug use necessitates coordinated investigation from multiple disciplines and timely dissemination of scientific findings. In addition, this work demands adherence to the highest standards of confidentiality and ethical use of genetic information to best inform future prevention efforts.