Can common variants in the body’s antioxidant machinery shape who develops hypertension or diabetes years later? Researchers at Kermanshah University of Medical Sciences addressed this question within the Ravansar Noncommunicable Disease (RaNCD) cohort, the first cohort study in a Kurdish population and part of the national PERSIAN initiative. Adults aged 35 to 65 were recruited between 2014 and 2017 and followed annually through 2023, an 8-year prospective follow-up. Of 10,047 participants at recruitment, 509 were analyzed: 149 controls and 123, 119, and 118 individuals who developed hypertension (HTN), type 2 diabetes mellitus (T2DM), and cardiovascular disease (CVD), respectively. The study examined two variants, Nrf2 (rs6721961) and NQO1 (rs1800566), using Cox regression and generalized structural equation modeling (GSEM).
Carriers of recessive (T allele) genotypes of both genes had higher BMI, waist circumference, total cholesterol, LDL-C, AST, GGT, uric acid, malondialdehyde, and lower total antioxidant capacity. Mediterranean diet adherence did not differ significantly between genotype groups. In survival analysis, the group carrying a homozygous TT genotype of Nrf2 or NQO1 had the highest HTN risk (crude HR=2.50), which persisted through all adjusted models (Model 5: HR=2.82). For T2DM, carriers of both Nrf2 GT and NQO1 CT showed the strongest association (Model 5: HR=3.15), followed by Nrf2 GT carriers alone (HR=1.97). No genotype group showed a consistent association with CVD. Allele-level analyses pointed the same way for T2DM (Nrf2 HR=2.19; NQO1 HR=1.66) and HTN (Nrf2 HR=1.43; NQO1 HR=1.46). Covariate-adjusted marginal-effects plots added a biochemical view: Groups 4 (Nrf2 GT and NQO1 CT) and 5 had higher TOS and MDA, and Group 4 showed the least favorable pattern across several markers, including fasting blood sugar, uric acid, urea, and GGT. The highest CRP, total cholesterol, LDL-C, creatinine, and urea were seen in Group 3, while Groups 1 and 2 showed consistently smaller increases than Groups 3 to 5.
GSEM was used to ask how these genotypes might act. Directly, Nrf2 GT was associated with T2DM (OR=2.82), Nrf2 TT with HTN (OR=3.24), and NQO1 CT with HTN (OR=1.46) and T2DM (OR=1.97). The latent oxidative stress and inflammatory (OSI) construct was the strongest mediator, associated with HTN (OR=2.30), T2DM (OR=2.36), and CVD (OR=3.07); obesity was associated with T2DM (OR=1.75). For Nrf2 TT, the indirect effect on HTN through OSI was OR=2.92, giving a total effect of OR=5.11. The NQO1 CT genotype raised HTN risk indirectly through OSI (OR=1.26) and T2DM risk through OSI (OR=1.79). Mediation estimates indicated that about 50% of the Nrf2 GT effect on T2DM was mediated through oxidative stress, about 30% of the Nrf2 TT effect on HTN through obesity and dyslipidemia, and 40–60% of the NQO1 CT effect on HTN and T2DM through oxidative stress and fatty liver index. The NQO1 TT genotype had no significant direct effect, yet showed indirect effects through OSI on HTN (OR=1.82), T2DM (OR=1.36), and CVD (OR=2.14). Neither variant was directly linked to CVD, but indirect pathways through OSI, dyslipidemia, and uric acid were significant.
The authors conclude that Nrf2 and NQO1 variants are associated with cardiometabolic risk, particularly HTN and T2DM, largely through oxidative stress, inflammation, and metabolic dysregulation. These results describe the pattern observed in this Iranian Kurdish cohort and the models applied to it; extending them to other populations will require further studies. If confirmed, redox-related variants could support early risk
stratification and more personalized
Scientific Reports