Modifying effects of the HFE polymorphisms on the association between lead burden and cognitive decline.In the United States United States, officially United States of America, republic (2005 est. pop. 295,734,000), 3,539,227 sq mi (9,166,598 sq km), North America. The United States is the world's third largest country in population and the fourth largest country in area. the population of persons age 65 years and older is projected to increase 2-fold to 75 million in the next 30 years, and a concomitant upsurge in the number of individuals with dementia is expected (U.S. Census Bureau Noun 1. Census Bureau - the bureau of the Commerce Department responsible for taking the census; provides demographic information and analyses about the population of the United States Bureau of the Census 2000a, 2000b). Cognitive decline, a risk factor for dementia, may be a transition stage spanning normal cognition and onset of diseases associated with dementia (Bischkopf et al. 2002; Burns and Zaudig 2002; Pratico et al. 2002). Lead has long been recognized as a neurotoxicant; the associations between lead and cognitive impairment among workers in leadrelated industries and poorer cognitive development in children have been well reproduced (Barth et al. 2002; Bleecker et al. 1997; Lanphear et al. 2000). The few studies that have been conducted among low-level leadexposed older adults have generally reported inverse associations between lead burden and cognitive function cognitive function Neurology Any mental process that involves symbolic operations–eg, perception, memory, creation of imagery, and thinking; CFs encompasses awareness and capacity for judgment (Muldoon et al. 1996; Nordberg et al. 2000; Payton et al. 1998; Weisskopf et al. 2004; Wright et al. 2003). With half-life estimates ranging from 5 to 20 years for cortical bone cortical bone n. See cortical substance. , and more than 1 year for trabecular bone trabecular bone n. See spongy bone. (Hu et al. 1998; Kim et al. 1997), lead levels in bone may better reflect long-term body burden of lead than blood lead, which has a half-life of approximately 30 days (Hu 2001). In addition, bone lead measures correlate well with measures of cumulative external lead levels and integrated blood lead levels, two commonly used indices of cumulative lead exposure (Bleecker et al. 1997). Iron metabolism may play a critical role in neurodegenerative processes (Lee et al. 2006; Todorich and Connor 2004). Although iron is vital for cellular processes, plasma iron which is not bound to transferrin transferrin /trans·fer·rin/ (-fer´in) a glycoprotein mainly produced in the liver, binding and transporting iron, closely related to the apoferritin of the intestinal mucosa. trans·fer·rin n. may be toxic. This nontransferrin-bound iron represents the portion of body iron likely to cause cellular oxidative damage, a purported mechanism in the pathogenesis of neurodegenerative diseases neurodegenerative diseases diseases characterized by neurodegeneration. Lesions are microscopic only but in chronic disease with massive involvement there may be grossly visible atrophy of affected nervous tissue. , and serve as a catalyst in the neuronal production of free radicals (Eaton and Qian 2002; Samson and Nelson 2000). Two variants in the hemochromatosis Hemochromatosis Definition Hemochromatosis is an inherited blood disorder that causes the body to retain excessive amounts of iron. This iron overload can lead to serious health consequences, most notably cirrhosis of the liver. (HFE HFE Hemochromatosis HFE Human Factors Engineering HFE Human Factors in Electronics HFE Hydrofluoroether (cleaning solvent) HFE Hope For Europe HFE Horizontal Fiscal Equalisation HFE Heat Flow Experiment HFE Forward Current Gain ) gene, C282Y and H63D, are commonly found in the U.S. population, especially among whites, and are associated with hereditary hemochromatosis, a disease of iron overload Iron overload A side effect of frequent blood transfusions in which the body accumulates abnormally high levels of iron. Iron deposits can form in organs, particularly the heart, and cause life-threatening damage. . Several recent studies have reported an association between these HFE polymorphisms and neurodegenerative diseases such as Alzheimer disease Alzheimer disease Degenerative brain disorder. It occurs in middle to late adult life, destroying neurons and connections in the cerebral cortex and resulting in significant loss of brain mass. (Berlin et al. 2004; Moalem et al. 2000; Sampietro et al. 2001). Furthermore, carriers of these polymorphisms who do not have clinical signs of iron overload are observed to have higher levels of nontransferrin-bound iron in addition to body iron measures higher than wild-types (Adams et al. 2005; Beutler et al. 2003; Datz et al. 1998; de Valk et al. 2000; Garry et al. 1997). These studies have led to a growing interest in the interaction of iron and lead metabolism in the process of neurodegeneration. As HFE variant alleles are associated with neurodegenerative processes similar to those seen in lead toxicity, and the presence of iron enhances the oxidative effects of lead (Adonaylo and Oteiza 1999), HFE variant alleles may magnify mag·ni·fy v. To increase the apparent size of, especially with a lens. the neurologic damage caused by lead. Therefore, we examined the modifying effect of the HFE alleles on the association between body lead burden and change in performance on the Mini-Mental State Examination The mini-mental state examination (MMSE) or Folstein test is a brief 30-point questionnaire test that is used to assess cognition. It is commonly used in medicine to screen for dementia. (MMSE MMSE Mini Mental State Examination MMSE Minimum Mean Squared Error MMSE Mini-Mental Status Examination MMSE Multiuse Mission Support Equipment MMSE Multimission Support Equipment MMSE Multi Media Service Environment ), a test of global cognitive function, in a cohort of older, community-dwelling men. Materials and Methods Participants in the current study were drawn from the Normative Aging Study (NAS (1) See network access server. (2) (Network Attached Storage) A