The complexity of identifying gene environment

The complexity of identifying gene-environment interactions for Crohn\'s disease should be acknowledged. It is important to understand the design of the studies and the methodical implications of grouping multiple genetic variants into a single analysis. Helbig et al. were the first to use a case-only design to explore statistical interaction and the current meta-analysis adopted a similar design. A multiplicative interaction as demonstrated here does not indicate which group is at a higher absolute risk from the environmental exposure; case-only studies cannot be used to assess for additive interactions, and it remains possible that the absolute risk of smoking in variant carriers would be higher than in those with wild-type (). The similar results obtained from the two quoted studies are intriguing and point to the importance of assessing genetic and environmental factors in sub-phenotypes of CD. In addition to age, disease location, disease behaviour and other subphenotypes may influence gene-environment interactions. Both and smoking are associated with ileal CD and furthermore, ileal and colonic CD have been shown to be in part genetically-determined phenotypes ().
Given the vital role of the ubiquitin-proteasome system (UPS) in propelling the cell division ARCA and sustaining cell survival, UPS inhibition is being intensively explored as a therapeutic strategy for treating malignancy, which is surely fueled by the impressive efficacy demonstrated by proteasome inhibitors bortezomib (BZM) and carfilzomib (CFZ) in treating multiple myeloma (MM) (() and references therein). However, severe cardiovascular adverse effects such as sudden death, arrhythmia, angina, heart failure, and pulmonary hypertension to name a few, have been observed in MM patients treated with regimens containing BZM or CFZ (() and references therein). Most cardiovascular complications are reversible if the use of proteasome inhibitors is timely terminated but prematurely ceasing proteasome inhibitor treatment due to severe unintended effects will obviously limit the clinical benefit of these efficacious agents. Hence, it is extremely important to achieve a better understanding of the underlying causes as it can guide the development of targeted strategies and measures to prevent and manage the life-threatening cardiovascular adverse effects. Prior experimental studies have demonstrated that genetic and pharmacological inhibition of the proteasome in the cardiomyocyte compartment exacerbates acute myocardial ischemia/reperfusion injury and the maladaptive cardiac remodeling and heart failure induced by acute pressure overload () through perturbation of protein quality control and exacerbation of proteotoxicity while chronic cardiac proteasome functional insufficiency has been established to play a major role in the genesis and progression of cardiac proteinopathy (), pressure overloaded maladaptive cardiac remodeling and failure (), and diabetic cardiomyopathy (). These prior reports certainly presented a compelling argument for a notion that derangements caused by acute or sustained proteasome inhibition in the cardiomyocyte compartment contribute to at least some of the cardiovascular complications occurred in MM patients receiving proteasome inhibitor-containing chemotherapies. Proteasome malfunction was also implicated in vascular pathology such as atherosclerosis as well as vascular ageing and pharmacologically induced chronic proteasome inhibition was shown to cause coronary artery constriction, hasten high fat diet induced atherosclerosis, and result in restrictive cardiomyopathy in pigs (), suggesting that chronic vascular injury and remodeling could also be an mechanism underlying some of the cardiovascular adversity induced by treatment with a proteasome inhibitor. However, many of the acute cardiovascular complications such as sudden death, arrhythmia, and myocardial ischemia occurred during or shortly after CFZ infusion are quite difficult to explain with the long term cardiovascular toxicities observed so far in animal experiments. Now, this situation is likely changed for good.