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Apolipoprotein E Genotype Predicts 24-Month Bayley Scales Infant Development Score

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Apolipoprotein E Genotype Predicts 24-Month Bayley Scales Infant Development Score 0031-3998/03/5406-0819 PEDIATRIC RESEARCH Vol. 54, No. 6, 2003 Copyright © 2003 International Pediatric Research Foundation, Inc. Printed in U.S.A. Apolipoprotein E Genotype Predicts 24-Month Bayley Scales Infant Development Score ROBERT O. WRIGHT, HOWARD HU, EDWIN K. SILVERMAN, SHIRNG W. TSAIH, JOEL SCHWARTZ, DAVID BELLINGER, EDUARDO PALAZUELOS, SCOTT T. WEISS, AND MAURICIO HERNANDEZ-AVILA Departments of Pediatrics [R.O.W.] and Neurology [D.B.], Children’s Hospital Boston, Boston, Massachusetts 02115, U.S.A.; The Channing Laboratory [R.O.W., H.H., E.K.S., S.W.T., J.S., S.T.W.], Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, U.S.A.; Department of Environmental Health [R.O.W., H.H., S.W.T., J.S.], Harvard School of Public Health, Boston, Massachusetts 02115, U.S.A.; American British Cowdray Hospital [E.P.], 18901 México City, México; and Instituto Nacional de Salud Pública [E.P., M.H.-A.], Instituto Nacional de Perinatologia, 62508 Mexico City, Centro de Investigacion en Salud, Poblacional, National Institute of Public Health Mexico, 62508 Cuernavaca, México ABSTRACT Apolipoprotein E (APOE) regulates cholesterol and fatty acid confidence interval: 0.1-8.7; p ϭ 0.04) higher 24-mo MDI. In the metabolism, and may mediate synaptogenesis during neurode- stratified regression models, the negative effects for umbilical velopment. To our knowledge, the effects of APOE4 isoforms on cord blood lead level on 24-mo MDI score was approximately infant development have not been studied. This study was nested 4-fold greater among APOE3/APOE2 carriers than among within a cohort of mother-infant pairs living in and around APOE4 carriers. These results suggest that subjects with the E4 Mexico City. A multiple linear regression model was constructed isoform of APOE may have advantages over those with the E2 or using the 24-mo Mental Development Index (MDI) of the Bayley E3 isoforms with respect to early life neuronal/brain Scale as the primary outcome and infant APOE genotype as the development. (Pediatr Res 54: 819–825, 2003) primary risk factor of interest. Regression models stratified on APOE genotype were constructed to explore effect modification. Of 311 subjects, 53 (17%) carried at least one copy of the Abbreviations APOE4 allele. Mean (SD) MDI scores among carriers with at APOE, apolipoprotein E gene least one copy of APOE4 were 94.1 (14.3) and among E3/E2 ApoE, apolipoprotein E protein carriers were 91.2 (14.0). After adjustment for covariates, MDI, Mental Development Index APOE4 carrier status was associated with a 4.4 point (95% BSID, Bayley Scales of Infant Development Apolipoprotein E (ApoE, protein; APOE, gene) is an intra- is taken up by neurons via various ApoE receptors and incor- cellular cholesterol and fatty acid transport protein that plays porated into cell membrane structures and myelin (4, 5). The an important role in neuronal metabolism. The gene for this metabolism of cholesterol is believed to play a major role in protein has been localized on chromosome 19, and there are neurite outgrowth and synaptogenesis (1–3), processes that are three common alleles—E2, E3, and E4—which differ only on critical to neurodevelopment. Although the APOE4 isoform the basis of one or two amino acids on positions 112 and 158 has been demonstrated to be an important risk factor for (1, 2). ApoE is unique among lipoproteins in that it is involved neurodegeneration, the role of ApoE genetic variants in neu- in the recovery response of injured nerve tissue (3). In the rodevelopment is also becoming increasingly apparent (6–8). brain, ApoE is synthesized by astrocytes and secreted into the In conjunction with our understanding of the role of choles- extracellular space, where it then binds to cholesterol. There it terol and ApoE in neurodevelopment is an increasing recogni- tion that genetic factors that alter the host response to environ- Received November 8, 2002; accepted May 26, 2003. mental toxins may be particularly important during critical Correspondence: Robert O. Wright, MD, MPH, Division of Emergency Medicine, developmental windows that occur during fetal life (9, 10). Children’s Hospital, Boston, 300 Longwood Avenue, Boston, MA 02115, U.S.A.; email: Because cholesterol and fatty acids are critical to brain devel- [email protected] Supported in part by grants from the National Institute of Environmental Health opment, genetic factors that regulate their metabolism may Sciences: K23 ES 00381 and R01 ES 007821 influence development independently or may serve as modifi- DOI: 10.1203/01.PDR.0000090927.53818.DE ers of the response to maternal diet or maternal exposure to 819 820 WRIGHT ET AL. neurotoxins. Genetic susceptibility may account for a large Bayley Scales of Infant Development-II (BSID-II; Spanish proportion of the variance in response to environmental toxins, version). All participating mothers received a detailed expla- such as lead. Because ApoE is critical to synaptogenesis nation of the study and its procedures, as