specialized file server that connects to the network. A NAS device contains a slimmed-down operating system and a file system and processes only I/O requests by supporting the popular ), a community-based, prospective cohort study A cohort study is a form of longitudinal study used in medicine and social science. It is one type of study design. In medicine, it is usually undertaken to obtain evidence to try to refute the existence of a suspected association between cause and disease; failure to refute initiated in 1963 at the Veterans Affairs Veterans Affairs is a term of the business that deals with the relation between a government and its veteran communities, usually administered by the designated government agency. (VA) Outpatient Clinic in Boston to examine factors related to healthy aging (Bell et al. 1972). The cohort consisted of 2,280 men 21-81 years of age at the time of enrollment (1963-1968) who had successfully completed a screening process to ensure participants were free of known chronic medical conditions See carpal tunnel syndrome, computer vision syndrome, dry eyes and deep vein thrombosis. . Most cohort members were of northern European descent. Overall, their smoking and alcohol consumption patterns were similar to men of comparable age in the U.S. population. Every 3-5 years, study participants were asked to undergo extensive evaluations including medical and physical examinations and laboratory tests. They also completed questionnaires on smoking history, diet, and other factors potentially related to aging and health. To date, the annual attrition due to all causes has been less than 1%, and more than 80% have responded to mailed questionnaires supplementing on-site examinations (Hu et al. 1996). This study has been approved by the Human Subjects Committees of the Boston VA Medical Center, the Brigham and Women's Hospital Brigham and Women's Hospital (BWH) is a hospital in the Longwood Area of the Boston, Massachusetts neighborhood of Mission Hill. With Massachusetts General Hospital, it is one of the two founding members of Partners HealthCare. , and the Harvard School of Public Health The Harvard School of Public Health is (colloquially, HSPH) is one of the professional graduate schools of Harvard University. Located in Longwood Area of the Boston, Massachusetts neighborhood of Mission Hill, next to Harvard Medical School and Cambridge, Massachusetts, . Study population. Beginning in 1991, bone lead measurements were taken using K-X-ray fluorescence (KXRF) among active participants who gave written informed consent. In 1993, cognitive function assessments were initiated. At the time of the present study, 1,055 study participants had completed at least one cognitive assessment; whereas 540 men had two or more assessments. The first and second cognitive assessments were on average 3.2 years apart. Of the men with two cognitive measures, 420 had at least one bone lead measurement. In 2000, NAS participants (n = 730) were genotyped for two HFE polymorphisms based on archived blood samples. In all, our analyses included the 358 men with at least two cognitive assessments, complete covariate information, HFE genotyping data, and at least one measure of bone lead. Bone lead KXRF measurement. In vivo in vivo /in vi·vo/ (ve´vo) [L.] within the living body. in vi·vo adj. Within a living organism. in vivo adv. bone measurements were taken using a K-X-ray fluorescence (KXRF) instrument (ABIOMED, Inc., Danvers, MA) at the midtibia (shin bone) and the patella patella (pətĕl`ə): see kneecap. (knee cap bone) (Aro et al. 2000). The sites were chosen to be representative of the two predominant bone types: cortical bone (tibia tibia: see leg. ) and trabecular bone (patella). These measurements had units of micrograms of lead per gram bone mineral. The bone measurement taken closest in time to the baseline cognitive assessment served as a proxy for tissue lead burden. The instrument also provides an estimate of the uncertainty for each measurement equivalent to the standard deviation In statistics, the average amount a number varies from the average number in a series of numbers. (statistics) standard deviation - (SD) A measure of the range of values in a set of numbers. of repeated measurements. Lead estimates with uncertainty values]>] tibia and > 15 [micro]g/g for patella were excluded as unreliable, a standard protocol in analyses of bone lead (Hu et al. 1998). Negative estimates of bone lead concentrations may occur for lead values close to zero. As recoding Noun 1. recoding - converting from one code to another coding, steganography, cryptography, secret writing - act of writing in code or cipher the negative values to the minimum detectable limit may induce bias and reduce efficiency in the statistical analyses, KXRF-measured bone lead concentration estimates were used in the analysis without recoding (Kim et al. 1997). HFE genotyping. We genotyped participants for both the C282Y and H63D polymorphisms of the HFE gene (GenBank accession no. Z92910; http://www.ncbi.nlm. nih.gov/sites/entrez) using archived blood. Puregene DNA DNA: see nucleic acid. DNA or deoxyribonucleic acid One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. isolation kits (Gentra Systems, Inc., Minneapolis, MN) were used to extract the DNA from the blood sample. The H63D polymorphism polymorphism, of minerals, property of crystallizing in two or more distinct forms. Calcium carbonate is dimorphous (two forms), crystallizing as calcite or aragonite. Titanium dioxide is trimorphous; its three forms are brookite, anatase (or octahedrite), and rutile. was genotyped by polymerase chain reaction polymerase chain reaction (pŏl`ĭmərās') (PCR), laboratory process in which a particular DNA segment from a mixture of DNA chains is rapidly replicated, producing a large, readily analyzed sample of a piece of DNA; the process is (PCR PCR polymerase chain reaction. PCR abbr. polymerase chain reaction Polymerase chain reaction (PCR) ) followed by restriction fragment length polymorphism restriction fragment length polymorphism n. Abbr. RFLP Intraspecies variations in the length of DNA fragments