Modifying Effects of the HFE Polymorphisms on the Association between Lead Burden and Cognitive Decline

BACKGROUND: As iron and lead promote oxidative damage, and hemochromatosis (HFE) gene polymorphisms increase body iron burden, HFE variant alleles may modify the lead burden and cognitive decline relationship. OBJECTIVE: Our goal was to assess the modifying effects of HFE variants on the lead burden and cognitive decline relation in older adults. METHODS: We measured tibia and patella lead using K-X-ray fluorescence (1991–1999) among participants of the Normative Aging Study, a longitudinal study of community-dwelling men from greater Boston. We assessed cognitive function with the Mini-Mental State Examination (MMSE) twice (1993–1998 and 1995–2000) and genotyped participants for HFE polymorphisms. We estimated the adjusted mean differences in lead-associated annual cognitive decline across HFE genotype groups (n = 358). RESULTS: Higher tibia lead was associated with steeper cognitive decline among participants with at least one HFE variant allele compared with men with only wild-type alleles (p interaction = 0.03), such that a 15 μg/g increase in tibia lead was associated with a 0.2 point annual decrement in MMSE score among HFE variant allele carriers. This difference in scores among men with at least one variant allele was comparable to the difference in baseline MMSE scores that we observed among men who were 4 years apart in age. Moreover, the deleterious association between tibia lead and cognitive decline appeared progressively worse in participants with increasingly more copies of HFE variant alleles (p-trend = 0.008). Results for patella lead were similar. CONCLUSION: Our findings suggest that HFE polymorphisms greatly enhance susceptibility to lead-related cognitive impairment in a pattern consistent with allelelic dose.