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Background  Kidneys have an important function in blood pressure (BP) regulation and elevated BP may lead to kidney failure. Chr2p12-p13 region linked to BP traits in multiple studies harbours a potential candidate for BP and renal function,  N-acetyltransferase 8 (NAT8)  expressed in embryonic and adult kidney and associated with nephrotoxicity response.    Methods/Results  We report the first study exploring  NAT8  as a potential candidate gene for blood pressure and kidney function. The resequencing (n = 42, random Estonian samples) identified 15  NAT8  polymorphisms, including 6 novel variants. The diversity of  NAT8  5' upstream region (π/bp = 0.00320) exceeded up to 10 times the variation in the  NAT8  genic region (π/bp = 0.00037) as well as the average variation (π/bp = 0.00040) for the promoters of 29 reference genes associated with hypertension. We suggest that a potential source for such high variation could be an active gene conversion process from  NAT8B  duplicate gene to  NAT8 . Similarly to  NAT8 , several reference genes with the most variable upstream regions have also duplicate copies. The  NAT8  promoter SNPs were targeted with pilot quantitative association studies for blood pressure (n = 137, healthy unrelated individuals) and for the index of kidney function – estimated glomerular filtration rate (eGFR; n = 157 hypertensives with and without nephropathy). Minor alleles of these polymorphisms revealed a significant protective effect against elevated systolic BP as well as kidney failure in hypertension patients (p < 0.05; linear regression model, addictive effect).    Conclusion  The full resequencing and pilot association study of a novel positional candidate gene for blood pressure and renal function, human  N-acetyltransferase 8 , suggested a contribution of highly variable  NAT8  promoter polymorphisms in determination of systolic blood pressure and eGFR. Based on  in silico  analysis, we raise the hypothesis that the alternative SNP alleles of the  NAT8  upstream region may have differential effect on gene expression.

N-acetyltransferase 8, a positional candidate for blood pressure and renal regulation: resequencing, association and in silico study