Physical health and incident late-life depression: modification by cytokine genes

Inflammatory cytokines have been implicated in the pathophysiology of depression, potentially underlying its association with worse physical health. Cytokine production is influenced by the transcriptional activity of several polymorphisms. We hypothesized that alleles related to higher proinflammatory and/or lower anti-inflammatory cytokine production would strengthen the association between physical disorders and late-life depression. In a 2-year prospective study of a community sample of 521 older people, information on number of physical disorders, diagnosis of depression (Geriatric Mental State), and genotypes for 6 pro-inflammatory (tumor necrosis factor-α −850C/T and −308G/A, interleukin (IL)-1β −511C/T and +3953C/T, IL-6 −174G/C, IL-8 −251T/A) and 2 anti-inflammatory (IL-4 +33T/C, IL-10 −1082G/A) cytokine polymorphisms were ascertained. Total numbers of potential risk alleles were calculated for pro- and anti-inflammatory cytokine genes. Interactions between baseline physical disorders and cytokine genotypes were investigated for incident depression. The associations between physical disorders and incident depression were significant in the presence of 2 alleles related to higher proinflammatory cytokine production (tumor necrosis factor-α −850T and IL-8 −251A), and 1 allele related to lower anti-inflammatory cytokine production (IL-4 +33C). Significant gene-environment interactions, independent of all covariates, were found for total number of risk alleles on both pro- and anti-inflammatory cytokine genes in addition to the above 3 individual single nucleotide polymorphisms. The present findings support cytokine-mediated inflammatory pathways underlying at least some of the well-recognized association between worse physical health and late-life depression, and provide novel evidence of a genetic basis for this.