Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

BACKGROUND: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. METHODS: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. RESULTS: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. CONCLUSIONS: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Abstract: Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate

Effects of Biotic and Abiotic Setting on a Host-Pathogen Relationship: How Environmental and Community Characteristics Influence Infection Prevalence and Intensity of Amphibian Chytrid on California's Central Coast

In the face of swift anthropogenic change, it is essential to examine the broad ecological context for species of concern using a variety of approaches in order to understand their interactions in a natural context. Host-pathogen relationships offer a close interaction to examine how each are acted upon by biotic and abiotic conditions. Batrachochytrium dendrobatidis, an emerging infectious disease of amphibians, has been implicated with wholesale loss and marked declines in amphibian species across the globe, thus understanding its dynamics across amphibian hosts and in complex, natural environments is a key area for conservation focus.For this dissertation, I tested the importance of various biotic and abiotic factors in the relationship between B. dendrobatidis and three co-occurring amphibian hosts, as well as across metrics of host physiological health. In Chapter 1, I ranked environmental conditions that favor B. dendrobatidis success in two native and one introduced amphibian tadpole species. I found top models favoring B. dendrobatidis infection included: a) a positive relationship with amphibian community diversity, b) elevated B. dendrobatidis infection in co-occurring infected amphibian species, and c) a varying, but strong relationship with assorted vegetative cover types. In Chapter 2, I asked which factor, Bd infection, amphibian community diversity, and predator diversity, best explained tadpole physiological metrics including, body condition, total white blood cell count, and neutrophil to lymphocyte ratio, for three species of tadpole. The most important factors predicting tadpole body condition varied markedly by species. Tadpole body condition was positively correlated with Bd infection and predator diversity for the introduced Lithobates catesbeiana, negatively correlated with amphibian community diversity for Rana draytonii, and positively correlated with predator diversity index for Pseudacris regilla. While the only factor that impacted neutrophil to lymphocyte ratios was Bd infection in bullfrogs, with white blood cell counts, I again saw a difference in the way the different species responded to the various stressors in their environment. Bd infection was the top driver in elevating white blood cell counts in P. regilla, while only amphibian diversity had this effect for R. draytonii. Predator diversity had a negative effect on white blood cell counts in L. catesbeiana. This diversity of responses is useful from a management perspective, as it may allow conservation practitioners to shift habitat suitability to species of interest. Given the differences in how the amphibians respond, a handful of concrete management recommendations for native amphibians emerge:1. Decrease Bd by decreasing co-occurring species; provide ponds specialized for species in a site, thus decreasing in-pond diversity, but maintaining amphibian diversity across the site2. Increase sunning sites for R. draytonii and P. regilla and maintain habitat complexity3. Create or maintain smaller, exposed, ephemeral ponds for P. regilla 4. Create or maintain larger, shallower, ephemeral ponds for R. draytonii 4. Improve water quality for R. draytonii5. Decrease amphibian species diversity by controlling introduced species, particularly bullfrog tadpoles, adults, and introduced fishMy dissertation demonstrates the importance of taking a broad approach to examine ecological relationships by designing studies across various species, combining perspectives such as pathogen success and metrics of host physiological stress, and taking into account a suite of likely interacting biotic and abiotic factors. Broad studies such as this can help to avoid spurious conservation decisions given limited time and resources to protect rapidly declining species

Do a threatened native amphibian and its invasive congener differ in response to human alteration of the landscape?

Anthropogenic changes to habitat are a global phenomenon and the impact of these changes may act in tandem to cause loss of biodiversity. One major global change is the introduction of invasive species. In order to determine whether other human impacts might correlate with populations of invaders, we examined the habitat correlates of distribution, persistence and reproduction of a global invader, the American bullfrog (Rana catesbeiana). We then compared these correlates with those of a threatened, native congener, the California red-legged frog (Rana draytonii). We found striking differences between the two species in response to habitat fragmentation and degradation. Our work suggests that human alteration of habitat, in particular the hydrology of freshwater sites and through building roads, favors this invasive species across the landscape

Experimental Infection and Repeat Survey Data Indicate the Amphibian Chytrid Batrachochytrium dendrobatidis May Not Occur on Freshwater Crustaceans in Northern Queensland, Australia

Chytridiomycosis is a fatal disease of amphibians, caused by the amphibian chytrid Batrachochytrium dendrobatidis. The disease is unusual in that it may drive many amphibian species to local extinction during outbreaks. These dramatic declines in host population numbers could be facilitated if the pathogen can grow as a saprobe or on alternative hosts, a feature common to other chytrid species. This is also supported by in vitro work that demonstrates B. dendrobatidis can grow and reproduce in the absence of amphibian cells. In a previous study, B. dendrobatidis was detected on freshwater shrimp from rain forest streams in northern Queensland, Australia, using diagnostic PCR. We set out to confirm and further investigate the presence of B. dendrobatidis on crustaceans by carrying out more extensive sampling of shrimp in the field, experimental B. dendrobatidis infection trials using shrimp and crayfish, and PCR verification of the presence of B. dendrobatidis from shrimp samples that previously tested positive. We could not confirm the presence of B. dendrobatidis on shrimp, and report that original positive tests in shrimp reported by Rowley et al. (2006) were likely false. Thus, we suggest that shrimp may not be an important reservoir host for B. dendrobatidis

Managers’ Attitudes Toward Codes of Ethics: Are There Gender Differences?

codes of ethics, ethical standards, gender differences, managers’ attitudes,