Role of Nrf2 and NQO1 genetic variants in cardiometabolic diseases: an 8-year prospective study of genetic, dietary, biochemical, and oxidative stress markers in Iranian Kurdish Adults.

Abstract

This study assessed the association between Nrf2 (rs6721961) and NQO1 (rs1800566) polymorphisms and cardiometabolic diseases (CMDs) in the Kurdish population of Iran. We analyzed 509 Kurdish individuals. Biochemical markers were measured using commercial kits, and genotypes were determined via PCR-RFLP. Dietary patterns were evaluated using the food frequency questionnaire. Associations were analyzed using linear/Cox regression, margins plots, and generalized structural equation modeling (GSEM). We found biochemical, oxidative stress, and anthropometric parameters were significantly elevated in individuals carrying the recessive genotypes of Nrf2 and NQO1. Cox regression analysis revealed that homozygous recessive genotypes of each or both polymorphisms were strongly associated with an increased risk of hypertension (HTN) over time (HR = 2.82; 95% CI: 1.4-5.3). Similarly, carriers of the Nrf2 GT (HR = 1.75; 95% CI: 1.0-3.2) and carriers of both Nrf2 GT and NQO1 CT (HR = 3.15; 95% CI: 1.7-5.9) were significantly linked to a higher risk of type 2 diabetes mellitus (T2DM). According to GSEM analysis, Nrf2 GT and NQO1 (CT and TT) genotypes indirectly increased the risk of cardiovascular disease through inflammatory and oxidative stress pathways, fatty liver index, and dyslipidemia. This study demonstrates Nrf2 (rs6721961) and NQO1 (rs1800566) polymorphisms are significantly associated with an increased risk of CMDs, particularly HTN and T2DM, primarily through oxidative stress, inflammation, and metabolic dysregulation. These findings highlight the potential role of redox-related genetic variants in early risk prediction and personalized prevention strategies among genetically susceptible populations.

Key Findings

• Nrf2 (rs6721961) and NQO1 (rs1800566) polymorphisms are significantly associated with increased risk of cardiometabolic diseases, particularly hypertension and type 2 diabetes mellitus.
• Homozygous recessive genotypes of Nrf2 and NQO1 correlate with elevated biochemical, oxidative stress, and anthropometric parameters.
• Nrf2 and NQO1 genotypes indirectly increase cardiovascular disease risk through inflammatory and oxidative stress pathways, fatty liver index, and dyslipidemia.

Clinical Significance

Citation

Kohsari Maryam, Amiri Mohammad, Moradinazar Mehdiet al.. Role of Nrf2 and NQO1 genetic variants in cardiometabolic diseases: an 8-year prospective study of genetic, dietary, biochemical, and oxidative stress markers in Iranian Kurdish Adults. Scientific reports. 2026-Jun-07.