Black carbon, blood pressure, and miRNA-related SNPs (SMN) complex. GEMIN3 is a DEAD-box RNA helicase that binds directly with the SMN, and GEMIN4 is thought to play a role as cofactor in this response (Charroux et al. 2000). Together, GEMIN3 and GEMIN4 play a critical role in the processing of pre- miRNA by introducing the miRNA precursor to the RISC (Murashov et al. 2007). Along with the AGO proteins, these genes form a complex with the miRNA to create a ribonu- cleoprotein (Maniataki and Mourelatos 2005). Previously, the GEMIN3 SNP rs197414, for which we observed much lower BP among the few carriers, has been associated with higher bladder cancer rates (Yang et al. 2008). A study found that the GEMIN4 rs7813 vari- ant was associated with in vitro hepatocellular carcinoma cell line growth inhibition com- pared with the wild-type allele, suggesting that the amino acid change caused by this SNP might have physiologic significance (Wan et al. 2004). Some mechanisms of BC effects may be different for SBP and DBP. For example, other studies have observed stronger associa- tions between ambient pollutant exposures and DBP as opposed to SBP in human (Fakhri et al. 2009) and animal studies (Bartoli et al. 2009) in controlled environments. The mechanisms for these differences are not well understood. Systolic pressure rises with age; by contrast, diastolic pressure increases until around age 50 years and falls with increasing years (Burt et al. 1995). The role of SBP and DBP in predicting downstream health con- sequences remains controversial. Some recent reports have suggested that SBP should be the primary risk factor reported in older individu- als (Williams et al. 2008). However, within the Framingham Heart Study, isolated dia- stolic hypertension was a cardiovascular risk factor (Franklin et al. 2009). Subjects with this condition were found to have about two times the cardiovascular risk with normal BP, and increased cardiovascular risk among subjects with isolated diastolic hypertension was con- firmed in a multivariate-adjusted model. We previously examined genetic polymor- phisms in two specific pathways as modifi- ers of the effects of air pollution within the NAS: oxidative stress and metal process- ing. We chose these pathways because prior work suggested a) that particulate air pollu- tion generated oxidative stress, and b) that the soluble metal component of particulate air pollution was responsible for part of the effect. Specifically, we examined SNPs in genes related to oxidative stress as modifiers of the effects of particles on heart rate variability (Chahine et al. 2007), on endothelial mark- ers (Madrigano et al. 2009), and on plasma homocysteine (Ren et al. 2010). We have also examined them as modifiers of the effects of ozone on lung function (Alexeeff et al. 2007), and we have examined associations with SNPs in metal-processing genes and heart rate vari- ability (Park et al. 2006; Ren et al. 2010). Recently, we reported that polymorphisms in oxidative defense genes did not signifi- cantly modify the association of BC with BP, although there were trends in that direction (Mordukhovich et al. 2009). Taken together, these studies suggest that these pathways may be important for air pollution effects, although confirmation for other related outcomes and in other cohorts will be required. In another recent paper, we demonstrated that BC exposure is associated with epigenetic changes—specifically, a reduction in LINE-1 methylation (Baccarelli et al. 2009). miRNAs are other important epigenetic mechanisms of gene expression control. Here we explored a novel pathway, polymorphisms in genes responsible for processing miRNAs, and found evidence for effect modification of BC on BP. Again, it will be important to deter- mine whether these same polymorphisms modify effects on other end points and in other cohorts. Although we believe our findings suggest altered susceptibility to BC exposures result- ing from alterations in miRNA-processing related genotypes, we acknowledge that there are some limitations to our analysis. Despite these observations, we are not able to ascer- tain whether the polymorphisms described here modify the associations with BC because they are more susceptible to downregulation or because their basal activity makes individu- als more susceptible to downstream changes in biological function. It is possible that both mechanisms may be at work. Additionally, it is also possible that observed associations could be attributable to LD between the genotyped SNPs and some other causal variant. For each of the SNP-by-BC interactions examined, we limited our investigation to associations under a recessive model of inheritance to maximize power to detect interactions, and therefore we may have overlooked some true associations that would only be observed under other addi- tive or dominant models of inheritance. On the other hand, we also face the problem of multiple comparisons, as we examined mul- tiple SNPs in the miRNA pathway. We tested interactions with 19 SNPs in this study, and multiple testing is subject to false positives. However, whereas studies of large numbers of genes incorporate corrections for multiple testing, we did not test separate independent hypotheses. Rather, we tested consistency of the pattern of association examined and not just the significance of the most significant association for the 10 genes examined. We also acknowledge that there may be some misclassification of exposure in our analysis. Our study uses stationary measures of air pollution to represent personal exposures. Environmental Health Perspectives • volume 118 | number 7 | July 2010 Prior research indicates that when looking at longitudinal air pollution, most error is of the Berkson type. To the extent that this error is classical, simulation studies have shown that it is highly unlikely to bias away from the even in the presence of covariates. This indi- cates that this exposure misclassification may lead to an underestimation of the health effects of air pollution (Zeger et al. 2000). In addi- tion, several studies, including one conducted in the greater Boston area, have found that lon- gitudinal measures of ambient particulate con- centrations are representative of longitudinal variation in personal exposures (Rojas-Bracho et al. 2000). BC concentrations are spatially heterogeneous because of the numerous local (mobile) sources. Therefore, measurement error in our BC exposure metric would likely attenuate the true association. Given that we found significant positive associations for BC, it is unlikely that this error would affect our conclusions. Our study population is homog- enous, consisting entirely of elderly men, and we have restricted our analysis to white indi- viduals. The median distance of the participant homes from the central site monitoring station was 17.6 km. However, our findings are con- sistent with studies of particulate air pollution conducted in more heterogeneous populations. Conclusions We have used a pathway approach to investi- gate how the processing of miRNAs may be a susceptibility factor for traffic particle–induced cardiovascular effects. Individual miRNAs may have multiple targets; more research is needed to address the relation between BC exposure and BP among diverse study populations and to clarify the mechanisms underlying the asso- ciation between BC and BP. These results pro- vide support for the hypothesis of the toxic effects of traffic pollution as measured by BC and contribute to growing understand- ing about the role of epigenetic modification and response to environmental stresses such as exposure to BC. In cardiovascular research, these results may be used to explore inter- actions with BC. Further investigations are needed to replicate our findings in other large cohort studies. Ref Rencs Alexeeff SE, Litonjua AA, Suh H, Sparrow D, Vokonas PS, Schwartz J. 2007. Ozone exposure and lung function: effect modified by obesity and airways hyperresponsiveness in the VA Normative Aging Study. Chest 132(6):1890–1897. Asada S, Takahashi T, Isodono K, Adachi A, Imoto H, Ogata T, et al. 2008. Downregulation of Dicer expression by serum withdrawal sensitizes human endothelial cells to apoptosis. Am J Physiol Heart Circ Physiol 295(6):H2512–H2521. Auchincloss AH, Roux AV, Dvonch JT, Brown PL, Barr RG, Daviglus ML, et al. 2008. Associations between recent exposure to ambient fine particulate matter and blood pressure in the multi-ethnic study of atherosclerosis (MESA). Environ Health Perspect 116:486–491. Baccarelli A, Wright RO, Bollati V, Tarantini L, Litonjua AA, Suh HH, et al. 2009. Rapid DNA methylation changes after 947