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

Abstract

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.

N-acetyltransferase 2 haplotype modifies risks for both dyslipidemia and urinary bladder cancer

“…This finding also supports the association of the haplotype with differential systemic NAT2 activity (i.e. acetylator phenotype) [7]. This suggests that the differential risks of dyslipidemia and urinary bladder cancer are associated with and influenced by the NAT2 acetylator phenotype (Table 1).…”

“…For instance, rs35246381-C, which is in linkage disequilibrium with rs1495741-G, is associated with elevated serum levels of caffeine metabolites (e.g. 5-acetylamino-6-amino-3-methyluracil and 5-acetylamino-6-formylamino-3-methyluracil), which can be attributed to relatively high NAT2 activity [7]. This finding also supports the association of the haplotype with differential systemic NAT2 activity (i.e.…”

“…G and A). rs1495741-A [relative allele frequency (RAF) 0.65; 65%] increases urinary bladder cancer risk, whereas rs1495741-G (RAF 0.35; 35%) increases dyslipidemia risk [7].…”

“…We recently reported on the identification of a novel haplotype in NAT2. As illustrated in Table 1, the haplotype is comprised of seven, non-coding variants (rs1495741, rs4921913, rs4921914, rs4921915, rs146812806, rs35246381 and rs35570672) and has been linked to dyslipidemia by multiple, independent GWAS [7]. The haplotype is located approximately 14 kb downstream of the NAT2-coding region (ch8:18,272,377-18,272,881; GRCh38/hg38) and, thus, represents a non-coding, intergenic haplotype.…”

Relationships and Mendelian Randomization of Gut Microbe-Derived Metabolites with Metabolic Syndrome Traits in the METSIM Cohort

“…N-acetylputrescine was associated with higher levels of triglycerides and HDL-C. Similarly, Hong et al found that SNP rs35570672-T, which is associated with hyperlipidemia, was also associated with elevated levels of N-acetylputrescine [ 57 ]. Increased levels of N-acetylputrescine have been associated with disease severity in patients with liver and kidney disease [ 58 ].…”