well as counseling on processes involved in brain development, this raises the ques- how to reduce environmental lead exposure. tion of whether genetic variants of APOE may also be associ- Blood lead measurements. Umbilical cord blood samples ated with differential effects on neurodevelopment. Given this were collected in trace metal-free tubes at delivery. Blood background, we studied the role of APOE genotypes on infant samples were analyzed using an atomic absorption spectrom- development and explored interactions between APOE geno- etry instrument (Perkin-Elmer 3000, Chelmsford, MA, USA) types and fetal exposure to the neurotoxin lead. at the metals laboratory of the American British Cowdray Hospital in Mexico City. External blinded quality-control sam- METHODS ples were provided throughout the study period by the Mater- nal and Child Health Bureau and the Wisconsin State Labora- Study population. The study protocol was approved by the tory of Hygiene Cooperative Blood Lead Proficiency Testing Human Subjects Committees of the National Institute of Public Program. These analyses demonstrated acceptable precision Health of Mexico, the participating hospitals, the Brigham and and accuracy with a correlation coefficient of 0.99 and a mean Women’s Hospital, and the Harvard School of Public Health difference of 0.17 ␮g/dL (SD ϭ 0.68). The detection limit for and was conducted under an established interinstitutional col- this assay is 1 ␮g/dL. laboration among Harvard University, the Center for Popula- Measurements of child development and potential con- tion Health Research of the National Institute of Public Health founders. The BSID-II is a revision and restandardization of in Mexico, the American British Cowdray Medical Center, and the BSID, one of the most widely used tests of infant devel- the National Institute of Perinatology of Mexico. The study opment. Scores have been shown to be sensitive to a variety of cohort was recruited from three maternity hospitals in Mexico prenatal, perinatal, and postnatal insults, including lead expo- City (Mexican Social Security Institute, Manuel Gea Gonzalez sure (11–14). A Spanish version of the BSID (BSID-IIS) was Hospital, and National Institute of Perinatology) and was developed by our research group before this study. The team designed to determine the effects of calcium supplementation administering the BSID-IIS was led and trained by Dr. Bell- during lactation on infant lead kinetics and neurodevelopment. inger, with standardization and quality control checks con- We have previously reported the effect of maternal bone lead in ducted through reviews of videotaped interviews. Mental De- predicting infant development in this cohort (11). velopment Index (MDI) scores at 24 mo of age were used as Between 1994 and 1995, 1382 women were found to be the primary outcome measure. eligible for the trial. Exclusion criteria included no intention to Maternal IQ, an important potential confounder, was as- breast-feed; factors that would interfere with data collection, sessed using the Vocabulary and Block Design components of such as living outside Mexico City; and conditions related to the Wechsler Adult Intelligence Score, which has been trans- calcium metabolism and requirements, such as multiple fe- lated into Spanish and used in Mexico. Of the 424 subjects tuses, preeclampsia, or pregnancy-related hypertensive disor- with archived blood, 311 returned for a 24-mo BSID ders or cardiac disease, gestational diabetes, history of repeated assessment. urinary infections, history of kidney stone formation, seizure Genotyping. Although each subject had signed an approved disorder requiring daily medications, and ingestion of cortico- consent form signifying willingness to have blood archived for steroids. Also excluded from the study were premature neo- unspecified future testing, we took additional steps to protect nates (Ͻ37 wk) and newborns with birth weight Ͻ2000 g. the confidentiality of the APOE genotype data. To protect the Baseline information on health status and social and demo- subjects from any undue consequences that the results might graphic characteristics as well as written consent were obtained have with respect to employment or health coverage, we from all 1382 eligible participating mothers. One month post- created a new data file for the cohort, anonymized and kept partum, potential participants attended our research center. Of separate from the master data file. Data on all exposure vari- the 1382 initially eligible mother-infant pairs, 617 (44.6%) ables and covariates of interest were downloaded into this file, agreed to participate in the trial. For the purposes of this as were the APOE genotype data. All subject identifiers were analysis, 424 infants had archived blood available for geno- then deleted from the new anonymous file, and the APOE typing. This study was conducted in these 424 infants. genotype data were deleted from the master file. The genotyp- Anthropometric data from the mother and the newborn and ing and anonymization procedures were approved by the Hu- umbilical cord and maternal venous blood samples were gath- man Subjects Committee of Brigham and Women’s Hospital.
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