Table1_Non-coding and intergenic genetic variants of human arylamine N-acetyltransferase 2 (NAT2) gene are associated with differential plasma lipid and cholesterol levels and cardiometabolic disorders.docx

Arylamine N-acetyltransferase 2 (NAT2) is a phase II metabolic enzyme, best known for metabolism of aromatic amines and hydrazines. Genetic variants occurring in the NAT2 coding region have been well-defined and are known to affect the enzyme activity or protein stability. Individuals can be categorized into rapid, intermediate, and slow acetylator phenotypes that significantly alter their ability to metabolize arylamines, including drugs (e.g., isoniazid) and carcinogens (e.g., 4-aminobiphenyl). However, functional studies on non-coding or intergenic variants of NAT2 are lacking. Multiple, independent genome wide association studies (GWAS) have reported that non-coding or intergenic variants of NAT2 are associated with elevated plasma lipid and cholesterol levels, as well as cardiometabolic disorders, suggesting a novel cellular role of NAT2 in lipid and cholesterol homeostasis. The current review highlights and summarizes GWAS reports that are relevant to this association. We also present a new finding that seven, non-coding, intergenic NAT2 variants (i.e., rs4921913, rs4921914, rs4921915, rs146812806, rs35246381, rs35570672, and rs1495741), which have been associated with plasma lipid and cholesterol levels, are in linkage disequilibrium with one another, and thus form a novel haplotype. The dyslipidemia risk alleles of non-coding NAT2 variants are associated with rapid NAT2 acetylator phenotype, suggesting that differential systemic NAT2 activity might be a risk factor for developing dyslipidemia. The current review also discusses the findings of recent reports that are supportive of the role of NAT2 in lipid or cholesterol synthesis and transport. In summary, we review data suggesting that human NAT2 is a novel genetic factor that influences plasma lipid and cholesterol levels and alters the risk of cardiometabolic disorders. The proposed novel role of NAT2 merits further investigations.

芳香胺N-乙酰基转移酶2（Arylamine N-acetyltransferase 2，NAT2）是一种II相代谢酶，因介导芳香胺与肼类物质的代谢而为人熟知。NAT2编码区的遗传变异已得到充分鉴定，且已知这些变异会影响酶活性或蛋白质稳定性。个体可被分为快速、中间及慢速乙酰化表型，这三类表型会显著改变其代谢芳胺类物质的能力，包括药物（如异烟肼）与致癌物（如4-氨基联苯）。然而，目前针对NAT2非编码区或基因间区变异的功能研究仍较为匮乏。多项独立的全基因组关联研究（Genome Wide Association Study，GWAS）均报道，NAT2的非编码区或基因间区变异与血浆脂质、胆固醇水平升高及心脏代谢紊乱相关，这提示NAT2在脂质与胆固醇稳态中存在全新的细胞学功能。本综述重点梳理并总结了与该关联相关的GWAS研究成果。此外，我们还报道了一项新发现：7个与血浆脂质、胆固醇水平相关的NAT2非编码基因间区变异（即rs4921913、rs4921914、rs4921915、rs146812806、rs35246381、rs35570672及rs1495741）彼此处于连锁不平衡状态，由此构成了一种全新的单倍型。NAT2非编码变异的血脂异常风险等位基因与快速乙酰化表型相关，这提示系统性NAT2活性差异可能是血脂异常发生的风险因素。本综述还讨论了近期发表的、支持NAT2参与脂质或胆固醇合成与转运的相关研究结果。综上，本文综述的研究数据表明，人类NAT2是一种全新的遗传因子，可影响血浆脂质与胆固醇水平，并改变心脏代谢紊乱的发病风险。NAT2的这一全新功能值得开展进一步研究。