The paraoxonase gene family consists of three members (PON1, PON2, and PON3) with both distinct and overlapping roles in human health. These enzymes influence oxidative stress, inflammation, and bacterial infections, along with a large number of diseases and disorders, such as atherosclerosis. The wide-reaching effects of the PON gene family make them an important and highly advantageous subject of study. Their ability to be modified by diet, lifestyle, and environmental exposures, as well as various polymorphisms and genetic influences, provide for a complex, highly modifiable internal form of individual protection. The overall goal of this project was to determine what factors affect individual variations in paraoxonase activity, as well as the influence of individual PON members on health and exposure outcomes. The initial study in this project provided the first data about intra-individual PON1 variations over a time of about 15 years, showing levels remain relatively stable in an agricultural population. This study also contributed data regarding the polymorphic distributions of influential PON SNPs and the influence of lifestyle factors on PON1 activity. The use of a twin population for the next study allowed for examination of the heritability of PON1 activity and antioxidant capacity, and provided novel data regarding the influence of genetic variations on PON1 activity. To further attempt to eliminate the complexity of influences on these genes and individual polymorphisms, the third study in this project characterized an innovative transgenic Drosophila melanogaster model with the goal of analyzing the influence of individual PON family members on exposure and disease outcomes without the effects of compensation from other PONs. By further elucidating the effects of the PONs at the individual level, human populations will be able to be advised regarding the most at-risk individuals and modifiable changes to improve PON levels, and therefore overall health.

A família paraoxonase (PON1, PON2 e PON3) tem sido objeto de grande interesse por prevenir o estresse oxidativo e o processo inflamatório, condições importantes na carcinogênese. O Linfoma Difuso de Grandes Células B (LDGCB) consiste no subtipo histológico mais comum dentre os linfomas, doenças que se originam a partir das células do tecido linfoide e exibem distintos comportamentos clínicos, fatores patológicos e características epidemiológicas. Há escassez de dados sobre a atuação das paraoxonases na susceptibilidade diferencial ao risco de linfomas. Deste modo, o objetivo do presente estudo foi investigar a frequência alélica e genotípica dos polimorfismos 192QR e 55LM, no gene da PON1, e 148AG e 311SC, no gene da PON2 e o efeito desses polimorfismos sobre as atividades da enzima PON e perfil lipídico em 182 indivíduos (78 pacientes com LDGCB e 104 indivíduos saudáveis). O sangue foi coletado, em 4 momentos, para a determinação do perfil lipídico e das atividades arilesterase e paraoxonase da PON. O DNA foi extraído de leucócitos do sangue periférico pelo método de extração salina. A análise dos polimorfismos foi realizada por PCR/RFLP. Não houve diferença estatística na distribuição de genótipos e frequência de alelos dos polimorfismos nos genes da PON1 e PON2. A atividade sérica da arilesterase apresentou valores significativamente maiores apenas entre os indivíduos saudáveis (p=0,001). As variantes 55MM e 192QQ, do gene da PON1, influenciaram as atividades arilesterase (p=0,011) e paraoxonase (0,001). O polimorfismo PON2 311SS associou-se a atividade arilesterase (p=0,021). A concentração de autoanticorpos oxLDL foi alterada, pela presença do genótipo 55LM (p=0,037) nos indivíduos com LDGCB / The paraoxonase family (PON1, PON2 and PON3) have been the subject of great interest, since they are responsible for preventing oxidative stress and inflammation, conditions important in carcinogenesis. The Diffuse Large B Cell Lymphoma (DLBCL) is the most common histological subtype among lymphomas, diseases that originate from cells of the lymphoid tissue and exhibit clinically distinct behaviors and pathological and epidemiological factors. There are paucity of data on the activity of paraoxonase in the differential susceptibility to the risk of lymphoma. Thus, the objective of this study was to investigate the genotypic and allelic frequency of polymorphisms 192QR and 55LM, in the PON1 gene