Interactions between PPAR-α and inflammation-related cytokine genes on the development of Alzheimer's disease, observed by the Epistasis project
Heun R., Kölsch H., Ibrahim-Verbaas CA., Combarros O., Aulchenko YS., Breteler M., Schuur M., van Duijn CM., Hammond N., Belbin O., Cortina-Borja M., Wilcock GK., Brown K., Barber R., Kehoe PG., Coto E., Alvarez V., Lehmann MG., Deloukas P., Mateo I., Morgan K., Warden DR., Smith AD., Lehmann DJ.
Neuroinflammation contributes to the pathogenesis of sporadic Alzheimer's disease (AD). Variations in genes relevant to inflammation may be candidate genes for AD risk. Whole-genome association studies have identified relevant new and known genes. Their combined effects do not explain 100% of the risk, genetic interactions may contribute. We investigated whether genes involved in inflammation, i.e. PPAR-α, interleukins (IL) IL1α, IL-1β, IL-6, and IL-10 may interact to increase AD risk. Methods: The Epistasis Project identifies interactions that affect the risk of AD. Genotyping of single nucleotide polymorphisms (SNPs) in PPARA, IL1A, IL1B, IL6 and IL10 was performed. Possible associations were analyzed by fitting logistic regression models with AD as outcome, controlling for centre, age, sex and presence of apolipoprotein ε4 allele (APOEε4). Adjusted synergy factors were derived from interaction terms (p < 0.05 two-sided). Results: We observed four significant interactions between different SNPs in PPARA and in interleukins IL1A, IL1B, IL10 that may affect AD risk. There were no significant interactions between PPARA and IL6. Conclusions: In addition to an association of the PPARA L162V polymorphism with the AD risk, we observed four significant interactions between SNPs in PPARA and SNPs in IL1A, IL1B and IL10 affecting AD risk. We prove that gene-gene interactions explain part of the heritability of AD and are to be considered when assessing the genetic risk. Necessary replications will require between 1450 and 2950 of both cases and controls, depending on the prevalence of the SNP, to have 80% power to detect the observed synergy factors.