Iron Metabolism Genes, Low-Level Lead Exposure, and QT Interval Sung Kyun Park,1 Howard Hu,1,2,3 Robert O. Wright,1,2,3 Joel Schwartz,2,3 Yawen Cheng,4 David Sparrow,5 Pantel S. Vokonas,5 and Marc G. Weisskopf2 1Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan, USA; 2Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA; 3Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; 4College of Public Health, National Taiwan University, Taipei, Taiwan; 5VA Normative Aging Study, Veterans Affairs Boston Healthcare System, and the Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA Abstract Background: Cumulative exposure to lead has been shown to be associated with depression of electrocardiographic conduction, such as QT interval (time from start of the Q wave to end of the T wave) . Because iron can enhance the oxidative effects of lead, we examined whether polymorphisms in iron metabolism genes [hemochromatosis (HFE) , transferrin (TF) C2, and heme oxygenase-1 (HMOX-1) ] increase susceptibility to the effects of lead on QT interval in 613 community-dwelling older men. Methods: We used standard 12-lead electrocardiograms, K-shell X-ray fluorescence, and graphite furnace atomic absorption spectrometry to measure QT interval, bone lead, and blood lead levels, respectively. Results: A one-interquartile-range increase in tibia lead level (13 µg/g) was associated with a 11.35‑msec [95% confidence interval (CI) , 4.05–18.65 msec] and a 6.81-msec (95% CI, 1.67–11.95 msec) increase in the heart-rate–corrected QT interval among persons carrying long HMOX-1 alleles and at least one copy of an HFE variant, respectively, but had no effect in persons with short and middle HMOX-1 alleles and the wild-type HFE genotype. The lengthening of the heart-rate–corrected QT interval with higher tibia lead and blood lead became more pronounced as the total number (0 vs. 1 vs. ≥ 2) of gene variants increased (tibia, p-trend = 0.01 ; blood, p-trend = 0.04) . This synergy seems to be driven by a joint effect between HFE variant and HMOX-1 L alleles. Conclusion: We found evidence that gene variants related to iron metabolism increase the impacts of low-level lead exposure on the prolonged QT interval. This is the first such report, so these results should be interpreted cautiously and need to be independently verified. Key words: gene–environment interaction, heme oxygenase-1, hemochromatosis, iron, lead, transferrin. Environ Health Perspect 117:80–85 (2009) . doi:10.1289/ehp.11559 available via http://dx.doi.org/ [Online 22 August 2008] Address correspondence to S.K. Park, SPH II-M6240, Department of Environmental Health Sciences, University of Michigan School of Public Health, 109 S. Observatory St., Ann Arbor, MI 48109 USA. Telephone: (734) 936-1719. Fax: (734) 763-8095. E-mail: sungkyun@umich.edu We thank B. Mukherjee for statistical assistance in the false-positive report probability. This research was supported primarily by National Institute of Environmental Health Sciences grants R01-ES05257, R01-ES07821, P42-ES05947, K23-ES00381, and K01-ES012653. The VA Normative Aging Study is supported by the Cooperative Studies Program/Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center. The authors declare they have no competing financial interests. Received 8 April 2008 ; accepted 22 August 2008. The full version of this article is available for free in HTML or PDF formats. |