Genetic drug target validation using Mendelian randomisation

Mendelian randomisation (MR) analysis is an important tool to elucidate the causal relevance of environmental and biological risk factors for disease. However, causal inference is undermined if genetic variants used to instrument a risk factor also influence alternative disease-pathways (horizontal pleiotropy). Here we report how the 'no horizontal pleiotropy assumption' is strengthened when proteins are the risk factors of interest. Proteins are typically the proximal effectors of biological processes encoded in the genome. Moreover, proteins are the targets of most medicines, so MR studies of drug targets are becoming a fundamental tool in drug development. To enable such studies, we introduce a mathematical framework that contrasts MR analysis of proteins with that of risk factors located more distally in the causal chain from gene to disease. We illustrate key model decisions and introduce an analytical framework for maximising power and evaluating the robustness of analyses

Mendelian randomization for studying the effects of perturbing drug targets [version 1; peer review: awaiting peer review]

Drugs whose targets have genetic evidence to support efficacy and safety are more likely to be approved after clinical development. In this paper, we provide an overview of how natural sequence variation in the genes that encode drug targets can be used in Mendelian randomization analyses to offer insight into mechanism-based efficacy and adverse effects. Large databases of summary level genetic association data are increasingly available and can be leveraged to identify and validate variants that serve as proxies for drug target perturbation. As with all empirical research, Mendelian randomization has limitations including genetic confounding, its consideration of lifelong effects, and issues related to heterogeneity across different tissues and populations. When appropriately applied, Mendelian randomization provides a useful empirical framework for using population level data to improve the success rates of the drug development pipeline

Mendelian randomization for studying the effects of perturbing drug targets [version 2; peer review: 3 approved, 1 approved with reservations]

Drugs whose targets have genetic evidence to support efficacy and safety are more likely to be approved after clinical development. In this paper, we provide an overview of how natural sequence variation in the genes that encode drug targets can be used in Mendelian randomization analyses to offer insight into mechanism-based efficacy and adverse effects. Large databases of summary level genetic association data are increasingly available and can be leveraged to identify and validate variants that serve as proxies for drug target perturbation. As with all empirical research, Mendelian randomization has limitations including genetic confounding, its consideration of lifelong effects, and issues related to heterogeneity across different tissues and populations. When appropriately applied, Mendelian randomization provides a useful empirical framework for using population level data to improve the success rates of the drug development pipeline

A vivência da sexualidade por adolescentes portadoras de deficiência visual

Devido às transformações ocorridas na adolescência, as indefinições que a acompanham, somadas à deficiência visual, justifica-se um estudo sobre a vivência da sexualidade das adolescentes portadoras de deficiência visual inseridas na sociedade e na comunidade escolar. Foram entrevistadas cinco adolescentes em um Centro de Apoio Pedagógico, com questões que buscaram o conhecimento e a compreensão sobre as causa da sua deficiência visual, composição e orientações familiares, experiência afetivo-sexual e o nível de conhecimento acerca de assuntos relacionados à sexualidade, dentre eles métodos contraceptivos e doenças sexualmente transmissíveis. Os resultados mostram que estas adolescentes apresentam as mesmas características de desenvolvimento da sexualidade da sua faixa etária, embora possuam características individuais. Percebeu-se o desconhecimento sobre métodos contraceptivos e doenças sexualmente transmissíveis com informações superficiais. Torna-se imprescindível que o conhecimento se faça de forma acessível para esta população.En razón de las transformaciones sufridas durante la adolescencia, las indefiniciones que a acompañan, sumándose la deficiencia visual, se justifica un estudio sobre la experiencia de la sexualidad de las adolescentes afectadas por deficiencia visual insertas en la sociedad y en la comunidad escolar. Fueron entrevistadas cinco adolescentes en un Centro de Apoyo Pedagógico con preguntas que buscaron el conocimiento y comprensión de la causa de su deficiencia visual, composición y orientaciones familiares, experiencia afectivo-sexual, nivel de conocimientos acerca de asuntos relacionados con la sexualidad, sin excluir métodos anticonceptivos y enfermedades de transmisión sexual. Los resultados muestran que estas adolescentes presentan las mismas características de desarrollo de la sexualidad de su faja etaria, sin embargo poseen características particulares. Se percibió el desconocimiento respecto de métodos anticonceptivos y enfermedades de transmisión sexual, temas acerca de los cuales estaban superficialmente informadas. Es imprescindible que el conocimiento se transmita de modo accesible para esta población.The combination between transformations in adolescence, the indefiniteness they are accompanied by and the visual impairment justifies a study about the sexual experience of female, visually impaired adolescents included in society and in the school community. Five adolescents were interviewed at a Pedagogical Support Center. Questions attempted to find out their knowledge and understanding about the cause of their visual impairment, family composition and orientations, affective-sexual experience, level of knowledge about sexuality-related issues, including contraceptive methods and sexually transmitted diseases. Results revealed that these adolescents display the same sexuality development characteristics of their age group, though they have particular characteristics. It was observed there is a lack of knowledge regarding contraceptive methods and sexually transmitted diseases, of which the adolescents have superficial information. Making knowledge on the referred issues accessible to this population is indispensible

