Nitric oxide synthase (NOS) single nucleotide polymorphisms are associated with coronary heart disease and hypertension in the INTERGENE study

• 3351 individuals had genotype data for 58 tag-SNPs in NOS1, NOS2 and NOS3 genes.
• 4 SNPs were associated with CHD and 5 SNPs with hypertension.
• Only NOS1 rs3782218’s association with CHD held for Bonferroni correction.
• Haplotype analysis suggests the T-allele of rs3782218 is a marker for a true effect.

ObjectiveNitric oxide synthase (NOS) exists in three distinct isoforms, each encoded by a specific gene: neuronal NOS (NOS1 gene), inducible NOS (NOS2 gene) and endothelial NOS (NOS3 gene). Single nucleotide polymorphisms (SNPs) in NOS genes have been associated with cardiovascular pathology. We aimed to comprehensively investigate which NOS gene variants are most strongly associated with coronary heart disease (CHD) and hypertension, using a set of tagging SNPs with good coverage across the 3 genes.Method and resultsCHD cases (n = 560) and randomly selected population controls (n = 2791) were genotyped at 58 SNPs in the NOS genes. Control individuals with systolic blood pressure ⩾140, diastolic blood pressure ⩾90 or on antihypertensive medication were defined as hypertensive. A structured stepwise logistic regression approach was used to select the SNPs most strongly associated with CHD and hypertension.NOS1 SNP rs3782218 showed the most consistent association with both phenotypes, odds ratio 0.59 (95% confidence interval 0.44–0.80) and 0.81 (0.67–0.97) per T-allele for CHD and hypertension respectively. For CHD, another NOS1 SNP (rs2682826) and a NOS3 SNP (rs1549758) also showed effect. For hypertension associations were seen for additional SNPs including NOS3 SNP rs3918226, previously associated with hypertension in genome-wide association study (GWAS) data.ConclusionWe found a previously unreported association between NOS1 SNP rs3782218 and both CHD and hypertension, and confirmed NOS1 as the most important NOS risk gene for CHD. In contrast, variants in all three NOS genes were seen to be associated with hypertension in the same source population.