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HDL and infection

The concept of raising high-density lipoprotein (HDL) cholesterol using pharmacological intervention to reduce cardiovascular risk has been discredited with a string of failed studies and investigational agents. However, the spotlight has not shifted completely from HDL cholesterol, with new evidence adding support for a role for HDLs in immunity.
A key study (1) reported novel findings based on data from 97,166 individuals in the Copenhagen General Population Study and 9,387 from the Copenhagen City Heart Study with measurements of HDL cholesterol at baseline. The primary endpoint of both studies was any infectious disease requiring hospital admission, ascertained in the Danish health registries from baseline in 2003–13 or 1991–94 through 2014.
Overall, 9% of individuals in the Copenhagen General Population Study and 31% in the Copenhagen City Heart Study experienced one or more infectious disease events. There was a U-shaped association between HDL cholesterol concentration and risk of any infection. Notably, an HDL cholesterol <0.8 mmol/L (31 mg/dL) and >2.6 mmol/L (100 mg/dL) had a higher risk for any infection compared with a value of 2.2–2.3 mmol/L (85–95 mg/dL). Hazard ratios and 95% confidence interval [CI] were 1.75, 1.31–2.34 and 1.43, 1.16–1.76, respectively, for the Copenhagen General Population Study, and 2.00, 1.16–3.43 and 1.13, 0.80–1.60, respectively, for the Copenhagen City Heart Study. These findings are relevant given that, in the general population, 21% of subjects had low HDL cholesterol and 8% had high HDL cholesterol levels.
Furthermore, the authors also showed that variants of genes encoding hepatic lipoprotein lipase, LIPC, and cholesterol ester transfer protein, CETP, were consistently associated with a reduced risk for infections.
The association between low HDL cholesterol and increased risk of infectious events is supported by experimental studies which have shown that HDLs plays a role in the development of immune cells, modulation of immune cell function and activity, as well as the neutralization and clearance of endotoxins. In contrast, the mechanism(s) for the association between high HDL cholesterol levels and increased risk for infection is less clear. It may be that these individuals with higher HDL cholesterol have higher levels of functionally defective HDLs as a consequence of different co-morbidities; of relevance, estimated glomerular filtration rate, indicative of reduced kidney function, was lower in individuals in the Copenhagen General Population Study with HDL cholesterol levels >2.6 mmol/L, and might partly explain this association.
In the second report (2), HDL functionality, specifically its cholesterol efflux capacity, was shown to be significantly impaired in older subjects with sepsis. This was a prospective study in patients with sepsis (n=10, mean age ± standard deviation 80?±?2 years) who were enrolled within the first 24?hours of admission to the emergency department, and 10 healthy controls (77?±?2 years). Compared with controls, patients with sepsis had significantly lower mean percent cholesterol efflux (24.1?±?1.2% versus 31.5?±?1.0%, p? 
These two studies implicate a role for HDLs in infection; further study is clearly merited.
1. Madsen CM, Varbo A, Tybjærg-Hansen A et al. U-shaped relationship of HDL and risk of infectious disease: two prospective population-based cohort studies. Eur Heart J 2017; doi:10.1093/eurheartj/ehx665. [Epub ahead of print]
2. Guirgis FW, Leeuwenburgh C, Grijalva V et al. HDL cholesterol efflux is impaired in older patients with early sepsis: a subanalysis of a prospective pilot study. Shock 2017; doi: 10.1097/SHK.0000000000001030. [Epub ahead of print]
U-shaped relationship of HDL and risk of infectious disease: two prospective population-based cohort studies.

Madsen CM, Varbo A, Tybjærg-Hansen A et al