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

A novel haplotype in N -acetyltransferase 2 ( NAT2 ) composed of seven non-coding variants (rs1495741, rs4921913, rs4921914, rs4921915, rs146812806, rs35246381, and rs35570672) has been linked to dyslipidemia by multiple, independent genome-wide association studies. The haplotype is located approximately 14 kb downstream of NAT2-coding region (ch8:18,272,377-18,272,881; GRCh38/hg38) and represents a non-coding, intergenic haplotype. Interestingly, the same dyslipidemia NAT2 haplotype is also linked to urinary bladder cancer risk. Dyslipidemia risk alleles are associated with rapid acetylator phenotype, whereas bladder cancer risk alleles are associated with slow acetylator, suggesting that the level of systemic NAT2 activity modifies the risk of these pathologies. We speculate that rs1495741 (and its associated haplotype) belongs to a distal regulatory element of human NAT2 gene (e.g., enhancer or silencer), and the genetic variation at the newly discovered haplotype results in a differential level of NAT2 gene expression. Understanding how this NAT2 haplotype contributes to not only urinary bladder cancer but also to dyslipidemia will ultimately help devise strategies to identify and protect susceptible individuals.