generated by the action of restriction enzymes and caused by mutations that alter the sites at which these enzymes act, changing (RFLP RFLP abbr. restriction fragment length polymorphism RFLP restriction fragment length polymorphism. RFLP ) analysis as previously described (Cardoso et al. 1998; Wright et al. 2004). Similarly, the C282Y polymorphism was genotyped by separate PCR and RFLP procedures (Cardoso et al. 1998; Feder et al. 1996). As a quality control measure, 10% of samples were randomly selected and run in duplicate. Genotypes were also determined on control blood known to be from persons homozygous ho·mo·zy·gous adj. Having the same alleles at one or more gene loci on homologous chromosome segments. Homozygous Identical genes controlling a specified inherited trait. for the wild-type genotype and heterozygous het·er·o·zy·gous adj. 1. Having different alleles at one or more corresponding chromosomal loci. 2. Of or relating to a heterozygote. and homozygous for each HFE variant genotype. The full data set was anonymized after genotyping to protect our study members and to conform to Verb 1. conform to - satisfy a condition or restriction; "Does this paper meet the requirements for the degree?" fit, meet coordinate - be co-ordinated; "These activities coordinate well" current Institutional Review Board policies. Assessment of cognitive function. One of the tests included in the cognitive assessment battery was the MMSE, a global examination of cognitive function that assesses orientation, immediate and short-term recall, verbal and written skills, and attention and ability to follow commands (Crum et al. 1993; Folstein et al. 1975). The test is commonly used in epidemiologic studies to evaluate cognitive status (Farmer et al. 1995; Izaks et al. 1995; Knopman et al. 2003). Scores range from 0 to 30, with higher score denoting better cognitive performance, although in our analysis the highest possible score was 29 because of deletion of the question "What county are we in?" from our tally. Other studies have reported that most Massachusetts residents do not know in which county they reside as counties in Massachusetts This is a list of Massachusetts counties, consisting of the 14 Massachusetts counties. Massachusetts has abolished seven of its fourteen county governments, leaving five counties with county-level local government and two, Nantucket County and Suffolk County, with combined do not have strong governmental function (Tombaugh and McIntyre 1992). Statistical analysis. Because of small sample sizes in some strata of HFE genotypes, we classified HFE genotypes in two different manners: binary [wild-type (having only HFE wild-type alleles), any HFE variant allele allele (əlēl`): see genetics. allele Any one of two or more alternative forms of a gene that may occur alternatively at a given site on a chromosome. ]; and dose (wild-type, one HFE variant allele, two HFE variant alleles). Our measure of change in cognition was the average annual rate of decline in MMSE score, defined as (MMSE score at second visit - MMSE score at baseline visit)/(years between assessments), for each participant. We analyzed lead levels in tibia and patella separately. To assess effect modification effect modification Epidemiology An interaction among multiple possible cause-and-effect relationships, where the estimate of the effect of one factor on a disease process depends on other factors in the study , we fitted multiple linear regression Linear regression A statistical technique for fitting a straight line to a set of data points. models of average annual rate of decline in MMSE score, in which we included a term for the lead biomarker, indicator variables for the HFE genotype classification, and cross-product terms between HFE genotype and lead biomarker, along with terms for age, years of education, smoking status (current, never, past), pack-years smoked, nondrinker, alcohol consumption (grams/day), English as first language (yes, no), computer experience (yes, no) and diabetes (diagnosis or fasting glucose fasting glucose Fasting blood sugar, fasting plasma glucose Endocrinology Glucose obtained from a Pt who has had nothing–except water by mouth for 8+ hrs; FG is used in evaluating Pts for possible DM Ref range 65-115 mg/dL non-diabetic; 110-140 mg/dL, [less than] 126 mg/dL). Values of covariates used in the analyses were those reported at the baseline MMSE assessment. Stroke and Alzheimer disease predict MMSE score, but as so few men in our study population had such conditions, these conditions were not considered in our analyses. We assessed the linearity of the association between lead and annual rate of cognitive decline within class of HFE genotype by fitting a penalized pe·nal·ize tr.v. pe·nal·ized, pe·nal·iz·ing, pe·nal·iz·es 1. To subject to a penalty, especially for infringement of a law or official regulation. See Synonyms at punish. 2. spline In computer graphics, a smooth curve that runs through a series of given points. The term is often used to refer to any curve, because long before computers, a spline was a flat, pliable strip of wood or metal that was bent into a desired shape for drawing curves on paper. See Bezier and B-spline. for the lead biomarker and adjusting for covariates using the generalized additive models function in R software (http://www.r-project. org/). A penalized spline is a technique for flexibly modeling dose-response by dividing the range of exposure into intervals, and fitting a separate cubic polynomial polynomial, mathematical expression which is a finite sum, each term being a constant times a product of one or more variables raised to powers. With only one variable the general form of a polynomial is a0xn+a within each interval. A penalty term is added to the log likelihood that is proportional to how "wiggly" the resulting dose-response curve dose-response curve A graphic representation of the effects that varous doses of an agent–eg, ionizing radiation or a chemotherapeutic agent, have on a given parameter–eg, cell viability, mutation frequency, DNA damage, tumor growth or metastasis or is, which prevents excessive nonlinearity (Wood and Augustin 2002). The optimal degree of smoothing was determined by the generalized cross-validation criterion, which is, in practice, an approximation of Akaike's information criterion There are a number of statistics that can act as an information criterion. They include:
