The interaction between the gene SOD1 rs2070424 and the plasma zinc/copper ratio predicts renal function impairment

Jingsi Chen^1,2*Jiaju Ge^1,2Jiayuan Song^1,2Tian-Ci Wang^1,2Yuqin Ma³Xiaoyan Qian³Chang Zhou^1,2Qiuguo Wang^1,2Senlin Zhu^1,2Xiyu Wu^1,2Hongzhen Du⁴Li-Qiang Qin^1,2*Zengning Li^4,5*

• ¹Soochow University, Suzhou, China
• ²Suzhou Medical College of Soochow University SSPH Department of Nutrition and Food Hygiene, Suzhou, China
• ³Suzhou Industrial Park Center for Disease Control and Prevention, Suzhou, China
• ⁴The First Hospital of Hebei Medical University, Shijiazhuang, China
• ⁵Hospital of Stomatology Hebei Medical University, Shijiazhuang, China

[Background] Essential trace elements zinc and copper have been suggested to play a role in renal function. However, the balance between these elements and their interaction with genetic variation in Superoxide Dismutase 1 (SOD1) remains unclear. [Methods] We conducted a prospective study involving 1,274 middle-aged and elderly participants from the "135" cohort in 2015. Cox regression analyses were used to assess associations between plasma trace elements, SOD1 polymorphism (rs2070424), and their interactions with impaired renal function. To evaluate predictive utility, we compared discrimination and reclassification using ROC analysis and the net reclassification and integrated discrimination indices (NRI, IDI). [Results] After adjusting for multiple variables, the hazard ratios (HRs) (95% CI) comparing the highest to the lowest tertiles were 1.303 (1.037, 1.637) for zinc, 1.615 (1.275, 2.046) for the zinc/copper ratio, and 0.709 (0.558, 0.900) for copper. Compared with the GG genotype, the AG and AA genotypes were positively associated impaired renal function (HR: 1.282, 95% CI: 1.003, 1.639). Positive associations between impaired renal function and plasma zinc (P for interaction: 0.006), as well as the zinc/copper ratio (P for interaction: <0.001), were modified by rs2070424 genotypes. The adjusted HRs comparing tertile 3 with tertile 1 for impaired renal function were: AA/AG carriers—zinc 1.359 (1.055–1.749); zinc/copper ratio 1.642 (1.267–2.128); GG carriers—zinc 1.065 (0.623–1.819); zinc/copper ratio 1.584 (0.889–2.822). In prediction analyses, the zinc/copper ratio showed higher discrimination (AUC) than single-metal models and improved reclassification (NRI, IDI), providing partial evidence of incremental value. [Conclusion] Decline in renal function was positively correlated with plasma zinc and the zinc/copper ratio and negatively correlated with plasma copper. The relationship between impaired renal function and both zinc and the zinc/copper ratio was modified by rs2070424 genotypes. Taken together, considering zinc/copper ratio provides a more informative summary than single-metal measures and shows partial incremental discrimination.