Genetic association of NOS3 rs1799983 variant and hypertension across multiple rural Indonesian populations: a multi-ethnic population-based study

Abstract

Hypertension is a complex polygenic disorder where genetic variants become clinically relevant primarily when they contribute to endothelial dysfunction. While the NOS3 rs1799983 variant is known to impair endothelial function, data regarding its genotypic and allelic frequency and association with hypertension in Indonesian rural populations remains limited. The present study aimed to investigate the genotypic and allelic frequency of NOS3 rs1799983 and examine its association with hypertension across multiple ethnic groups in rural Indonesian populations. This population-based case-control study included 798 individuals with hypertension and 448 subjects with normal blood pressure from four primarily rural Indonesian regions: Papua, Pamijahan, Morotai, and Natuna. Genotyping of the NOS3 rs1799983 variant was performed using real-time polymerase chain reaction. Multiple logistic regression models were employed to evaluate the association between genotypes and hypertension. In the pooled population, no significant unadjusted categorical association existed between the NOS3 variant and hypertension ( p  = 0.069). Subgroup analysis revealed a nominal unadjusted association in Morotai under the dominant model (OR = 1.675, p  = 0.017), which lost statistical significance following false discovery rate (FDR) correction (adjusted p  = 0.051). Numerically, GT + TT carriers exhibited significantly higher mean systolic blood pressure (SBP) in the Morotai normotensive control group, an effect that survived FDR correction (adjusted p  = 0.016). Conversely, unadjusted SBP elevations among GT + TT carriers within the hypertensive cohorts (overall p  = 0.024; Morotai p  = 0.016) became non-significant after FDR correction (adjusted p  = 0.064). Crucially, after adjusting for confounders using multivariate analysis, the GT + TT genotypes emerged as an independent predictor of increased hypertension risk in both the pooled population (aOR = 1.392, 95% CI: 1.045–1.853, p  = 0.024) and the Morotai subpopulation (aOR = 2.056, p  = 0.002). The T allele of the NOS3 rs1799983 variant was rare in the studied populations. While no significant association was found between the NOS3 rs1799983 variant and hypertension overall, a modest association was observed under a dominant model specifically within the rural Morotai population. Further research incorporating physiopathological assessments of endothelial function is required to definitively link this variant to hypertension in these rural groups.