Association of LPA variants with risk of coronary disease and the implications for Lipoprotein(a)-lowering therapies: a mendelian randomization analysis

Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25% to 35% have not provided any evidence that lowering Lp(a) level reduces CHD risk.To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD.A mendelian randomization analysis was conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data, whereas summarized data included 62 240 patients with CHD and 127 299 controls. Data were analyzed from November 2016 to March 2018.Genetic LPA score and plasma Lp(a) mass concentration.Coronary heart disease.Of the included study participants, 53% were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR], 0.942; 95% CI, 0.933-0.951; P = 3 × 10-37), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (OR, 0.855; 95% CI, 0.818-0.893; P = 2 × 10-12). Thus, a 101.5-mg/dL change (95% CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk.The clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (ie, 1 mmol/L)

Neutrophil-mediated IL-6 receptor trans-signaling and the risk of chronic obstructive pulmonary disease and asthma

The Asp358Ala variant in the interleukin-6 receptor (IL-6R) gene has been implicated in asthma, autoimmune and cardiovascular disorders, but its role in other respiratory conditions such as chronic obstructive pulmonary disease (COPD) has not been investigated. The aims of this study were to evaluate whether there is an association between Asp358Ala and COPD or asthma risk, and to explore the role of the Asp358Ala variant in sIL-6R shedding from neutrophils and its pro-inflammatory effects in the lung. We undertook logistic regression using data from the UK Biobank and the ECLIPSE COPD cohort. Results were meta-analyzed with summary data from a further three COPD cohorts (7,519 total cases and 35,653 total controls), showing no association between Asp358Ala and COPD (OR = 1.02 [95% CI: 0.96, 1.07]). Data from the UK Biobank showed a positive association between the Asp358Ala variant and atopic asthma (OR = 1.07 [1.01, 1.13]). In a series of in vitro studies using blood samples from 37 participants, we found that shedding of sIL-6R from neutrophils was greater in carriers of the Asp358Ala minor allele than in non-carriers. Human pulmonary artery endothelial cells cultured with serum from homozygous carriers showed an increase in MCP-1 release in carriers of the minor allele, with the difference eliminated upon addition of tocilizumab. In conclusion, there is evidence that neutrophils may be an important source of sIL-6R in the lungs, and the Asp358Ala variant may have pro-inflammatory effects in lung cells. However, we were unable to identify evidence for an association between Asp358Ala and COPD.This work was supported by the UK Medical Research Council [MR/L003120/1 and MR/J00345X/1]; the British Heart Foundation [RG/13/13/30194]; the UK National Institute for Health Research Cambridge Biomedical Research Centre; and the Cambridge NIHR BRC Cell Phenotyping Hub. The Cardiovascular Epidemiology Unit at the University of Cambridge is supported by the UK Medical Research Council [G0800270]; the British Heart Foundation [SP/09/002]; and the UK National Institute for Health Research Cambridge Biomedical Research Centre. The ECLIPSE study is supported by GlaxoSmithKline [SCO104960]. The COPDGene study was supported by National Institutes of Health [R01 HL089897 and R01 HL089856]. The Norway GenKOLS study is supported by GlaxoSmithKline [RES11080]. The VA Normative Aging Study is supported by the Cooperative Studies Program/Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center, Boston, MA. Funding to pay the Open Access publication charges for this article was provided by University of Cambridge block grants from the Research Councils UK and the Charity Open Access Fund

Neutrophil-mediated IL-6 receptor trans-signaling and the risk of chronic obstructive pulmonary disease and asthma

