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 microg/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.


CONCLUSIONS
Our findings suggest that HFE polymorphisms greatly enhance susceptibility to lead-related cognitive impairment in a pattern consistent with allelelic dose.
Wang
Florence T
FT
Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA. Florence.Wang@i3drugsafety.com
Hu
Howard
H
Schwartz
Joel
J
Weuve
Jennifer
J
Spiro
Avron S
AS
Sparrow
David
D
Nie
Huiling
H
Silverman
Edwin K
EK
Weiss
Scott T
ST
Wright
Robert O
RO
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D015415:Biomarkers / Q000032:analysis; D001900:Boston / Q000453:epidemiology; D003072:Cognition Disorders / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D004785:Environmental Pollutants / Q000032:analysis*; D005838:Genotype; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007854:Lead / Q000032:analysis*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D010329:Patella / Q000737:chemistry*; D011110:Polymorphism, Genetic; D011569:Psychiatric Status Rating Scales; D013977:Tibia / Q000737:chemistry*
D015415:Biomarkers; D004785:Environmental Pollutants; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D007854:Lead