APOE ε4 is associated with higher vitamin D levels in targeted replacement mice and humans

The allele epsilon 4 of apolipoprotein E (APOE), which is a key regulator of lipid metabolism, represents a risk factor for cardiovascular diseases and Alzheimer's disease. Despite its adverse effects, the allele is common and shows a nonrandom global distribution that is thought to be the result of evolutionary adaptation. One hypothesis proposes that the APOE epsilon 4 allele protects against vitamin D deficiency. Here we present, for the first time, experimental and epidemiological evidence that the APOE epsilon 4 allele is indeed associated with higher serum vitamin D [25(OH) D] levels. In APOE4 targeted replacement mice, significantly higher 25(OH) D levels were found compared with those in APOE2 and APOE3 mice (70.9 vs. 41.8 and 27.8 nM, P<0.05). Furthermore, multivariate adjusted models show a positive association of the APOE epsilon 4 allele with 25(OH) D levels in a small collective of human subjects (n = 93; P = 0.072) and a general population sample (n = 699; P = 0.003). The novel link suggests epsilon 4 as a modulator of vitamin D status. Although this result agrees well with evolutionary aspects, it appears contradictory with regard to chronic diseases, especially cardiovascular disease. Large prospective cohort studies are now needed to investigate the potential implications of this finding for chronic disease risks.-Huebbe, P., Nebel, A., Siegert, S., Moehring, J., Boesch-Saadatmandi, C., Most, E., Pallauf, J., Egert, S., Muller, M. J., Schreiber, S., Nothlings, U., Rimbach, G. APOE epsilon 4 is associated with higher vitamin D levels in targeted replacement mice and humans. FASEB J. 25, 3262-3270 (2011). www.fasebj.org