Blood lead levels, iron metabolism gene polymorphisms and homocysteine: a gene-environment interaction study.

Abstract

Homocysteine has been causally associated with various adverse health outcomes. Evidence supporting the relationship between lead and homocysteine levels has been accumulating, but most prior studies have not focused on the interaction with genetic polymorphisms. From a community-based prospective cohort, we analysed 386 participants (aged 41-71 years) with information regarding blood lead and plasma homocysteine levels. Blood lead levels were measured between 2001 and 2003, and plasma homocysteine levels were measured in 2007. Interactions of lead levels with 42 genotyped single-nucleotide polymorphisms (SNPs) in five genes (<i>TF</i>, <i>HFE</i>, <i>CBS</i>, <i>BHMT</i> and <i>MTR</i>) were assessed via a 2-degree of freedom (df) joint test and a 1-df interaction test. In secondary analyses using imputation, we further assessed 58 imputed SNPs in the <i>TF</i> and <i>MTHFR</i> genes. Blood lead concentrations were positively associated with plasma homocysteine levels (p=0.0276). Six SNPs in the <i>TF</i> and <i>MTR</i> genes were screened using the 2-df joint test, and among them, three SNPs in the <i>TF</i> gene showed interactions with lead with respect to homocysteine levels through the 1-df interaction test (p<0.0083). Seven SNPs in the <i>MTHFR</i> gene were associated with homocysteine levels at an α-level of 0.05, but the associations did not persist after Bonferroni correction. These SNPs did not show interactions with lead levels. Blood lead levels were positively associated with plasma homocysteine levels measured 4-6 years later, and three SNPs in the <i>TF</i> gene modified the association.