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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.