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. 2014 Feb;22(2):216-20.
doi: 10.1038/ejhg.2013.116. Epub 2013 Jun 5.

The sex-specific associations of the aromatase gene with Alzheimer's disease and its interaction with IL10 in the Epistasis Project

Christopher Medway  1 , Onofre Combarros  2 , Mario Cortina-Borja  3 , Helen T Butler  4 , Carla A Ibrahim-Verbaas  5 , Renée F A G de Bruijn  5 , Peter J Koudstaal  6 , Cornelia M van Duijn  7 , M Arfan Ikram  8 , Ignacio Mateo  2 , Pascual Sánchez-Juan  2 , Michael G Lehmann  9 , Reinhard Heun  10 , Heike Kölsch  11 , Panos Deloukas  12 , Naomi Hammond  12 , Eliecer Coto  13 , Victoria Alvarez  13 , Patrick G Kehoe  14 , Rachel Barber  14 , Gordon K Wilcock  15 , Kristelle Brown  1 , Olivia Belbin  1 , Donald R Warden  9 , A David Smith  9 , Kevin Morgan  1 , Donald J Lehmann  9
Affiliations

The sex-specific associations of the aromatase gene with Alzheimer's disease and its interaction with IL10 in the Epistasis Project

Christopher Medway et al. Eur J Hum Genet. 2014 Feb.

Abstract

Epistasis between interleukin-10 (IL10) and aromatase gene polymorphisms has previously been reported to modify the risk of Alzheimer's disease (AD). However, although the main effects of aromatase variants suggest a sex-specific effect in AD, there has been insufficient power to detect sex-specific epistasis between these genes to date. Here we used the cohort of 1757 AD patients and 6294 controls in the Epistasis Project. We replicated the previously reported main effects of aromatase polymorphisms in AD risk in women, for example, adjusted odds ratio of disease for rs1065778 GG=1.22 (95% confidence interval: 1.01-1.48, P=0.03). We also confirmed a reported epistatic interaction between IL10 rs1800896 and aromatase (CYP19A1) rs1062033, again only in women: adjusted synergy factor=1.94 (1.16-3.25, 0.01). Aromatase, a rate-limiting enzyme in the synthesis of estrogens, is expressed in AD-relevant brain regions ,and is downregulated during the disease. IL-10 is an anti-inflammatory cytokine. Given that estrogens have neuroprotective and anti-inflammatory activities and regulate microglial cytokine production, epistasis is biologically plausible. Diminishing serum estrogen in postmenopausal women, coupled with suboptimal brain estrogen synthesis, may contribute to the inflammatory state, that is a pathological hallmark of AD.

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