Extreme high high-density lipoprotein (HDL) cholesterol may paradoxically increase risk

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Extreme high high-density lipoprotein (HDL) cholesterol may paradoxically increase risk

Usually, high-density lipoprotein (HDL) cholesterol concentrations are inversely associated with cardiovascular disease and mortality. But there is some data to suggest that extremely high HDL cholesterol might increase cardiovascular risk, that is an occurrence of a U curve relationship. Madsen CM and associates [2] checked this out in two prospective cohort studies – Copenhagen City Heart Study and the Copenhagen General Population Study including a total of 52 268 males and 64 240 females. During a 745 452 person-years of follow-up, they could demonstrate a U-curve relationship of HDL cholesterol with higher mortality at both extremes in both men and women. The HDL level with lowest all cause mortality was 73 mg/dL (95% confidence interval 54-77 mg/dL) in males and 93 mg/dL (95% confidence interval 69-97 mg/dL) in females.

At the other extreme, a hazard ratio of 2.06 for all cause mortality was noted in men with HDL cholesterol level of 116 mg/dL or more. In women a hazard ratio of 1.68 for all cause mortality was noted with HDL cholesterol levels of 135 mg/dL or more.

It is possible that genetic mutations leading to high HDL cholesterol also confer adverse cardiovascular risk. An alternate possibility is that extremely high HDL cholesterol levels are due to dysfunctional form [2].

It has been noted that loss of function mutations of SCARB1 gene encoding the major transporter of HDL cholesterol which delivers it to liver for excretion results in marked increases in HDL cholesterol level as well as paradoxically increased risk of coronary artery disease [3].


  1. Madsen CM, Varbo A, Nordestgaard BG. Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies. Eur Heart J. 2017 Aug 21;38(32):2478-2486.
  2. Singh K, Rohatgi A. Examining the paradox of high high-density lipoprotein and elevated cardiovascular risk. J Thorac Dis. 2018 Jan;10(1):109-112.
  3. Zanoni P, Khetarpal SA, Larach DB, Hancock-Cerutti WF, Millar JS1, Cuchel M, DerOhannessian S, Kontush A, Surendran P, Saleheen D, Trompet S, Jukema JW, De Craen A, Deloukas P, Sattar N, Ford I, Packard C, Majumder Aa, Alam DS, Di Angelantonio E, Abecasis G, Chowdhury R, Erdmann J, Nordestgaard BG, Nielsen SF, Tybjærg-Hansen A, Schmidt RF, Kuulasmaa K, Liu DJ, Perola M, Blankenberg S, Salomaa V, Männistö S, Amouyel P, Arveiler D, Ferrieres J, Müller-Nurasyid M, Ferrario M, Kee F, Willer CJ, Samani N, Schunkert H, Butterworth AS, Howson JM, Peloso GM, Stitziel NO, Danesh J, Kathiresan S, Rader DJ; CHD Exome+ Consortium; CARDIoGRAM Exome Consortium; Global Lipids Genetics Consortium. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science. 2016 Mar 11;351(6278):1166-71.