To assess whether participants with C282Y and H63D alleles have different leadassociated cognitive changes, we also conducted exploratory analyses to evaluate the association of lead on cognitive decline by HFE genotype groups (e.g., wild-type, H63D homozygotes, C282Y heterozygotes). Finally, to assess the robustness of our results, we first restricted our analyses to white participants, then repeated the analyses after removing outliers identified by the generalized extreme studentized deviation (ESD (1) (Electronic Software Distribution) Distributing new software and upgrades via the network rather than individual installations on each machine. See ESL. ) method (Rosner 1983). All statistical analyses were conducted using SAS (1) (SAS Institute Inc., Cary, NC, www.sas.com) A software company that specializes in data warehousing and decision support software based on the SAS System. Founded in 1976, SAS is one of the world's largest privately held software companies. See SAS System. (version 8.2; SAS Inc., Cary, NC) and R version 2.1.1. We used partial F-tests and likelihood ratio tests for statistical hypothesis testing One may be faced with the problem of making a definite decision with respect to an uncertain hypothesis which is known only through its observable consequences. A statistical hypothesis test, or more briefly, hypothesis test . The p-value of significance was < 0.05 Results Median concentrations of bone lead in our study population were 19 and 23 [micro]g/g for tibia and patella, respectively. Participants who were younger, more educated, native English speakers, or who had computer experience on average had lower bone lead levels (Table 1). Bone lead concentrations were slightly higher among men with lower baseline cognitive scores. Thirty-six percent of men had at least one HFE variant allele. Both genotype distributions conformed to Hardy-Weinberg expected frequencies (C282Y: [[chi].sup.2] =0.53, p = 0.47; H63D: [[chi].sup.2] =0.18, p = 0.67). Nine participants in our population were heterozygous for both C282Y and H63D polymorphisms (known as compound heterozygotes Compound heterozygotes Individuals who have one gene in a pair with one mutation and the other gene in the pair has a different mutation. Mentioned in: Pyruvate Kinase Deficiency ). Although bone lead levels appeared higher in the four participants who were C282Y homozygotes, these measures were not significantly different than the bone lead levels among wild-types. Characteristics of men with only HFE wildtype alleles were similar to those of variant allele carriers with the exception of report of computer experience (Table 2). Compared with men in the larger NAS cohort who had only one MMSE score, men in our study population had similar average baseline MMSE scores and only slightly lower mean bone lead levels (data not shown). The distribution of HFE genotypes was also similar in these two groups. Men with and without bone lead measures had similar baseline characteristics, distribution of HFE genotypes, and MMSE scores (data not shown). The average annual rate of decline in MMSE scores was modestly though not significantly worse among HFE variant allele carriers than among men with only HFE wild-type alleles {difference in annual rate of change: -1.77 points/year [95% confidence interval confidence interval, n a statistical device used to determine the range within which an acceptable datum would fall. Confidence intervals are usually expressed in percentages, typically 95% or 99%. (CI), -3.88 to 0.35]}, results not shown). Higher tibia lead was associated with a steeper decline in MMSE scores among participants with at least one HFE variant allele compared with wild-types (p = 0.03; Table 3, model 1). Among participants with any HFE variant allele, an interquartile range In descriptive statistics, the interquartile range (IQR), also called the midspread, middle fifty and middle of the #s, is a measure of statistical dispersion, being equal to the difference between the third and first quartiles. (IQR IQR Interquartile Range (statistics) IQR Internet Quick Reference IQR Individual Qualification Record IQR Internal Quality Review ) increment in tibia lead (15 [micro]g/g) was associated with a 0.22-point annual decrement To subtract a number from another number. Decrementing a counter means to subtract 1 or some other number from its current value. in MMSE score (95% CI, -0.39 to -0.05). This annual change in MMSE score among variant allele carriers was approximately equivalent to the difference in baseline MMSE scores between men in our study population who were 4 years apart in age. In contrast, although tibia lead level was associated with decline in MMSE score among wild-types as well, this association was smaller in magnitude and not statistically significant. We used covariateadjusted penalized splines to explore the linearity of the association between tibia lead level and change in MMSE score by HFE genotype, as shown in Figure 1. Even though the association of lead burden with cognitive decline among men with only HFE wild-type alleles appeared linear (optimal degree of smoothing: 1, p = 0.72), the association appeared curvilinear curvilinear a line appearing as a curve; nonlinear. curvilinear regression see curvilinear regression. , specifically, steeper with greater lead burden in the variant allele carriers. The test for deviation from linearity for the tibia lead-cognitive change association among the variant allele carriers was nearly significant (optimal degree of smoothing: 1.68, p = 0.08), suggesting that, among variant allele carriers, a unit increase in lead burden may be associated with disproportionately greater cognitive decline at high lead burden than at low lead burden.
Table 1. Baseline characteristics of study participants ( n= 358)
by bone lead measures [median [mu]g/g (IQR)].
