Association between the NAT1 1095C > A polymorphism and homocysteine concentration.
Association between the NAT1 1095C > A polymorphism and homocysteine concentration.
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NAT1 1095C > A 多态性与同型半胱氨酸浓度之间的关联。
DOI：
10.1002/ajmg.a.31475
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发表时间：
2006
期刊：
影响因子：
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通讯作者：
Whitehead,AlexanderS
中科院分区：
文献类型：
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作者：
Stanisławska-Sachadyn,Anna;Jensen,LiselotteE;Kealey,Carmel;Woodside,JayneV;Young,IanS;Scott,JohnM;Murray,Liam;Boreham,ColinA;McNulty,Helene;Strain,JJ;Whitehead,AlexanderS
N-乙酰转移酶1 [NAT 1（EC 2.3. 1.5）]通过分别催化它们的O-乙酰化和N-乙酰化，促进各种芳基胺和杂环胺（包括几种已知的致癌物）的活化或失活[Hein等人，2000; Hein，2002]。此外，在许多不同组织中表达的NAT 1 [Ward等人，1995]，乙酰化叶酸分解代谢物对氨基苯甲酰谷氨酸盐，使其成为主要排泄形式，N-乙酰基-对氨基苯甲酰谷氨酸盐[Minchin，1995; Ward等，1995年]。迄今为止，已经报道了具有已知功能特征的NAT 1基因内的几种单核苷酸多态性[Hein等人，2000年]。由于NAT 1在叶酸催化剂中的作用以及乙酰化叶酸催化剂对叶酸代谢方面的可能反馈抑制，已经表明该酶的变体可以改变细胞内叶酸含量，从而改变叶酸/高半胱氨酸代谢和表型[Minchin，1995; Ward et al.，1995年]。由NAT 1 mRNA 30非翻译区（UTR）位置1088和1095处的A核苷酸指定的NAT 1 * 10等位基因最近与出生缺陷风险增加相关。Lammer等人[2004 a，B]报道，对于母亲吸烟的妊娠，后代NAT 1 1088 AA和1095 AA基因型（单独或一起分析时）与口面裂的风险密切相关。同一组还观察到，在怀孕早期缺乏母体多种维生素使用以及后代NAT 11095 AA基因型赋予口面裂的风险增加[Lammer等人，2004年a]。詹森等人[2005]随后发表的证据表明，脊柱裂的风险受到后代NAT 1 1095 A等位基因和母亲吸烟之间相互作用的影响。1995; Bell等人，1995; Hein等人，2000; Yang等人，2000年]。然而，其他人已经表明它编码具有与野生型NAT 1 * 4等位基因所指定的活性相似的活性的酶[Grant et al.，1997年]。目前还没有发表的研究调查NAT 1 * 10对叶酸/同型半胱氨酸表型的影响，这可能是观察到的该NAT 1变体与上述两类出生缺陷相关性的基础。然而，母体低叶酸/高同型半胱氨酸与脊柱裂出生结局风险增加之间的关系已得到充分证实[米尔斯等人，1995]并且已经报道母体低叶酸状态可能导致口面裂病因[Prescott等，2002年]。因此，我们研究了一组育龄健康成人，以确定NAT 1 1095 C> A多态性与叶酸/同型半胱氨酸表型之间的关联（如果有的话）。特别是，我们评估了吸烟者亚组中的这种关联。
N-acetyltransferase 1 [NAT1 (EC 2.3. 1.5)] facilitates the activation or deactivation of various arylamine and heterocyclic amines, including several known carcinogens, by catalyzing their O-acetylation and N-acetylation, respectively [Hein et al., 2000; Hein, 2002]. In addition, NAT1, which is expressed in many different tissues [Ward et al., 1995], acetylates the folate catabolite p-aminobenzoylglutamate, to its primary excretory form, N-acetyl-p-aminobenzoylglutamate [Minchin, 1995; Ward et al., 1995]. Several single nucleotide polymorphisms within the NAT1 gene with known functional characterization have been reported to date [Hein et al., 2000]. Due to the role of NAT1 in folate catabolism and the possible feedback inhibition of aspects of folate metabolism by acetylated folate catabolites, it has been suggested that variants of this enzyme may change intracellular folate content, thereby modifying folate/homocysteine metabolism and phenotype [Minchin, 1995; Ward et al., 1995]. The NAT1* 10 allele, specified by A nucleotides at positions 1088 and 1095 of the NAT1 mRNA 30 untranslated region (UTR), has recently been associated with an increased risk of birth defects. Lammer et al.[2004a, b] reported that for pregnancies in which the mother smoked, the offspring NAT1 1088AA and 1095AA genotypes (either when analyzed separately or together) are strongly associated with the risk of orofacial clefts. The same group also observed that lack of maternal multivitamin use during early pregnancy together with offspring NAT1 1095AA genotype conferred an increased risk of orofacial clefts [Lammer et al., 2004a]. Jensen et al.[2005] subsequently published evidence that the risk of spina bifida was influenced by an interaction between the offspring NAT1 1095A allele and maternal smoking.Some reports suggest that the NAT1* 10 allele is associated with a rapid acetylating phenotype [Badawi et al., 1995; Bell et al., 1995; Hein et al., 2000; Yang et al., 2000]. However, others have indicated that it encodes an enzyme with activity similar to that specified by the wild-type NAT1* 4 allele [Grant et al., 1997]. There have been no published studies investigating the impact of NAT1* 10 on folate/homocysteine phenotype that might underlie the observed association of this NAT1 variant with the above two classes of birth defects. However, the relationship between maternal low folate/high homocysteine and increased risk of spina bifida birth outcome is well established [Mills et al., 1995] and it has been reported that maternal low folate status may contribute to orofacial cleft etiology [Prescott et al., 2002]. We therefore examined a population of healthy adults of reproductive age to determine the association, if any, between the NAT1 1095C> A polymorphism and aspects of folate/homocysteine phenotype. In particular, we assessed such associations in the subset of smokers.