Coronary heart disease (CHD) is the leading cause of mortality and disability worldwide, and accounts for 13% of global deaths and 370,000 deaths annually in the US. Accumulating evidence suggests exposure to inorganic arsenic (As) and other (often co-occurring) toxic metals may be an independent risk factor for CHD. Although most individuals are simultaneously exposed to different metals, most studies focused on the toxicity of individual metals. Combinations of exposures may have different, and possibly stronger, effects than each exposure separately. However, there were no large epidemiologic studies on either the effects of metal mixtures (specific combinations of metals) or metal–metal interactions on CHD risk. Moreover, the inadequacy of data on genetic susceptibility masks the effects of environmental exposures. Conversely, genetic studies often ignore that effects of genetic factors on CHD are modulated by varying levels of environmental factors. Data on gene–metal interactions can identify population subgroups with much higher disease risks. However, the few studies focused on gene–metal interactions in CHD had limited sample sizes (n = ~200), tested a single exposure only, considered only <200 genetic variants in <20 genes, and included homogenous study populations with a limited range of exposure to assess full dose–response relationship. Several genome-wide interaction studies (GWIS) on cardiovascular traits identified genetic markers not previously reported by genome-wide association studies. However, no GWIS has investigated gene–metal interactions in CHD. While studies on gene–metal interactions are critical to provide insights into disease biology, metabolomics—the systematic analysis of low molecular weight metabolites in response to external exposures—offers another approach to elucidate mechanisms by which metal mixtures may lead to CHD. However, no studies investigated the interplay of metal mixtures and metabolomics profiles in CHD risk. We propose to: 1) evaluate the roles of metals and metal mixtures in CHD risk; 2) assess genetic susceptibility to the effects of metals and metal mixtures on the risk of CHD; and 3) identify the potential urinary metabolites associated with both CHD risk and metals/metal mixtures. We will leverage data and samples from three prospective cohorts—the Health Effects of Arsenic Longitudinal Study (HEALS), the Strong Heart Family Study (SHFS), and the Multi-Ethnic Study of Atherosclerosis (MESA)—that include diverse adult populations. We anticipate our results will show that metal mixtures and genetic susceptibility both contribute to CHD risk . They may also increase knowledge of potential underlying mechanisms (altered urinary metabolites or genetic pathways) by which metals and metal mixtures promote CHD. Supporting studies of combined exposures or mixtures is one of the goals of the NIEHS Strategic Plan 2018–2023 to advance environmental health sciences. This project will address an important public health issue and clinical topic with the potential to provide evidence on the biological mechanism of metal mixture toxicity on CHD development and can improve clinical understanding for prevention and controlling exposures in the US and abroad.

Project narrative This project aims to 1) evaluate the role of metals and metal mixtures in the risk of coronary heart disease (CHD); 2) to assess the genetic susceptibility to the effect of metals and metal mixtures on the risk of CHD; and 3) to identify the potential urinary metabolites that are associated with both CHD risk and metals/metal mixtures. We will pool data from three prospective cohorts consisting of diverse populations. This study can provide insight into the relationship between metal exposures and CHD risk, with implications for preventing and controlling exposures in the US and abroad.