Abstract
The ATP-binding cassette transporter A1 encoded by ABCA1 plays an integral role in the efflux of cellular cholesterol and phospholipids, but may also be a central mediator of β-amyloid (Aβ) processing. Here, genetic association of the common R219K variant of ABCA1 is shown with cerebrospinal fluid (CSF) Aβ1–42 levels, reinforcing emerging evidence of a connection between lipid and Aβ metabolism. In support of this finding we demonstrate for the first time that CSF cholesterol and Aβ1–42 are correlated. To affirm the plausible impact of ABCA1 variation on cholesterol and related traits as well as to empower a survey of possible interactions (e.g. age, gender, and smoking), a large Swedish population consisting of over 2,700 individuals was enlisted and extensive measures of plasma lipid parameters carried out. These analyses revealed that R219K has a strong effect on apolipoprotein B (APOB) and LDL-cholesterol (LDL-C) among smokers (P=0.000055 and P=0.00059, respectively), but not among non-smokers. In contrast, no effect was evident with apolipoprotein A (APOA1) or HDL-cholesterol (HDL-C) levels. Plasma APOB and LDL-C, but not APOA1 and HDL-C, were shown to be markedly elevated in smokers versus non-smokers, affirming that smoking may selectively impact the former pathway. No other genetic markers in ABCA1 exhibit effects as large as R219K, although a modest independent effect of R1587K was observed. Our data illuminate a possible genetic link between Aβ and cholesterol metabolism, but also provide an intriguing example of an environmental exposure that may modify a genotype–phenotype relationship.
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Acknowledgements
Financial support was provided by Pfizer Inc., The Swedish Medical Research Council, Loo and Hans Ostermans Foundation, The Swedish Old Servants Foundation (Gamla Tjänarinnor), Åke Wibergs Foundation, Torsten and Ragnar Söderbergs Foundation, Fredrik and Ingrid Thurings Foundation, The Swedish Alzheimer’s Foundation (Alzheimer’sfonden), and the Swedish Heart and Lung Foundation.
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Katzov, H., Bennet, A.M., Höglund, K. et al. Quantitative trait loci in ABCA1 modify cerebrospinal fluid amyloid-β1-42 and plasma apolipoprotein levels. J Hum Genet 51, 171–179 (2006). https://doi.org/10.1007/s10038-005-0341-x
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DOI: https://doi.org/10.1007/s10038-005-0341-x
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