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

ABSTRACT: 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.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 (pi/bp = 0.00320) exceeded up to 10 times the variation in the NAT8 genic region (pi/bp = 0.00037) as well as the average variation (pi/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).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.

SUBMITTER: Juhanson P

PROVIDER: S-EPMC2330028 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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

Juhanson Peeter P Kepp Katrin K Org Elin E Org Elin E Veldre Gudrun G Kelgo Piret P Rosenberg Mai M Viigimaa Margus M Laan Maris M

BMC medical genetics 20080410

<h4>Background</h4>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.<h4>Methods/results</h4>We report the first study exploring NAT8 as a potential candidate gene for blood pressure and kidney function. The ...[more]

PMID: 18402670

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Project description:The outcome of Genome-Wide Association Studies (GWAS) has challenged the field of blood pressure (BP) genetics as previous candidate genes have not been among the top loci in these scans. We used Affymetrix 500K genotyping data of KORA S3 cohort (n = 1,644; Southern-Germany) to address (i) SNP coverage in 160 BP candidate genes; (ii) the evidence for associations with BP traits in genome-wide and replication data, and haplotype analysis. In total, 160 gene regions (genic region+/-10 kb) covered 2,411 SNPs across 11.4 Mb. Marker densities in genes varied from 0 (n = 11) to 0.6 SNPs/kb. On average 52.5% of the HAPMAP SNPs per gene were captured. No evidence for association with BP was obtained for 1,449 tested SNPs. Considerable associations (P<10(-3)) were detected for the genes, where >50% of HAPMAP SNPs were tagged. In general, genes with higher marker density (>0.2 SNPs/kb) revealed a better chance to reach close to significance associations. Although, none of the detected P-values remained significant after Bonferroni correction (P<0.05/2319, P<2.15 x 10(-5)), the strength of some detected associations was close to this level: rs10889553 (LEPR) and systolic BP (SBP) (P = 4.5 x 10(-5)) as well as rs10954174 (LEP) and diastolic BP (DBP) (P = 5.20 x 10(-5)). In total, 12 markers in 7 genes (ADRA2A, LEP, LEPR, PTGER3, SLC2A1, SLC4A2, SLC8A1) revealed considerable association (P<10(-3)) either with SBP, DBP, and/or hypertension (HYP). None of these were confirmed in replication samples (KORA S4, HYPEST, BRIGHT). However, supportive evidence for the association of rs10889553 (LEPR) and rs11195419 (ADRA2A) with BP was obtained in meta-analysis across samples stratified either by body mass index, smoking or alcohol consumption. Haplotype analysis highlighted LEPR and PTGER3. In conclusion, the lack of associations in BP candidate genes may be attributed to inadequate marker coverage on the genome-wide arrays, small phenotypic effects of the loci and/or complex interaction with life-style and metabolic parameters.

Dataset Information

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

Publications

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

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