Mutation inAPOA1predicts increased risk of ischaemic heart disease and total mortality without low HDL cholesterol levels

Abstract

. Haase CL, Frikke‐Schmidt R, Nordestgaard BG, Kateifides AK, Kardassis D, Nielsen LB, Andersen CB, Køber L, Johnsen AH, Grande P, Zannis VI, Tybjærg‐Hansen A (Copenhagen University Hospitals and Faculty of Health Sciences, University of Copenhagen, Denmark; University of Crete Medical School, Heraklion, Greece; Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA). Mutation in APOA1 predicts increased risk of ischaemic heart disease and total mortality without low HDL cholesterol levels. J Intern Med 2011; 270: 136–146. Objectives. To determine whether mutations in APOA1 affect levels of high‐density lipoprotein (HDL) cholesterol and to predict risk of ischaemic heart disease (IHD) and total mortality in the general population. Background. Epidemiologically, risk of IHD is inversely related to HDL cholesterol levels. Mutations in apolipoprotein (apo) A‐I, the major protein constituent of HDL, might be associated with low HDL cholesterol and predispose to IHD and early death. Design. We resequenced APOA1 in 190 individuals and examined the effect of mutations on HDL cholesterol, risk of IHD, myocardial infarction (MI) and mortality in 10 440 individuals in the prospective Copenhagen City Heart Study followed for 31 years. Results were validated in an independent case–control study (n = 16 035). Additionally, we determined plasma ratios of mutant to wildtype (WT) apoA‐I in human heterozygotes and functional effects of mutations in adenovirus‐transfected mice. Results. We identified a new mutation, A164S (1 : 500 in the general population), which predicted hazard ratios for IHD, MI and total mortality of 3.2 [95% confidence interval (CI): 1.6–6.5], 5.5 (95% CI: 2.6–11.7) and 2.5 (95% CI: 1.3–4.8), respectively, in heterozygotes compared with noncarriers. Mean reduction in survival time in heterozygotes was 10 years (P < 0.0001). Results for IHD and MI were confirmed in the case–control study. Furthermore, the ratio of mutant S164 to WT A164 apoA‐I in plasma of heterozygotes was reduced. In addition, A164S heterozygotes had normal plasma lipid and lipoprotein levels, including HDL cholesterol and apoA‐I, and this finding was confirmed in adenovirus‐transfected mice. Conclusions. A164S is the first mutation in APOA1 to be described that predicts an increased risk of IHD, MI and total mortality without low HDL cholesterol levels.

Is High-Density Lipoprotein Cholesterol Causally Related to Kidney Function?

“…However, this was not the case: after contrasting findings, 14 recent large-scale studies dissecting the genetic architecture of lipid metabolism showed that increased low-density lipoprotein (LDL) cholesterol and triglyceride levels seem to be causally related to cardiovascular risk, but this was not the case for HDL cholesterol levels. 15–17 This is in line with interventional trials with CETP (cholesteryl ester transfer protein) inhibitors that increased HDL cholesterol by >100% but did not decrease cardiovascular outcomes. 18 It is now widely accepted consensus that HDL cholesterol rather represents a surrogate marker that does probably not properly reflect real HDL functionality.…”

HDL Biogenesis, Remodeling, and Catabolism

“…Similar but not identical phenotypes were produced by expressing the bioengineered apoA-I[R160V/H162A] and apoA-I[R149A] mutants and the naturally occurring mutants apoA-I[R151C] Paris and apoA-I[L144R] Zaragosa (Haase et al 2011;Chroni et al 2005a;Koukos et al 2007b). This phenotype could be corrected by co-expression of the mutant with human LCAT.…”

Genetics of Coronary Artery Disease

“…67 For the effect of rare variants on CAD risk, the picture is complicated by the fact that some rare variants in APOA1 that associate with low HDL cholesterol, cause amyloidosis, and this, in addition to other symptoms, may manifest as CAD due to small vessel disease, increased intima media thickness, or in later stages as cardiomyopathy. Haase et al 68,69 resequenced the APOA1 gene in >10 000 individuals, genotyped the identified variants in >55 000 individuals from the general population, and reported that the apparent increased risk associated with nonsynonymous mutations in APOA1 became insignificant when variants previously associated with amyloidosis were removed from the analysis. In support, mutations in APOA1 reported to associate with endothelial dysfunction, increased arterial wall thickness, and premature coronary heart disease 70 have more recently been shown to cause systemic amyloidosis.…”