DETERMINANTS OF INTERINDIVIDUAL VARIABILITY IN ARSENIC SECONDARY METHYLATION EFFICIENCY IN A POPULATION FROM NORTHWEST MEXICO

Persistent Link:
http://hdl.handle.net/10150/203433
Title:
DETERMINANTS OF INTERINDIVIDUAL VARIABILITY IN ARSENIC SECONDARY METHYLATION EFFICIENCY IN A POPULATION FROM NORTHWEST MEXICO
Author:
Gomez Rubio, Paulina
Issue Date:
2011
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Chronic environmental exposure to inorganic arsenic is widely associated with human disease. Low human arsenic secondary methylation efficiency (SME), represented by high urinary monomethylarsonic acid (%uMMA) and low urinary dimethylarsinic acid to monomethylarsonic acid ratio (uDMA/uMMA), has been consistently associated with increased risk of arsenic-related diseases. Therefore the determination of factors modulating arsenic SME acquires particular importance. The aims of the present study are to identify novel factors of variability in arsenic secondary methylation, and to test for potential factors influencing arsenic SME for which there is equivocal literature support. A population of 808 subjects was recruited from northwest Mexico environmentally exposed to arsenic. The mean total urinary arsenic in the population was 171 μg/L. Great interindividual variability in %uMMA excretion was observed (0.85% - 40.5%). Three intronic polymorphisms in arsenic (3+ oxidation state) methyltransferase (AS3MT), the key gene in the metabolism of arsenic, were confirmed to be associated with increased arsenic SME in this study. Further analysis of this genomic region showed a large block of linkage disequilibrium (LD) comprising these three genetic variants and other 43 intronic polymorphisms within AS3MT and four additional genes. Genetic association analysis showed that all linked polymorphisms in this region except one were significantly associated with higher arsenic SME. The existence of this long region of LD associated with arsenic SME underscores the complexity of association studies involving any of these linked polymorphisms since there is no certainty of which polymorphism or gene is the causative of the association. In addition, a strong positive association between body mass index (BMI) and arsenic SME was observed in females but not in males. This association was replicated in two independently recruited populations of adult women. Moreover a unique finding of this study is the association between higher genetically estimated indigenous American (AME) ancestry and increased arsenic SME in this ancestrally admixed Mexican population. These results establish the importance of genetic and phenotypic factors in the efficiency of arsenic secondary methylation. Furthermore this study has identified several arsenic-associated risk factors that should be carefully considered in future studies seeking to better understand disease susceptibility in arsenic-exposed populations.
Type:
text; Electronic Dissertation
Keywords:
AS3MT; BMI; methylation; MMA; Pharmacology & Toxicology; Ancestry; Arsenic
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Pharmacology & Toxicology
Degree Grantor:
University of Arizona
Advisor:
Klimecki, Walter T.

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleDETERMINANTS OF INTERINDIVIDUAL VARIABILITY IN ARSENIC SECONDARY METHYLATION EFFICIENCY IN A POPULATION FROM NORTHWEST MEXICOen_US
dc.creatorGomez Rubio, Paulinaen_US
dc.contributor.authorGomez Rubio, Paulinaen_US
dc.date.issued2011-
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractChronic environmental exposure to inorganic arsenic is widely associated with human disease. Low human arsenic secondary methylation efficiency (SME), represented by high urinary monomethylarsonic acid (%uMMA) and low urinary dimethylarsinic acid to monomethylarsonic acid ratio (uDMA/uMMA), has been consistently associated with increased risk of arsenic-related diseases. Therefore the determination of factors modulating arsenic SME acquires particular importance. The aims of the present study are to identify novel factors of variability in arsenic secondary methylation, and to test for potential factors influencing arsenic SME for which there is equivocal literature support. A population of 808 subjects was recruited from northwest Mexico environmentally exposed to arsenic. The mean total urinary arsenic in the population was 171 μg/L. Great interindividual variability in %uMMA excretion was observed (0.85% - 40.5%). Three intronic polymorphisms in arsenic (3+ oxidation state) methyltransferase (AS3MT), the key gene in the metabolism of arsenic, were confirmed to be associated with increased arsenic SME in this study. Further analysis of this genomic region showed a large block of linkage disequilibrium (LD) comprising these three genetic variants and other 43 intronic polymorphisms within AS3MT and four additional genes. Genetic association analysis showed that all linked polymorphisms in this region except one were significantly associated with higher arsenic SME. The existence of this long region of LD associated with arsenic SME underscores the complexity of association studies involving any of these linked polymorphisms since there is no certainty of which polymorphism or gene is the causative of the association. In addition, a strong positive association between body mass index (BMI) and arsenic SME was observed in females but not in males. This association was replicated in two independently recruited populations of adult women. Moreover a unique finding of this study is the association between higher genetically estimated indigenous American (AME) ancestry and increased arsenic SME in this ancestrally admixed Mexican population. These results establish the importance of genetic and phenotypic factors in the efficiency of arsenic secondary methylation. Furthermore this study has identified several arsenic-associated risk factors that should be carefully considered in future studies seeking to better understand disease susceptibility in arsenic-exposed populations.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectAS3MTen_US
dc.subjectBMIen_US
dc.subjectmethylationen_US
dc.subjectMMAen_US
dc.subjectPharmacology & Toxicologyen_US
dc.subjectAncestryen_US
dc.subjectArsenicen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePharmacology & Toxicologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorKlimecki, Walter T.en_US
dc.contributor.committeememberFutscher, Bernard W.en_US
dc.contributor.committeememberGandolfi, A. Jayen_US
dc.contributor.committeememberLantz, Clark C.en_US
dc.contributor.committeememberSmith, Catharineen_US
dc.contributor.committeememberKlimecki, Walter T.en_US
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