Elevated homocysteine contributes to the progression of type 1 diabetic nephropathy: Evidence from Mendelian randomization and experimental validation.

Hyperhomocysteinemia has been identified as a potential metabolic risk factor for type 1 diabetes-related nephropathy (T1DN). However, the causal relationship between homocysteine (Hcy) and T1DN remains unclear. We performed univariable Mendelian randomization (MR) and multivariable MR analyses to investigate the causal effects of Hcy and B vitamins (vitamin B6, B12, and folate) on T1DN in a cohort of 19,406 individuals. Linkage disequilibrium score regression and colocalization analyses were conducted to examine genetic correlations. Additionally, 2-step MR analysis was employed to identify potential mediating factors. Our MR findings revealed that elevated Hcy levels were causally associated with the late stage of T1DN (OR = 1.33, 95% CI: 1.08-1.64; P < .0001; false discovery rate < 0.05). Multivariable MR analysis further confirmed that Hcy remained significantly associated with increased risk of late-stage T1DN (OR = 1.215; false discovery rate < 0.05), even after adjusting for kidney function and vitamin B6 levels. Two-step MR analysis suggested that estimated glomerular filtration rate mediated 3.21% of the effect of Hcy on T1DN. No causal relationship was observed between Hcy and the microalbuminuria stage of T1DN (OR = 0.963, 95% CI: 0.717-1.293). Furthermore, folate, vitamin B6, and vitamin B12 were not significantly associated with T1DN. Experimental results showed that Hcy inhibited HK-2 cell viability and induced cellular injury. Notably, treatment with losartan and sinomenine alleviated Hcy-induced cytotoxicity, indicating their potential protective effects. The findings of this study suggest that elevated Hcy levels represent an important risk factor contributing to the development of T1DN.