Tibia lead Patella lead
Age (years)
< 65 15 (9-20) 18 (13-27.5)
65-70 20 (14-28) 25 (17-34)
[less than or equal to] 71 25 (18-35) 28 (17-52)
Education
Never finished high school 30 (14-36) 33.5 (23-46)
High school graduate 21 (14-29) 27 (16-44)
Some college 19 (13-28) 25 (15-37)
College graduate 17 (11-22) 19 (13-29)
Smoking status
Never 17 (11-27) 21.5 (13-33)
Former 20 (14-29) 24 (16-36)
Current 19 (13.5-23.5) 27 (15-34)
Alcohol consumption
Yes 19 (13-26) 23 (15-35)
No 20 (12.5-30) 24 (17-36)
History of diabetes (a)
Yes 23 (14-35) 27 (17-38)
No 19 (13-27) 23 (15-35)
English as first language
Yes 19 (12-27) 22.5 (15-34)
No 24 (15-30) 27 (17-39)
Computer experience
Yes 15 (10-22) 20 (13.5-30)
No 21 (14-30) 26 (16-39)
Baseline MMSE scoreb
< 26 20.5 (13-30) 26.5 (15-39)
26-27 21 (13.5-27.5) 24 (15-38)
[less than or equal to] 28 16 (11-22.5) 21 (15-31)
HFE genotype
Wild-type (n = 228) 19 (13-29) 24 (15-37)
One or more HFE variant alleles 19.5 (12-26) 22 (14-34)
H63D heterozygotes (n = 69) 20.5 (11.5-25.5) 22 (14-33)
H63D homozygotes (n = 8) 17 (12.5-27) 23.5 (13-34)
C282Y heterozygotes (n = 40) 17 (13-21) 22 (14-34)
C282Y homozygotes (n = 4) 32.5 (21-39) 39 (16-61.5)
Compound heterozygotes (n = 15 (11-20) 21 (12-27)
9) (C282Y and H63D alleles)
IQR, interquartile range.
(a) History of diabetes defined as having reported diagnosis of
diabetes or having fasting glucose above 126 mg/dL. bHighest
possible MMSE score in our analysis was 29 because of deletion
of the question "What county are we in?"
Table 2. Baseline characteristics of participants by HFEgenotype
(n = 358).
HFE wild-type HFE variant
(n = 228) allele (n = 130)
Age [median years (IQR)] 67.2 (62.6-71.8) 67.7 [63.7-71.3]
Education [n (%)]
Never finished high school 19 (8.3) 9 (6.9)
High school graduate 64 (28.1) 36 (27.7)
Some college 64 (28.1) 33 (25.4)
College graduate 81 (35.5) 52 (40.0)
Smoking status [n (%)] (a)
Never 76 (33.3) 46 (35.4)
Former 138 (60.5) 81 (62.3)
Current 14 (6.1) 3 (2.3)
Alcohol consumption [median 5.8 (0.4-18.7) 6.0 (0-16.7)
g/day (IQR)]
History of diabetes (b) [n 24 (10.5) 13 (10.0)
(%)]
English as first language [n 199 (87.3) 118 (90.8)
(%)]
Computer experience [n (%)] 87 (38.2) 65 (50.0)
Patella lead [median [mu]g/g 24 (15, 37) 22 (14, 34)
(IQR)]
Tibia lead [median [mu]g/g 19.0 (13, 29) 19.5 (12, 26)
(IQR)]
Baseline MMSE score [median 27 (25, 28) 27 (26, 28)
(IQR)] (c)
IQR, interquartile range.
(a) Percentages may not add up to 100 because of rounding.
(b) History of diabetes defined as having reported diagnosis of diabetes
or having fasting glucose above 126 mg/dL. cHighest possible MMSE
score in our analysis was 29 because of deletion of the question
"What county are we in?"
Interestingly, the detrimental association between tibia lead and decline in MMSE was progressively larger with increasing number of HFE variant alleles: each IQR increment in tibia lead was associated with a -0.02-point/year change in MMSE score among wild-types, -0.14-point/year change among men with one HFE variant allele, and -0.63 point/year change among men with two HFE variant alleles (p < 0.01, Table 3, model 2). The pronounced difference in lead-associated cognitive decline between men with two variant alleles and men with only wild-type alleles was significant (p < 0.01, Table 3, model 2). This difference in change in MMSE scores among participants with two HFE variant alleles was comparable to the difference in baseline MMSE scores that we observed among men who were 11 years apart in age. We also examined the modification of the lead association with annual change in MMSE score by HFE genotype groups. The magnitudes of effect modification among H63D heterozygotes and C282Y heterozygotes were very similar to the magnitude of effect modification among one variant allele carriers. Similarly, the results for H63D homozygotes and C282Y homozygotes were similar to the results for two variant allele carriers (results not shown). Overall, the associations pertaining to patella lead were similar to although smaller in magnitude than those pertaining to tibia lead (results not shown). Results from analyses in which we excluded extreme values of bone lead were also similar, as were results in analyses in which we restricted the study population to whites (results not shown). Discussion In our population of older men, the deleterious association between long-term lead burden and rate of decline in cognitive function was significantly worse among HFE variant allele carriers than among wild-types. Furthermore, the detrimental association of lead with cognitive decline was magnified among participants with a greater number of either variant alleles (H63D or C282Y ); the largest drop in MMSE scores associated with lead burden was observed in men carrying two variant alleles. Of note, the magnitude of effect modification was linked to number and not to type of HFE variant alleles. Our study is the first to provide evidence that the neurodegenerative effects of these variants during aging may be in part due to genetic susceptibility to non-iron metals such as lead. Several studies have addressed cognitive function among adults who experienced chronic low-level lead exposure (Muldoon et al. 1996; Weisskopf et al. 2004; Wright et al. 2003). Among the