These data show that a genetic polymorphism which interacts with adverse socioenvironmental conditions to increase health risk late in life may also provide biological resilience against adversity earlier in life. Previous analyses in older adults indicate that the IL6
–174G allele sensitizes individual physiology to the pro-inflammatory influences of adverse socioenvironmental conditions as mediated by SNS activation (Cole et al., 2010
). The present data show that the same allele can have the opposite effect during adolescence, acting to desensitize individual physiology to the pro-inflammatory effects of adverse socioenvironmental conditions and related individual stress and social role burdens. This developmental dependence of G × SE interaction is predicted by the evolutionary genetics of age-dependent antagonistic pleiotropy (Williams, 1957
) and provides a plausible explanation for why the IL6
–174G allele continues to persist in the human gene pool despite the fact that it confers a substantial risk of inflammation-related disease and mortality in old age. To the extent that the same allele also confers a benefit in protecting younger bodies from the physiologic impact of adversity through peak reproductive maturity, its selective advantage in promoting inclusive fitness may offset the later survival disadvantages associated with increased inflammation in old age (Williams, 1957
). The IL6
–174 promoter polymorphism is therefore best construed not as a uniform genetic risk factor but, rather, as a genetic sensitivity factor that alters inflammatory regulation by external environmental conditions depending on individual developmental status.
The present analyses indicate that individual-level social and psychological factors may play a key role in mediating the impact of adverse social environments on inflammatory biology. The contribution of low-SES environment to the IL6
G × SE interaction was strongly associated with the degree to which adolescents assumed adult domestic roles (e.g., household work, caregiving, parental assistance) and experienced high levels of daily interpersonal stress (e.g., social conflict, punishment, harassment). These dynamics are anticipated by previous data suggesting that adverse socioenvironmental conditions may influence immune system gene expression via changes in individual-level social behavior and psychological conditions (Chen et al., 2009
) and by data documenting age-dependent increases in the association between adverse life circumstances and circulating IL-6 levels (Kiecolt-Glaser et al., 2003
). The present results are also consistent with previous laboratory studies indicating that adversity-related activation of the stress-responsive SNS activates IL6
transcription via catecholamine stimulation of the GATA1 transcription factor (Cole et al., 2010
). Thus, the present results not only identify the functional form of IL6
G × SE antagonistic pleiotropy but they do so in a biological context in which the molecular mechanisms of those dynamics can potentially be mapped in future studies.
The consistent functional form of statistically significant IL6 G × SE interactions across three conceptually distinct measures of socioenvironmental adversity (SES, individual stress, adult role burden) suggests the presence of a reliable biological mechanism and is unlikely to recur so consistently by chance alone. However, one unanticipated difference in the detailed pattern of results involves an apparently protective effect of IL6 GC heterozygosity in mitigating the elevated inflammation associated with low SES and social stress (see and ), but not that associated with adult role burden (see ). The basis for this difference is not clear and could be a statistical consequence of limited statistical power to precisely quantify an intermediate-magnitude correlation between adversity and inflammation in the GC heterozygote group (i.e., resulting in failure of an intermediate magnitude GC relationship to reach conventional statistical significance in analyses of SES or social stress but stochastic success in the case of adult role burden). Alternatively, the assumption of adult roles in adolescence may engage some additional biological processes that interact with the IL6 promoter polymorphism in ways that are not fully shared by low SES or social stress (e.g., effects of domestic work or employment on tissue wear and tear or sleep patterns, both of which might influence inflammatory biology). The mediational analyses reported here suggest a substantial degree of shared variance among low SES, social stress, and adult role burden in their relationships to inflammatory biology, but those associations do not rule out the possibility that each factor might also entail some distinctive psychological and biological influences that impinge differently on the IL6 promoter.
Several limitations need to be considered in interpreting the present findings. These data come from a cross-sectional observational study involving a relatively small cohort of adolescents from the Los Angeles metropolitan area and thus require replication in larger and more diverse samples. Future research should seek to map development-dependent changes in the nature of G × SE interactions within a single study framework that includes both young and older adults, or longitudinally in the context of lifespan development studies tracking individual biology from youth through old age. Additional studies will also be required to clarify the biological mechanism of the IL6
promoter polymorphism's opposite effects on inflammation in adolescent versus older adults, as well as the health implications of the present G × SE interaction. One plausible molecular mechanism for the observed age-dependent reversal of G × SE functional form would involve the developmentally linked expression in young people of either a dominant negative transcription factor that competes with GATA1 for binding to IL6
–174G but does not induce IL6
transcription (Smale, 2001
) or another transcription factor besides GATA1 that preferentially binds to the IL6
–174C allele following activation by stress biology (e.g., as does the GATA1 factor in older adults). In addition to further studies clarifying the molecular basis for age-dependent antagonistic pleiotropy at the IL6
–174 locus, additional studies will also be required to determine whether that polymorphism interacts in an age-dependent manner with other types of socioenvironmental adversity previously linked to chronic inflammation (e.g., interpersonal trauma, social threat, or social isolation; Cole et al., 2007
; Danese et al., 2008
; Danese et al., 2007
; Miller et al., 2008
Strengths of the present study include the focused testing of an a priori hypothesis derived from a well-established evolutionary genetic theory and clear separation of the observed G × SE interaction from a gene–environment correlation (i.e., no evidence of a direct causal effect of IL6
polymorphism on putatively environmental risk factors such as SES, stress, or economic/domestic burden). Biological data collection during adolescence reduces the likelihood that the observed differences in chronic inflammation represent consequences of chronic disease, as opposed to effects of G × SE interaction. Another advantage involves the strong representation of Latino and low-SES adolescents in the present sample, which should enhance the generalizability of the present findings. Statistical control for ethnicity in all reported findings ensures that the genetic effects observed here cannot be attributed to population ethnic stratification (Siegmund & Yakir, 2007
), and parallel control for BMI and sex ensures that observed G × SE relationships are independent of those variables’ known relationship to inflammation. As noted previously, the parallel form of G × SE interaction across multiple measures of socioenvironmental adversity (contextual SES, subjective individual stress, and a comparatively objective measure of adult role burden) lends confidence that the observed relationships between adversity and IL6
do not represent an isolated spurious finding.
The overarching implication of this study is that G × SE influences on health are likely to vary in form as a function individual developmental stage, much as do G × SE influences on neurobiology and behavior (Casey et al., 2009
). Antagonistic pleiotropy should be routinely anticipated in contemporary genetic research, because natural selection will have eradicated most asymmetrically risky alleles while driving asymmetrically beneficial alleles to fixation (Levins, 1968
; Williams, 1957
). What genetic variation does remain in the human population likely reflects evolution's hedged bets based on the optimal biological responses to the range of environmental conditions that have proven relatively prevalent or recurrent over our history as a species. Analytic approaches that assume the continued prevalence of generally advantageous or deleterious polymorphisms would seem to be searching through the few remaining genetic crumbs not already consumed by natural selection. More success can be anticipated for discovery strategies that embrace the consequences of natural selection and presume that remaining genetic polymorphisms generally interact with prevalent dimensions of environmental variation to shape phenotypic responses. The results of this study suggest that the somatic environment of the developing body and the social environment in which it resides constitute some of the key environmental determinants that shape the impact of genetic variation on human physiology and health.