Antagonistic Pleiotropy at the Human IL6 Promoter Confers Genetic Resilience to the Pro-Inflammatory Effects of Adverse Social Conditions in Adolescence

Social conditions interact with genes to influence human health and longevity (Finch, 2007; Hernandez & Blazer, 2006; Robinson, 2004). For example, twin studies have shown that even the most robust socioenvironmental health risk factor—low socioeconomic status (SES)—impacts health outcomes differently depending upon an individual's total genetic endowment (Johnson & Krueger, 2005; Krieger, Chen, Coull, & Selby, 2005; Lichtenstein, Harris, Pedersen, & McClearn, 1993; Osler, McGue, & Christensen, 2007). Analyses of Gene × Social Environment (G × SE) interactions in health now seek to determine which specific molecular pathways mediate the biological impact of adverse social conditions (Caspi & Moffitt, 2006; Cole, 2009; G. Miller, Chen, & Cole, 2009; G. E. Miller, Chen, Fok, et al., 2009) and which specific genetic polymorphisms moderate those effects to render some people resilient as others remain vulnerable (Cole et al., 2010; Johnson & Krueger, 2005; Kim-Cohen, Moffitt, Caspi, & Taylor, 2004; Moffitt, Caspi, & Rutter, 2005). Efforts to identify specific G × SE interactions have been complicated by frequent failures to replicate initial findings. Inconsistent results in subsequent studies have often been interpreted as indicating the absence of any true effect (Risch et al., 2009). However, the evolutionary genetic theory of antagonistic pleiotropy (Williams, 1957) suggests an alternative explanation: Differences in the magnitude of a true G × SE interaction are to be expected if the studied samples differ along some additional environmental dimension that affects the phenotypic expression of that interaction. One moderating dimension may be the changing “somatic environment” of the developing body (Williams, 1957). The evolutionary genetic theory of antagonistic pleiotropy was originally developed to explain the evolutionary maintenance of genetic features that are maladaptive late in life based on the assumption that they must be selectively advantageous earlier in life or else they would have been eradicated from the gene pool by adverse selection (Williams, 1957). In particular, genes that help individuals survive through the period of reproductive maturity (i.e., young adulthood) should be positively selected for, even if they also confer substantial fitness penalties later in life (i.e., older adulthood; Williams, 1957). Although theoretically logical, few instances of age-dependent antagonistic pleiotropy have actually been documented, particularly in the context of G × SE interactions. In the present study, we tested the hypothesis that a genetic polymorphism in the human IL6 promoter that was recently found to interact with adverse socioenvironmental conditions to increase chronic inflammation and mortality in older adults (Cole et al., 2010) would show the opposite effect in adolescents (i.e., would be associated with reduced inflammation during peak reproductive maturity). IL6 is a logical candidate gene for examining antagonistic pleiotropy because the pro-inflammatory cytokine that it encodes (Interleukin-6 [IL-6]) plays a major role in defending the body against acute infection (a dominant factor in survival through reproductive maturity; Finch, 2010) but also fuels chronic inflammatory processes that contribute to the metabolic, cardiovascular, neurodegenerative, and neoplastic diseases that dominate late-life mortality (Finch, 2007). IL-6 levels show a general age-dependent increase over the lifespan (Ershler & Keller, 2000; Kiecolt-Glaser et al., 2003) and up-regulate in response to adverse socioenviron-mental conditions (Cole et al., 2010; Kiecolt-Glaser et al., 2011; Kiecolt-Glaser et al., 2003; Powell et al., 2009; Stark, Avitsur, Hunzeker, Padgett, & Sheridan, 2002). A molecular basis for adversity-related increases in IL6 expression has been identified in the sympathetic nervous system's (SNS) activation of the GATA1 transcription factor (Cole et al., 2010). In addition, a polymorphism in the promoter sequence of the IL6 gene (rs1800795; IL6 –174G/C) has been found to modulate individual sensitivity to the effects of threatening or adverse environments in activating IL6 transcription (Cole et al., 2010). In people bearing the ancestral G allele of the polymorphism, adversity-induced activation of the GATA1 transcription factor leads to increased IL6 gene transcription, and those individuals show increased risk of inflammation-related disease and mortality when confronted by extended periods of significant life adversity (Cole et al., 2010). In contrast, individuals bearing the C allele of the polymorphism are protected from such effects, because the GATA1 transcription factor cannot efficiently bind to the IL6 –174 locus after SNS-induced activation (Cole et al., 2010). The IL6 –174G/C polymorphism thus provides one defined genetic element that influences individual sensitivity to the health effects of an adverse social environment (i.e., a specific G × SE interaction). Several additional studies have linked the same IL6 promoter polymorphism to the risk of a variety of somatic illnesses (DeMichele et al., 2009; DeMichele et al., 2003; Finch, 2007; Fishman et al., 1998; comprehensively reviewed at OMIM, 2010; SNPedia, 2010) as well as brain-mediated affective and motivational processes (Bull et al., 2009; Collado-Hidalgo, Bower, Ganz, Irwin, & Cole, 2008). Most of these studies have been conducted in older adults, and it is unclear whether similar IL6 G × SE interactions would occur in younger individuals, or whether the functional form of such interactions might be reversed, as predicted by antagonistic pleiotropy. We focused on adolescence because it is a period when children face increased personal exposure to and involvement in the environmental stressors that are believed to interact with the IL6 gene to influence inflammation (Larson & Amussen, 1991; Steinberg, 1990). In addition, IL-6 protein levels show an age-related increase (Kiecolt-Glaser et al., 2003), so adolescents would likely show more variance in inflammatory biology than would younger children. At the same time, the period of adolescence closely follows puberty, and the theory of age-related antagonistic pleiotropy implies that the differential effects of genes at younger ages would be most evident either before or soon after the attainment of reproductive maturity (Williams, 1957). Inflammation-related G × SE interaction in adolescence could have considerable significance for later health outcomes, because individual differences in chronic inflammation emerge early in life (Juonala et al., 2006), and socioenvironmental conditions appear to affect those dynamics both concurrently (Chen et al., 2006; Chen et al., 2009; Fuligni, Telzer, Bower, Cole, et al., 2009; Fuligni, Telzer, Bower, Irwin, et al., 2009; Howe et al., 2010; Kivimaki et al., 2005) and decades later in adulthood (Danese et al., 2008; Danese, Pariante, Caspi, Taylor, & Poulton, 2007; G. E. Miller, Chen, Fok, et al., 2009; Taylor, Lehman, Kiefe, & Seeman, 2006). In addition to driving the development of chronic diseases in adulthood (Finch, 2007), inflammation may also influence affective and social processes in young adults (Dantzer, O'Connor, Freund, Johnson, & Kelley, 2008; Eisenberger, Berkman, et al., 2010; Eisenberger, Inagaki, Mashal, & Irwin, 2010; Eisenberger, Inagaki, Rameson, Mashal, & Irwin, 2009). As such, inflammation-related G × SE dynamics may functionally parallel a growing body of literature documenting developmental evolution of G × SE interactions in the context of neurobiology and behavior (Casey et al., 2009).