Abstract
Studies on the role that genetic variation may play in a complex human disease can be empowered by an assessment of both disease risk in case-control or family models and of quantitative traits that reflect elements of disease etiology. An excellent example of this can be found for the ε4 allele of APOE in relation to Alzheimer’s disease (AD) for which association with both risk and age-at-onset (AAO) is evident. Following a recent demonstration that variants of the gene encoding angiotensin I converting enzyme (ACE) contribute to AD risk, we have explored the potential influence of ACE upon AAO in AD. A total of 2861 individuals from three European populations, including six independent AD samples, have been examined in this study. Three single nucleotide polymorphisms (SNPs) previously demonstrated to have maximum effects upon ACE plasma levels and that span the ACE locus were genotyped in these materials. A strong effect upon AAO was observed for marker rs4343 in exon 17 (P<0.0001), but evidence was also obtained indicating a possible independent effect of marker rs4291 (P=0.0095) located in the ACE promoter. Effects were consistent with data from previous studies suggesting association with AD in case-control models, whereby alleles demonstrated to confer risk to disease also appear to reduce AAO. Equivalent effects were evident regardless of APOE ε4 carrier status and in both males and females. These results provide an important complement to existing AD risk data, confirming that ACE harbors sequence variants that contribute to aspects of AD pathology.
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Acknowledgements
Generous financial support was provided by: Pfizer, Swedish Medical Research Council, Loo and Hans Ostermans Foundation, Knut and Alice Wallenberg Foundation, National Institute on Aging (R01 AG08724), Swedish Old Servants Foundation (Gamla Tjänarinnor), Åke Wibergs Foundation, Torsten and Ragnar Söderbergs Foundation, Fredrik and Ingrid Thurings Foundation, Petrus and Augusta Hedlunds Foundation, and Swedish Alzheimer Foundation (Alzheimerfonden). P.G.K. is supported by a Fellowship from the Sigmund Gestetner Fund and by BRACE (Bristol Research into Alzheimer’s and Care of the Elderly).
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Kehoe, P.G., Katzov, H., Andreasen, N. et al. Common variants of ACE contribute to variable age-at-onset of Alzheimer’s disease. Hum Genet 114, 478–483 (2004). https://doi.org/10.1007/s00439-004-1093-y
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DOI: https://doi.org/10.1007/s00439-004-1093-y