studies that used bone lead measures, tibia lead was more strongly associated with cognitive decline than were patella and blood leads (Payton et al. 1998; Weisskopf et al. 2004), suggesting that lead in tibia serves as a superior proxy for effective lead dose in the brain. As lead in the tibia has a substantially longer half-life than lead in the patella or blood (Hu 1998), these results indicate that long-term, chronic lead exposure may be more predictive of cognitive changes. Interestingly, the strongest interaction between lead and HFE variant alleles in our study was also observed with tibia lead measures. We are not aware of any other study that has evaluated the modifying effect of the HFE genotype on the association between lead and change in cognitive function. The HFE protein appears to regulate metal transport across cell membranes (Chung and Wessling-Resnick 2003), although its role in transporting iron and non-iron divalent divalent /di·va·lent/ (di-va´lent) bivalent; carrying a valence of two. di·va·lent adj. Bivalent. di·va metals across the blood brain barrier is unknown. Two common polymorphisms in the HFE gene, the C282Y and the H63D, have been implicated im·pli·cate tr.v. im·pli·cat·ed, im·pli·cat·ing, im·pli·cates 1. To involve or connect intimately or incriminatingly: evidence that implicates others in the plot. 2. in hereditary hemochromatosis, a disease associated with excess iron absorption (Feder et al. 1996; Hanson et al. 2001). In addition, persons who carry the HFE variant alleles but who lack clinical signs of hemochromatosis disease are reported to have significantly higher values of serum iron, transferrin saturation, and nontransferrin- bound iron than individuals with only HFE wild-type alleles (Beutler et al. 2003; Datz et al. 1998; Garry et al. 1997; Moura et al. 1998). HFE polymorphisms have also been reported to affect lead uptake (Bannon et al. 2003; Barton et al. 1994; Onalaja and Claudio 2000; Wright et al. 2004). In our analysis, men who were homozygous for C282Y appeared to have higher bone lead burden than men with other HFE genotypes, although we were not able to detect a statistically significant difference with our small sample size of C282Y homozygotes. This subject matter merits further examination in larger study populations. Although the relationship between HFE alleles and neurodegenerative diseases is not fully established, several recent studies have found positive associations between HFE variant alleles and Alzheimer disease. Researchers have reported the C282Y and H63D polymorphisms to be significantly more prevalent in subjects with Alzheimer disease compared with controls, and that persons with Alzheimer disease and HFE variant alleles were on average 6 years younger at the time of diagnosis than individuals with Alzheimer disease but with only the wild-type alleles (Moalem et al. 2000; Pulliam et al. 2003; Sampietro et al. 2001). Another study also observed earlier age of onset The age of onset is a medical term referring to the age at which an individual acquires, develops, or first experiences a condition or symptoms of a disease or disorder. Diseases are often categorized by their ages of onset as congenital, infantile, juvenile, or adult. of Alzheimer disease but only among H63D homozygotes (Berlin et al. 2004). In contrast, others have found no association between HFE alleles and Alzheimer disease (Berlin et al. 2004; Guerreiro et al. 2006). The discrepancies across studies may reflect that HFE polymorphisms do not independently impart cognitive risk but instead enhance the neurotoxicity neurotoxicity /neu·ro·tox·ic·i·ty/ (noor?o-tok-sis´it-e) the quality of exerting a destructive or poisonous effect upon nerve tissue. of agents such as lead. Interestingly, although the C282Y and H63D functional polymorphisms may differentially alter iron and divalent metal metabolism (Bomford 2002; Lyon and Frank 2001; Townsend and Drakesmith 2002), we observed these two polymorphisms to have comparable magnitudes of effect modification on the relation between lead and cognitive decline.
Table 3. Association with an interquartile (15 [mu]g/g) increase in
tibia lead biomarkers on change in MMSE score by class of HFEgenotype.
Model/class of HFE genotype Unadjusted mean difference in annual
rate of change in MMSE (95% CI)
Model 1: binary
Wild-type -0.02 (-0.10 to 0.05)
Any HFE variant allele -0.23 (-0.40 to -0.07)
Model 2: dose
Wild-type -0.02 (-0.10 to 0.05)
One HFE variant allele -0.15 (-0.33 to 0.03)
Two HFE variant alleles -0.62 (-1.03 to -0.22)
Model/class of HFE Adjusted (a) mean p-Value p-Value
genotype difference in annual interaction trend
rate of change of
MMSE (95% CI)
Model 1: binary 0.03 (b) NA
Wild-type -0.02 (-0.10 to
0.07)
Any HFE variant -0.22 (-0.39 to
allele -0.05)
Model 2: dose < 0.01 (c) < 0.01
Wild-type -0.02 (-0.10 to
0.07)
One HFE variant -0.14 (-0.33 to
allele 0.04)
Two HFE variant -0.63 (-1.04 to
alleles -0.21)
NA, not applicable.
(a) Adjusted for age, years of education, nonsmoker, former smoker,
pack-years, nondrinker, alcohol consumption, English as first language,
computer experience, and diabetes.
(b) p-Value for tibia lead and any HFE variant allele interaction.
(c)p-Value for tibia lead and two HFEvariant alleles interaction.
