The evolution of mendelian randomization for investigating drug effects.

Dipender Gill and Stephen Burgess discuss the accompanying study by James Yarmolinsky and colleagues investigating the associations between genetically-proxied inhibition of antihypertensive drug targets and risk of common cancer subtypes using Mendelian randomization.

Smoking, Systemic Inflammation, and Airflow Limitation: A Mendelian Randomization Analysis of 98 085 Individuals From the General Population.

INTRODUCTION: Smoking is associated with systemic and local inflammation in the lungs. Furthermore, in chronic obstructive pulmonary disease, which is often caused by smoking, there is often systemic inflammation that is linked to lung function impairment. However, the causal pathways linking smoking, systemic inflammation, and airflow limitation are still unknown. We tested whether higher tobacco consumption is associated with higher systemic inflammation, observationally and genetically and whether genetically higher systemic inflammation is associated with airflow limitation. METHODS: We included 98 085 individuals aged 20-100 years from the Copenhagen General Population Study; 36589 were former smokers and 16172 were current smokers. CHRNA3 rs1051730 genotype was used as a proxy for higher tobacco consumption and the IL6R rs2228145 genotype was used for higher systemic inflammation. Airflow limitation was defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <70%. RESULTS: Difference in plasma level of C-reactive protein was 4.8% (95% CI = 4.4% to 5.2%) per 10 pack-year increase and 1.6% (95% CI = 0.4% to 2.8%) per T allele. Corresponding differences were 1.2% (95% CI = 1.1% to 1.3%) and 0.5% (95% CI = 0.3% to 0.8%) for fibrinogen, 1.2% (95% CI = 1.2% to 1.3%) and 0.7% (95% CI = 0.5% to 1.0%) for α1-antitrypsin, 2.0% (95% CI = 1.8% to 2.1%) and 0.7% (95% CI = 0.4% to 1.1%) for leukocytes, 1.9% (95% CI = 1.8% to 2.1%) and 0.8% (95% CI = 0.4% to 1.2%) for neutrophils, and 0.8% (95% CI = 0.7% to 1.0%) and 0.4% (95% CI = 0.1% to 0.7%) for thrombocytes. The differences in these levels were lower for former smokers compared with current smokers. The IL6R rs2228145 genotype was associated with higher plasma acute-phase reactants but not with airflow limitation. Compared with the C/C genotype, the odds ratio for airflow limitation was 0.95 (95% CI = 0.89 to 1.02) for A/C genotype and 0.94 (95% CI = 0.87 to 1.01) for A/A genotype. CONCLUSIONS: Higher tobacco consumption is associated with higher systemic inflammation both genetically and observationally, whereas systemic inflammation was not associated with airflow limitation genetically. IMPLICATIONS: The association between higher tobacco consumption and higher systemic inflammation may be causal, and the association is stronger among current smokers compared to former smokers, indicating that smoking cessation may reduce the effects of smoking on systemic inflammation. Systemic inflammation does not seem to be a causal driver in development of airflow limitation. These findings can help to understand the pathogenic effects of smoking and the interplay between smoking, systemic inflammation, and airflow limitation and hence development and progression of chronic obstructive pulmonary disease.

Using Genetic Variants in the Targets of Lipid Lowering Therapies to Inform Drug Discovery and Development: Current and Future Treatment Options.

Mendelian randomization studies and "human knock-out" studies of rare loss-of-function coding variants suggest that plasma levels of low-density lipoprotein-cholesterol LDL-C, triglycerides (TGs), and lipoprotein(a) (Lp(a)) are causally associated with the risk of cardiovascular disease, and, therefore, therapies directed against these targets should reduce the risk of cardiovascular events. However, several therapies directed against these targets have failed to reduce the risk of cardiovascular events in large-scale randomized trials, thus suggesting that causality is not sufficient evidence to establish genetic target validation. Instead, the critical question that needs to be answered to improve drug discovery and development is how much a causal biomarker needs to be changed to produce a clinically meaningful benefit in a short-term trial. This review describes how to use naturally randomized genetic evidence to accurately anticipate the results of randomized trials evaluating current and future lipid lowering therapies, inform the design of randomized trials, and transform the drug discovery and development process.

One gene, many neuropsychiatric disorders: lessons from Mendelian diseases.

Recent human genetic studies have consistently shown that mutations in the same gene or same genomic region can increase the risk of a broad range of complex neuropsychiatric disorders. Despite the steadily increasing number of examples of such nonspecific effects on risk, the underlying biological causes remain mysterious. Here we investigate the phenomenon of such nonspecific risk by identifying Mendelian disease genes that are associated with multiple diseases and explore what is known about the underlying mechanisms in these more 'simple' examples. Our analyses make clear that there are a variety of mechanisms at work, emphasizing how challenging it will be to elucidate the causes of nonspecific risk in complex disease. Ultimately, we conclude that functional approaches will be critical for explaining the causes of nonspecific risk factors discovered by human genetic studies of neuropsychiatric disorders.

Asociación de la uricemia con la cardiopatía isquémica y la presión arterial: análisis mediante aleatorización mendeliana de 2 grandes cohortes / No disponible

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Mendelian randomization: application to cardiovascular disease.

In the absence of an ethical, practical, and economical randomized trial, the epidemiologist is left to explore other methods in efforts to assert causality. An approach based on genotypic variation has the potential to mitigate against some of the problems found within conventional observational studies. Genetic variations associated with risk factors of interest at the population level can be used as proxy measures for these risk factors and to generate estimates of causal effect. The potential and the possible limitations of this approach within the cardiovascular field are presented in this review.

Mendelian randomization in the era of genomewide association studies.

BACKGROUND: Observational epidemiology has been instrumental in identifying modifiable causes of common diseases, and, in turn, substantially impacting public health. Spurious associations in observational epidemiologic studies are most commonly caused by confounding due to social, behavioral, or environmental factors and can therefore be difficult to control. They may also be due to reverse causation-in which the phenotypic outcome subsequently influences an environmental exposure such that it is wrongly implicated in its pathogenesis-and selection bias. Randomized controlled trials are effective in dealing with the potential sources of error; however, their use is not always leveraged, for practical or ethical reasons. CONTENT: An alternative method, mendelian randomization, entails the use of genetic variants as proxies for the environmental exposures under investigation. The power of mendelian randomization lies in its ability to avoid the often substantial confounding seen in conventional observational epidemiology. Underpinning mendelian randomization is the principle of the independent assortment of alleles during meiosis, which, importantly in this context, also implies that they are independent of those behavioral and environmental factors that confound epidemiologic studies. By selecting genetic variants that influence exposure patterns or are associated with an intermediate phenotype of the disease, one can effectively re-create a randomized comparison. SUMMARY: In the past 4 years, genomewide association studies have yielded the first robust genetic associations with common diseases, which in turn should enable mendelian randomization to be even more informative, despite some limitations outlined in this review.

Mendelian genetics of male infertility.

Infertility is defined as the inability of a couple to conceive despite trying for a year, and it affects approximately 15% of the reproductive-age population. It is considered a genetically lethal factor, as the family lineage stops at that individual with no progeny produced. A genetic defect associated with an infertile individual cannot be transmitted to the offspring, ensuring the maintenance of reproductive fitness of the species. However, with the advent of assisted reproductive techniques (ART), we are now able to overcome sterility and bypass nature's protective mechanisms that developed through evolution to prevent fertilization by defective or deficient sperm.