and 148AG and 311SC, in the PON2 gene and the effect of these polymorphisms on PON enzyme activities and lipid profile in 182 subjects (78 patients with DLBCL and 104 healthy subjects). Blood was collected in four moments for the determination of lipid profile and paraoxonase and arylesterase activities of PON. The DNA was extracted from peripheral blood leukocytes by salt extraction method. The analysis of polymorphisms was performed by PCR/RFLP. There was no statistical difference in the distribution of genotypes and allele frequencies of polymorphisms in the PON1 and PON2 genes. The serum arylesterase activity was significantly higher only among healthy subjects (p=0.001). 192QQ and 55MM variants of the PON1 gene, influenced arylesterase (p=0.011) and paraoxonase (0.001) activities. The PON2 polymorphism was associated with 311SS arylesterase activity (p = 0.021). The concentration of oxLDL autoantibodies was altered by the presence of 55LM genotype (p = 0.037) in patients with DLBCL

A família paraoxonase (PON1, PON2 e PON3) tem sido objeto de grande interesse por prevenir o estresse oxidativo e o processo inflamatório, condições importantes na carcinogênese. O Linfoma Difuso de Grandes Células B (LDGCB) consiste no subtipo histológico mais comum dentre os linfomas, doenças que se originam a partir das células do tecido linfoide e exibem distintos comportamentos clínicos, fatores patológicos e características epidemiológicas. Há escassez de dados sobre a atuação das paraoxonases na susceptibilidade diferencial ao risco de linfomas. Deste modo, o objetivo do presente estudo foi investigar a frequência alélica e genotípica dos polimorfismos 192QR e 55LM, no gene da PON1, e 148AG e 311SC, no gene da PON2 e o efeito desses polimorfismos sobre as atividades da enzima PON e perfil lipídico em 182 indivíduos (78 pacientes com LDGCB e 104 indivíduos saudáveis). O sangue foi coletado, em 4 momentos, para a determinação do perfil lipídico e das atividades arilesterase e paraoxonase da PON. O DNA foi extraído de leucócitos do sangue periférico pelo método de extração salina. A análise dos polimorfismos foi realizada por PCR/RFLP. Não houve diferença estatística na distribuição de genótipos e frequência de alelos dos polimorfismos nos genes da PON1 e PON2. A atividade sérica da arilesterase apresentou valores significativamente maiores apenas entre os indivíduos saudáveis (p=0,001). As variantes 55MM e 192QQ, do gene da PON1, influenciaram as atividades arilesterase (p=0,011) e paraoxonase (0,001). O polimorfismo PON2 311SS associou-se a atividade arilesterase (p=0,021). A concentração de autoanticorpos oxLDL foi alterada, pela presença do genótipo 55LM (p=0,037) nos indivíduos com LDGCB / The paraoxonase family (PON1, PON2 and PON3) have been the subject of great interest, since they are responsible for preventing oxidative stress and inflammation, conditions important in carcinogenesis. The Diffuse Large B Cell Lymphoma (DLBCL) is the most common histological subtype among lymphomas, diseases that originate from cells of the lymphoid tissue and exhibit clinically distinct behaviors and pathological and epidemiological factors. There are paucity of data on the activity of paraoxonase in the differential susceptibility to the risk of lymphoma. Thus, the objective of this study was to investigate the genotypic and allelic frequency of polymorphisms 192QR and 55LM, in the PON1 gene and 148AG and 311SC, in the PON2 gene and the effect of these polymorphisms on PON enzyme activities and lipid profile in 182 subjects (78 patients with DLBCL and 104 healthy subjects). Blood was collected in four moments for the determination of lipid profile and paraoxonase and arylesterase activities of PON. The DNA was extracted from peripheral blood leukocytes by salt extraction method. The analysis of polymorphisms was performed by PCR/RFLP. There was no statistical difference in the distribution of genotypes and allele frequencies of polymorphisms in the PON1 and PON2 genes. The serum arylesterase activity was significantly higher only among healthy subjects (p=0.001). 192QQ and 55MM variants of the PON1 gene, influenced arylesterase (p=0.011) and paraoxonase (0.001) activities. The PON2 polymorphism was associated with 311SS arylesterase activity (p = 0.021). The concentration of oxLDL autoantibodies was altered by the presence of 55LM genotype (p = 0.037) in patients with DLBCL