Mutation in APOA1 predicts increased risk of ischaemic heart disease and total mortality without low HDL cholesterol levels

TY - JOUR

T1 - Mutation in APOA1 predicts increased risk of ischaemic heart disease and total mortality without low HDL cholesterol levels

AU - Haase, C L

AU - Frikke-Schmidt, R

AU - Nordestgaard, B G

AU - Kateifides, A K

AU - Kardassis, D

AU - Nielsen, Lars Bo

AU - Andersen, C B

AU - Køber, L

AU - Johnsen, A H

AU - Grande, P

AU - Zannis, V I

AU - Tybjaerg-Hansen, A

N1 - © 2011 The Association for the Publication of the Journal of Internal Medicine.

PY - 2011/8

Y1 - 2011/8

N2 - 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 10440 individuals in the prospective Copenhagen City Heart Study followed for 31years. Results were validated in an independent case-control study (n=16035). 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 10years (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.

AB - 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 10440 individuals in the prospective Copenhagen City Heart Study followed for 31years. Results were validated in an independent case-control study (n=16035). 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 10years (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.

KW - Adult

KW - Aged

KW - Animals

KW - Apolipoprotein A-I

KW - Case-Control Studies

KW - Denmark

KW - Female

KW - Humans

KW - Lipoproteins, HDL

KW - Male

KW - Mice

KW - Middle Aged

KW - Mutation

KW - Myocardial Ischemia

KW - Risk Factors

KW - Sequence Analysis, DNA

KW - Survival Analysis

U2 - 10.1111/j.1365-2796.2011.02381.x

DO - 10.1111/j.1365-2796.2011.02381.x

M3 - Journal article

C2 - 21443680

SN - 0955-7873

VL - 270

SP - 136

EP - 146

JO - Acta Medica Scandinavica

JF - Acta Medica Scandinavica

IS - 2

ER -