An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Behavioural Changes in Zoo Animals during the COVID-19 Pandemic: A Long-Term, Multi Species Comparison

Visitors are a prominent feature of the zoo environment and lives of zoo animals. The COVID-19 pandemic led to repeated and extended closure periods for zoos worldwide. This unique period in zoological history enabled the opportunity to investigate the consistency of behavioural responses of zoo animals to closures and subsequent reopenings. Bennett’s wallabies (Notamacropus rufogriseus), meerkats (Suricata suricatta), macaws (red and green: Ara chloropterus; blue and yellow: Ara ararauna; military: Ara militaris) and rabbits (Oryctolagus cuniculus domesticus) held at four zoological collections in the United Kingdom were studied during COVID-19 closures and subsequent reopening periods. Facilities were closed for three time periods during 2020 and 2021: March–June/July 2020; November–December 2020; January–April/May 2021. Behavioural data were captured during closures (maximum n = 3) and reopening periods (maximum n = 3) during five-min scans using instantaneous scan sampling with a one-minute inter-scan interval. General linear models (GLMs) and general linear mixed models (GLMMs) were used to investigate the relationship between observed behaviours and open/closed periods. Changes were observed in behaviour between open and closure periods in all species, and in some instances changes were also observed over time, with animals responding differently to different closure and reopening periods. However, no overt positive or negative impacts of the closures or reopening periods were identified for these species. The study species may have different relationships with zoo visitors, but no clear differences were seen across the species studied. The unique opportunity to study animals over a long period of time during repeated closure periods enabled a greater understanding of the impact of zoo visitors on animals. As with other work in this sphere, these data support the adaptability of zoo animals to zoo visitors. This work contributes to the growing field of research undertaken during the COVID-19 periods and enhances our understanding of the impact that these zoological closures had on a wider body of species in a number of facilities

Behavioural Changes in Zoo Animals during the COVID-19 Pandemic: A Long-Term, Multi Species Comparison

Visitors are a prominent feature of the zoo environment and lives of zoo animals. The COVID-19 pandemic led to repeated and extended closure periods for zoos worldwide. This unique period in zoological history enabled the opportunity to investigate the consistency of behavioural responses of zoo animals to closures and subsequent reopenings. Bennett&rsquo;s wallabies (Notamacropus rufogriseus), meerkats (Suricata suricatta), macaws (red and green: Ara chloropterus; blue and yellow: Ara ararauna; military: Ara militaris) and rabbits (Oryctolagus cuniculus domesticus) held at four zoological collections in the United Kingdom were studied during COVID-19 closures and subsequent reopening periods. Facilities were closed for three time periods during 2020 and 2021: March&ndash;June/July 2020; November&ndash;December 2020; January&ndash;April/May 2021. Behavioural data were captured during closures (maximum n = 3) and reopening periods (maximum n = 3) during five-min scans using instantaneous scan sampling with a one-minute inter-scan interval. General linear models (GLMs) and general linear mixed models (GLMMs) were used to investigate the relationship between observed behaviours and open/closed periods. Changes were observed in behaviour between open and closure periods in all species, and in some instances changes were also observed over time, with animals responding differently to different closure and reopening periods. However, no overt positive or negative impacts of the closures or reopening periods were identified for these species. The study species may have different relationships with zoo visitors, but no clear differences were seen across the species studied. The unique opportunity to study animals over a long period of time during repeated closure periods enabled a greater understanding of the impact of zoo visitors on animals. As with other work in this sphere, these data support the adaptability of zoo animals to zoo visitors. This work contributes to the growing field of research undertaken during the COVID-19 periods and enhances our understanding of the impact that these zoological closures had on a wider body of species in a number of facilities

Almost Marginal Conditional Stochastic Dominance

Marginal Conditional Stochastic Dominance (MCSD) developed by Shalit and Yitzhaki (1994) gives the conditions under which all risk-averse individuals prefer to increase the share of one risky asset over another in a given portfolio. In this paper, we extend this concept to provide conditions under which most (and not all) risk-averse investors be- have in this way. Instead of stochastic dominance rules, almost stochastic dominance is used to assess the superiority of one asset over another in a given portfolio. Almost stochastic dominance means that the expected utility of most risk-averse investors can be improved by increasing the share of the dominant asset at the expense of the dominated one, excluding investors with extreme forms of preferences. Switching from MCSD to Almost MCSD (AMCSD) helps to reduce the inconsistency between common practice in asset allocation and the elegant decision rules in modern portfolio theory inspired from stochastic dominance relations