It is not known how the HFE variant alleles may accelerate cognitive decline in the presence of lead. Lead and free iron are independently capable of promoting oxidative damage, a purported mechanism in the pathogenesis of neurodegenerative disease Neurodegenerative disease A disease in which the nervous system progressively and irreversibly deteriorates. Mentioned in: Amnesia (Jellinger 1999; Jenner 1993; Samson and Nelson 2000; Winterbourn 1995). In vitro in vitro /in vi·tro/ (in ve´tro) [L.] within a glass; observable in a test tube; in an artificial environment. in vi·tro adj. In an artificial environment outside a living organism. studies have suggested synergistic oxidative effects between lead and iron; lead appears to increase lipid oxidation in the presence of iron (Adonaylo and Oteiza 1999). Therefore, our findings may reflect the complex relationship between iron and lead metabolism where the metals interact to further increase damage and, consequently, cognitive decline. Unfortunately, we were not able to measure body iron status or magnitude of oxidative stress oxidative stress, n an imbalance of the prooxidant antioxidant ratio in which too few antioxidants are produced or ingested or too many oxidizing agents are produced. for our study population. Our current findings are an interesting juxtaposition to our previous report in which HFE variant alleles were associated with lower levels of internal lead dose biomarkers in the same cohort (Wright et al. 2004). If the HFE variant alleles affect cognition predominantly by lowering lead accumulation in the body tissues, one might expect the variant alleles to be associated with better cognitive performance. Instead, we found a suggestive association between HFE variant alleles and poorer cognitive function that is consistent with the prior reports linking HFE variant alleles to neurodegeneration. In addition, because the HFE variant alleles are not known to affect the relation of lead levels in tibia to lead levels in the brain, one would anticipate similar magnitudes of change in MMSE scores per unit increase in body lead burden among wild-types compared with variant allele carriers. Our data suggest quite the opposite, indicating that HFE variant alleles augment the toxicity of lead that is absorbed. There were several limitations to this study. Although the associations observed were significant, it is essential to attempt to reproduce such associations in larger populations. The mean interval between the two cognitive tests was 3.2 years. With a longer interval between testing or with additional MMSE assessments, we may be able to better describe the relationship between lead and cognitive changes by HFE genotype. As with any aging cohort, there was a potential for selection bias mainly because of differential attrition and survival. We were somewhat reassured, as the lead biomarker levels and first MMSE scores in persons who had completed only baseline cognitive assessment were similar to those found in our study population. The frequencies of HFE genotypes were also similar in the two groups. Moreover, baseline characteristics and MMSE scores did not differ in men with and without bone lead measures. The potential for misclassification should be considered. Although there may have been some measurement error in our bone lead data, such errors would most likely be nondifferential, and thus, bias our association estimates toward the null. It is possible that the modifying effects observed were caused by other polymorphisms in the HFE gene or polymorphisms in a proximal gene that is in tight linkage disequilibrium linkage disequilibrium n. The nonrandom association between two or more alleles such that certain combinations of alleles are more likely to occur together on a chromosome than other combinations of alleles. with these HFE polymorphisms, although we believe this is unlikely, as we did not find other genes known to regulate iron metabolism in this genomic region. As in any observational study, confounding confounding when the effects of two, or more, processes on results cannot be separated, the results are said to be confounded, a cause of bias in disease studies. confounding factor is a concern. We accounted for known strong predictors of cognitive function. As only one participant had suffered a stroke and none had been diagnosed with Alzheimer disease, we did not adjust for these factors in our final model. Of the men in our study population, 99% were white, making population stratification an unlikely confounder. Overall, crude and adjusted comparisons of MMSE change were similar, suggesting that strong confounding from an unmeasured source is unlikely. The MMSE is widely used to screen for dementia and has frequently been used to assess cognitive status and track longitudinal changes in cognitive function (Farmer et al. 1995; Izaks et al. 1995; Knopman et al. 2003). However, it is a relatively easy test for which a learning effect has been reported (Jacqmin-Gadda et al. 1997). A low degree of variability in MMSE scores among more highly educated persons is often observed (Crum et al. 1993). Therefore, the MMSE may have had low sensitivity in detecting cognitive impairment in our participants. Despite these limitations, the MMSE is among the most extensively characterized and most widely used tests of cognitive status for older adults, and performs with a reasonable degree of reproducibility and validity. Past studies have found high correlations between MMSE scores and scores on other well-described cognitive tests, such as the Blessed Information-Memory-Concentration test and reasonable sensitivity and specificity in delineating individuals with and without dementia (Crum et al. 1993; Stuss et al. 1996; Tombaugh and McIntyre 1992). Finally, persons with mild cognitive impairment mild cognitive impairment (MCI), n memory loss generally associated with aging; does not affect normal independent functioning of an individual. are found to have significantly worse MMSE scores than cognitively normal individuals (Bennett et al. 2002). Although we were not yet able to assess development of dementia in our population, cognitive decline is a strong predictor of subsequent dementia. Cognitively impaired individuals have a 10-15% annual risk of developing dementia compared with a 1-2% annual risk among healthy controls (Bischkopf et al. 2002; Knopman et al. 2003; Morris et al. 2001). Cognitive impairment has also been associated with a 3.1-to 5-fold increase in risk of developing Alzheimer disease, the most common cause of age-related dementia (Tuokko et al. 2003). Our findings