Effects of PON polymorphisms and haplotypes on molecular phenotype in Mexican-American mothers and children.
Effects of PON polymorphisms and haplotypes on molecular phenotype in Mexican-American mothers and children.
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DOI：
10.1002/em.20567
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发表时间：
2011-03
影响因子：
2.8
通讯作者：
Holland, Nina
中科院分区：
文献类型：
--
作者：
Huen, Karen;Barcellos, Lisa;Beckman, Kenneth;Rose, Sherri;Eskenazi, Brenda;Holland, Nina
对氧磷酶1(PON1)可防止低密度脂蛋白氧化，并使有机磷农药(OPs)的有毒氧衍生物失活。目前已在PON1基因中发现250多个SNPs，但对PON1基因变异的研究主要集中在少数启动子SNPs(-108、-162)和编码SNPs(192、55)。我们对来自墨西哥-美国出生队列的30名受试者的PON1基因进行了测序，发现了94个等位基因频率很小的多态，占5%，其中包括几个新的变异(6个SNPs，1个插入，2个缺失)。对来自同一队列的700名儿童和母亲的PON1基因及其3个SNPs PON1和PON3进行了基因分型。用芳香酯酶(AREase)和对氧磷酶(POase)两种底物特异性分析方法确定PON1的表型。12个PON1和2个PON2多态与AREase活性显著相关，37个多态与POase活性相关，但只有9个SNP与PON1-108或PON1192(R2>；0.20)不存在强连锁不平衡(LD)，这两个SNP对PON1数量和底物专一性活性有已知的影响。与单倍型中由多个SNP组成的单倍型相比，单个标签SNPs PON155和PON1192解释了相似的AREase变异范围。然而，PON155可以解释11-16%的POase活性，而同一单倍型区块中的6个SNP可以解释3倍以上的变异(36-56%)。虽然墨西哥人和高加索人PON簇中的LD结构相似，但许多多态的等位基因频率存在显著差异。与OP易感性和氧化应激相关的PON基因变异的功能效应也因年龄而异，在保护易受伤害的亚群时应考虑到这一点。
Paraoxonase 1 (PON1) prevents oxidation of low density lipoproteins and inactivates toxic oxon derivatives of organophosphate pesticides (OPs). Over 250 SNPs have been previously identified in the PON1 gene, yet studies of PON1 genetic variation focus primarily on a few promoter SNPs (-108,-162) and coding SNPs (192, 55). We sequenced the PON1 gene in 30 subjects from a Mexican-American birth cohort and identified 94 polymorphisms with minor allele frequencies > 5%, including several novel variants (6 SNPs, 1 insertion, 2 deletions). Variants of the PON1 gene and 3 SNPs from PON2 and PON3 were genotyped in 700 children and mothers from the same cohort. PON1 phenotype was established using two substrate-specific assays: arylesterase (AREase) and paraoxonase (POase). Twelve PON1 and two PON2 polymorphisms were significantly associated with AREase activity, and 37 polymorphisms with POase activity, however only nine were not in strong linkage disequilibrium (LD) with either PON1-108 or PON1192 (r2>0.20), SNPs with known effects on PON1 quantity and substrate-specific activity. Single tagSNPs PON155 and PON1192 accounted for similar ranges of AREase variation compared to haplotypes comprised of multiple SNPs within their haplotype blocks. However, PON155 explained 11-16% of POase activity, while six SNPs in the same haplotype block explained 3-fold more variance (36-56%). Although LD structure in the PON cluster seems similar between Mexicans and Caucasians, allele frequencies for many polymorphisms differed strikingly. Functional effects of PON genetic variation related to susceptibility to OPs and oxidative stress also differed by age, and should be considered in protecting vulnerable subpopulations.
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影响因子：
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作者：
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通讯作者：
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