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Stroke is the second leading cause of death and has contributed to increasing disease burden globally. The situation is even worse in China, which had the highest estimated lifetime risk of stroke. The general populations are synchronously exposed to multiple metals existed in the natural environment. Consequently, these metals can disturb body’s metabolic functions and contribute to adverse health effects, including stroke. It is essential to explore the associations of multiple metal exposures with stroke. A recent meta-analysis of 37 studies with different design suggested that single metal exposures of arsenic, lead, and copper were associated with higher risk of cardiovascular disease (CVD). Several prospective studies have also assessed the associations between risk of CVD and single metal exposures such as Background and Purpose—Circulating metals synchronously reflect multiple metal exposures from both natural and anthropogenic sources, which may be linked with the risk of stroke. However, there is a lack of prospective studies investigating the associations of multiple metal exposures with incident stroke. Methods—We performed a nested case-control study within the ongoing Dongfeng-Tongji cohort launched in 2008. A total of 1304 incident stroke cases (1035 ischemic strokes and 269 hemorrhagic strokes) were prospectively identified by December 31, 2016, and matched to incident identity sampled controls according to age (within 1 year), sex, and blood sampling date (within 1 month). We determined the concentrations of 24 plasma metals and assessed the associations of plasma multiple metal concentrations with incident stroke using conditional logistic regression and elastic net model. Results—The average follow-up was 6.1 years. After adjusting for established risk confounders, copper, molybdenum, and titanium were significantly associated with higher risk of ischemic stroke (odds ratios according to per interquartile range increase, 1.29 [95% CI, 1.13–1.46], 1.19 [95% CI, 1.05–1.35], and 1.30 [95% CI, 1.07–1.59]), whereas rubidium and selenium were associated with lower risk of hemorrhagic stroke (odds ratios according to per interquartile range increase, 0.66 [95% CI, 0.50–0.87] and 0.68 [95% CI, 0.51–0.91]). The predictive plasma metal scores based on multiple metal exposures were significantly associated with higher risk of ischemic and hemorrhagic stroke (adjusted odds ratios according to per interquartile range increase, 1.37 [95% CI, 1.20–1.56] and 1.53 [95% CI, 1.16–2.01]). Conclusions—Plasma copper, molybdenum, and titanium were associated with higher risk of ischemic stroke, whereas plasma rubidium and selenium were associated with lower risk of hemorrhagic stroke. These findings may have important public health implications given the ever-increasing burden of stroke worldwide. (Stroke. 2019;50:1661-1668. DOI: 10.1161/STROKEAHA.119.025060.)

Response by Xiao et al to Letter Regarding Article, “Circulating Multiple Metals and Incident Stroke in Chinese Adults: The Dongfeng-Tongji Cohort”