Abstract
Blood homocysteine level and related vitamin levels are associated with various health outcomes. We aimed to assess causal effects of blood homocysteine, folate, and cobalamin on kidney function in the general population by performing Mendelian randomization (MR) analysis. Genetic instruments for blood homocysteine, folate, and cobalamin levels were introduced from a previous genome-wide association (GWAS) meta-analysis of European individuals. Summary-level MR analysis was performed for the estimated glomerular filtration rate (eGFR) from the CKDGen consortium GWAS that included 567,460 European ancestry individuals. For replication, allele-score-based MR was performed with an independent U.K. Biobank cohort of 337,138 individuals of white British ancestry. In summary-level MR for the CKDGen data, high genetically predicted homocysteine levels were significantly associated with low eGFR (per 1 standard deviation, beta for eGFR change −0.95 (−1.21, −0.69) %), supported by pleiotropy-robust MR sensitivity analysis. Genetically predicted high folate levels were significantly associated with high eGFR change (0.86 (0.30, 1.42) %); however, causal estimates from cobalamin were nonsignificant (−0.11 (−0.33, 0.11) %). In the U.K. Biobank data, the results were consistently identified. Therefore, a high blood homocysteine level causally decreases eGFR. Future trials with appropriate homocysteine-lowering interventions may be helpful for the primary prevention of kidney function impairment.
Highlights
Genetic instruments for blood homocysteine, folate, and cobalamin levels were introduced from a previous genome-wide association study (GWAS) analyses [16,17]
High genetically predicted folate levels were significantly associated with high estimated glomerular filtration rate (eGFR) values, and the findings were consistent throughout the utilized Mendelian randomization (MR) sensitivity analyses
Of 11 cally predicted cobalamin levels were nonsignificantly associated with eGFR outcomes in the CKDGen data
Summary
Chronic kidney disease (CKD) is a major comorbidity associated with a large socioeconomic burden and risk of mortality [1]. The prevalence of kidney function impairment is increasing along with the global aging trend and the growing population with obesity. Appropriate lifestyle modifications and risk factor management, including the control of metabolic disorders, have been recommended to maintain healthy kidney function in the general population. High homocysteine levels are related to risks of cardiovascular diseases or kidney function impairment, in populations with kidney function impairment [4,5,6]. As observational findings have been conflicted and kidney function itself determines blood homocysteine levels [7,8], whether a high blood level of homocysteine is a causative factor for kidney function impairment has yet to be determined
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