Impact of the MIF -173G/C variant on cardiovascular disease risk: a meta-analysis of 9,047 participants

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Background The burden of cardiovascular diseases (CVDs) remains unclear in many regions of the world. Objectives The GBD (Global Burden of Disease) 2015 study integrated data on disease incidence, prevalence, and mortality to produce consistent, up-to-date estimates for cardiovascular burden. Methods CVD mortality was estimated from vital registration and verbal autopsy data. CVD prevalence was estimated using modeling software and data from health surveys, prospective cohorts, health system administrative data, and registries. Years lived with disability (YLD) were estimated by multiplying prevalence by disability weights. Years of life lost (YLL) were estimated by multiplying age-specific CVD deaths by a reference life expectancy. A sociodemographic index (SDI) was created for each location based on income per capita, educational attainment, and fertility. Results In 2015, there were an estimated 422.7 million cases of CVD (95% uncertainty interval: 415.53 to 427.87 million cases) and 17.92 million CVD deaths (95% uncertainty interval: 17.59 to 18.28 million CVD deaths). Declines in the age-standardized CVD death rate occurred between 1990 and 2015 in all high-income and some middle-income countries. Ischemic heart disease was the leading cause of CVD health lost globally, as well as in each world region, followed by stroke. As SDI increased beyond 0.25, the highest CVD mortality shifted from women to men. CVD mortality decreased sharply for both sexes in countries with an SDI >0.75. Conclusions CVDs remain a major cause of health loss for all regions of the world. Sociodemographic change over the past 25 years has been associated with dramatic declines in CVD in regions with very high SDI, but only a gradual decrease or no change in most regions. Future updates of the GBD study can be used to guide policymakers who are focused on reducing the overall burden of noncommunicable disease and achieving specific global health targets for CVD.

Key Points Cytokines are essential effector molecules of innate immunity that initiate and coordinate the cellular and humoral responses aimed, for example, at the eradication of microbial pathogens. Discovered in the late 1960s as a product of activated T cells, the cytokine macrophage migration inhibitory factor (MIF) has been discovered recently to carry out important functions as a mediator of the innate immune system. Constitutively expressed by a broad spectrum of cells and tissues, including monocytes and macrophages, MIF is rapidly released after exposure to microbial products and pro-inflammatory mediators, and in response to stress. After it is released, MIF induces pro-inflammatory biological responses that act as a regulator of immune responses. MIF activates the extracellular signal-regulated kinase 1 (ERK1)/ERK2–mitogen-activated protein kinase pathway, inhibits the activity of JUN activation domain-binding protein 1 (JAB1) — a co-activator of the activator protein 1 (AP1) — upregulates the expression of Toll-like receptor 4 to promote the recognition of endotoxin-expressing bacterial pathogens, sustains pro-inflammatory function by inhibiting p53-dependent apoptosis of macrophages and counter-regulates the immunosuppressive effects of glucocorticoids on immune cells. As a pro-inflammatory mediator, MIF has been shown to be implicated in the pathogenesis of severe sepsis and septic shock, acute respiratory distress syndrome, and several other inflammatory and autoimmune diseases, including rheumatoid arthritis, glomerulonephritis and inflammatory bowel diseases. Given its crucial role as a regulator of innate and acquired immunity, pharmacological or immunological modulation of MIF activity might offer new treatment opportunities for the management of acute and chronic inflammatory diseases.