The Asp358Ala variant in the interleukin-6 receptor (IL-6R) gene has been implicated in asthma, autoimmune and cardiovascular disorders, but its role in other respiratory conditions such as chronic obstructive pulmonary disease (COPD) has not been investigated. The aims of this study were to evaluate whether there is an association between Asp358Ala and COPD or asthma risk, and to explore the role of the Asp358Ala variant in sIL-6R shedding from neutrophils and its pro-inflammatory effects in the lung. We undertook logistic regression using data from the UK Biobank and the ECLIPSE COPD cohort. Results were meta-analyzed with summary data from a further three COPD cohorts (7,519 total cases and 35,653 total controls), showing no association between Asp358Ala and COPD (OR = 1.02 [95% CI: 0.96, 1.07]). Data from the UK Biobank showed a positive association between the Asp358Ala variant and atopic asthma (OR = 1.07 [1.01, 1.13]). In a series of in vitro studies using blood samples from 37 participants, we found that shedding of sIL-6R from neutrophils was greater in carriers of the Asp358Ala minor allele than in non-carriers. Human pulmonary artery endothelial cells cultured with serum from homozygous carriers showed an increase in MCP-1 release in carriers of the minor allele, with the difference eliminated upon addition of tocilizumab. In conclusion, there is evidence that neutrophils may be an important source of sIL-6R in the lungs, and the Asp358Ala variant may have pro-inflammatory effects in lung cells. However, we were unable to identify evidence for an association between Asp358Ala and COPD.This work was supported by the UK Medical Research Council [MR/L003120/1 and MR/J00345X/1]; the British Heart Foundation [RG/13/13/30194]; the UK National Institute for Health Research Cambridge Biomedical Research Centre; and the Cambridge NIHR BRC Cell Phenotyping Hub. The Cardiovascular Epidemiology Unit at the University of Cambridge is supported by the UK Medical Research Council [G0800270]; the British Heart Foundation [SP/09/002]; and the UK National Institute for Health Research Cambridge Biomedical Research Centre. The ECLIPSE study is supported by GlaxoSmithKline [SCO104960]. The COPDGene study was supported by National Institutes of Health [R01 HL089897 and R01 HL089856]. The Norway GenKOLS study is supported by GlaxoSmithKline [RES11080]. The VA Normative Aging Study is supported by the Cooperative Studies Program/Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center, Boston, MA. Funding to pay the Open Access publication charges for this article was provided by University of Cambridge block grants from the Research Councils UK and the Charity Open Access Fund

Predictors of gallstone composition in 1025 symptomatic gallstones from Northern Germany

BACKGROUND: Gallstones represent a prevalent and costly health problem. The changing epidemiology and the emerging non-surgical interventions for gallstone disease necessitate the definition of target populations for future therapies. This study aimed to define patterns of gallstone composition and identify demographic predictors of gallstone composition in a large sample of symptomatic gallstones from Northern Germany. METHODS: One thousand and seventy-four post-cholecystectomy gallstone specimens were obtained. Demographic and clinical information was provided by questionnaire (N = 1025 independent individuals with complete information). Two samples from each gallstone were analyzed using Fourier transformed infrared spectrometry. RESULTS: The most prevalent substance was cholesterol, which was detected in 95.0% of gallstone specimens. Bilirubin and bilirubinate were present in 30.0% and calcium was detected in 10.0% of the spectra. Ninety-two percent of measurements from the same stone yielded the same "main" substances, indicating a homogenous stone composition in most cases. Female sex and higher body mass index (BMI) were associated with the presence of cholesterol as a main substance in the gallstones (p < 0.001). CONCLUSION: The changing epidemiology of gallstone disease is reflected by a marked shift in stone composition: Only two percent of stones in this study were pigment stones as compared to 91% percent of stones containing cholesterol as a main substance. Obese individuals from Germany with a BMI > 30 kg/m(2 )have in 95% cholesterol-dominant gallstones and represent a potential target population for non-surgical interventions for the prevention or treatment of cholesterol stones

Perceived economic self‑sufficiency: a countryand generation‑comparative approach

We thank Michael Camasso and Radha Jagannathan as well as Asimina Christoforou, Gerbert Kraaykamp, Fay Makantasi, Tiziana Nazio, Kyriakos Pierrakakis, Jacqueline O’Reilly and Jan van Deth for their contribution to the CUPESSE project (Seventh Framework Programme; Grant Agreement No. 61325). CUPESSE received additional funding from the Mannheim Centre for European Social Research (MZES) and the Field of Focus 4 “Self-Regulation and Regulation: Individuals and Organisations” at Heidelberg University. We further acknowledge helpful comments on this article by two anonymous reviewers. Julian Rossello provided valuable research assistance.Electronic supplementary material The online version of this article (https ://doi.org/10.1057/ s4130 4-018-0186-3) contains supplementary material, which is available to authorized users.Existing datasets provided by statistical agencies (e.g. Eurostat) show that the economic and financial crisis that unfolded in 2008 significantly impacted the lives and livelihoods of young people across Europe. Taking these official statistics as a starting point, the collaborative research project “Cultural Pathways to Economic Self-Sufficiency and Entrepreneurship in Europe” (CUPESSE) generated new survey data on the economic and social situation of young Europeans (18–35 years). The CUPESSE dataset allows for country-comparative assessments of young people’s perceptions about their socio-economic situation. Furthermore, the dataset includes a variety of indicators examining the socio-economic situation of both young adults and their parents. In this data article, we introduce the CUPESSE dataset to political and social scientists in an attempt to spark a debate on the measurements, patterns and mechanisms of intergenerational transmission of economic self-sufficiency as well as its political implications.CUPESSE project (Seventh Framework Programme; Grant Agreement No. 61325