suggest that cumulative lead exposure may be particularly detrimental to the cognitive well-being of HFE variant allele carriers as they age. Given the high prevalence of variant allele carriers in North American North American named after North America. North American blastomycosis see North American blastomycosis. North American cattle tick see boophilusannulatus. and European populations and the long retention of lead in the body, our results indicate that lead-related cognitive impairment experienced by a large subset of older adults is likely more substantial than currently recognized. Although these early cognitive changes may have slight consequences on many affected individuals, these small decrements pose a major public health concern, translating into a much larger proportion of older individuals who are considered clinically impaired, a societal burden that is projected to grow substantially, given that older persons make up one of the fastest growing segments of our population (U.S. Census Bureau 2000a, 2000b). Our findings provide insight on the mechanisms and pathways of cognitive decline. As there is currently no cure for dementia, elucidating the biological mechanisms may facilitate the development of preventive measures and treatments to hinder the rate of cognitive decline. As longterm chronic lead exposure appears to be most detrimental to cognitive health in the later years, our findings stress the continued importance of public health interventions aimed at reducing occupational and environmental exposure to lead in younger populations including lead abatement efforts and lead exposure prevention programs. In summary, we have found the HFE polymorphisms to significantly modify the association between lead burden and the rate of cognitive decline. Persons with more copies of HFE variant alleles experienced greater cognitive decline per unit increase in bone lead biomarker level. REFERENCES Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD, et al. 2005. Hemochromatosis and ironoverload screening in a racially diverse population. N Engl J Med 352:1769-1778. Adonaylo VN, Oteiza PI. 1999. Pb2+ promotes lipid oxidation and alterations in membrane physical properties. Toxicology 132:19-32. 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It is miscible with cold water and is soluble in alcohol and ether. : the Fenton reaction. Toxicol Lett 82-83:969-974. Wood SN, Augustin NH. 2002. GAMs with integrated model selection using penalized regression splines and applications to environmental modelling. Ecolog Modelling 157:157-177. Wright RO, Tsaih SW, Schwartz J, Spiro A III, McDonald K, Weiss ST, et al. 2003. Lead exposure biomarkers and mini-mental status exam Mini-Mental Status Exam MMSE of Folstein Psychometric testing A screening mental status tests; a perfect score on the Folstein is 30; a score < 17 corresponds to probable dementia. scores in older men. Epidemiology 14:713-718. Wright RO, Silverman EK, Schwartz J, Tsaih SW, Senter J, Sparrow D, et al. 2004. Association between hemochromatosis genotype and lead exposure among elderly men: the Normative Aging Study. Environ Health Perspect 112:746-750. Address correspondence to F. Wang, i3 Drug Safety, 950 Winter St., Suite 3800, Waltham, MA 02451 USA. Telephone: (781) 472-8667. Fax: (781) 472-8464. E-mail: Florence.Wang@i3drugsafety.com This work was supported in part by the Cognition and Health in Aging Men Project (CHAMP) and the VA Normative Aging Study (NAS). CHAMP is supported by the Research Services of the U.S. Department of Veterans Affairs, the National Institutes of Health (NIH; AA08941, AG13006, AG14345, AG18436, ES05947, ES05257), and the U.S. Department of Agriculture, Agricultural Research Service (contract 53-K06-510). VA NAS is supported by the Cooperative Studies Program/ERIC, U.S. Department of Veterans Affairs, and is a research component of the Massachusetts Veterans Epidemiology Research and Information Center. F.T.W was supported by NIH grants CCT CCT Circuit CCT Commission Canadienne du Tourisme (Canadian Tourism Commission) CCT Correlated Color Temperature CCT Common Customs Tariff (EU) CCT Certificate of Completion of Training 110421 and ES007155. The authors declare they have no competing financial interests. Received 25 October 2006; accepted 10 May 2007. Florence T. Wang, (1) Howard Hu, (1) (2) (3) Joel Schwartz, (1) (4) Jennifer Weuve, Avron S. Spiro III, (5), (6) David Sparrow, (5) (7) Huiling Nie, (1) (3) Edwin K. Silverman, (3) Scott T. Weiss, (1) (3) and Robert O. Wright (1), (3), (8) (1) Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA; (2) Department of Environmental Health Sciences, University of Michigan (body, education) University of Michigan - A large cosmopolitan university in the Midwest USA. Over 50000 students are enrolled at the University of Michigan's three campuses. The students come from 50 states and over 100 foreign countries. School of Public Health, Ann Arbor, Michigan  “Ann Arbor” redirects here. For other uses, see Ann Arbor (disambiguation). Ann Arbor is a city in the U.S. state of Michigan and the county seat of Washtenaw County. , USA; (3) Channing Laboratory, Brigham and Women's Hospital, Boston, Massachusetts, USA; (4) Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA; (5)VA Boston Healthcare System The VA Boston Healthcare System is a set of hospitals run by the United States Department of Veterans Affairs in the Greater Boston area. It comprises nine campuses, with three major medical centers in Jamaica Plain, West Roxbury, and Brockton. , Boston, Massachusetts, USA; (6) Department of Epidemiology, Boston University School of Public Health Boston University School of Public Health (BUSPH) is Boston University's graduate School of Public Health. It is located in the heart of Boston University's Medical Campus in the South End neighborhood of Boston, Massachusetts. The Dean is Robert Meenan. , Boston, Massachusetts, USA; (7) Department of Medicine, Boston University School of Medicine Boston University School of Medicine (BUSM) is one of the graduate schools of Boston University. It is an American medical school located in the South End neighborhood of Boston, Massachusetts. , Boston, Massachusetts, USA; (8) Department of Medicine, Children's Hospital Boston Children's Hospital Boston is a children's hospital located in the Longwood Medical and Academic Area of Boston, Massachusetts. Located at 300 Longwood Avenue, Children's is adjacent both to its teaching affiliate, Harvard Medical School, and to Dana-Farber Cancer Institute. , Boston, Massachusetts, USA |
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