You are here
No causal effects of serum urate levels on the risk of chronic kidney disease: A Mendelian randomization study.
Wednesday,2019-05-22 16:34 America/Los_Angeles — ecterry
| Title | No causal effects of serum urate levels on the risk of chronic kidney disease: A Mendelian randomization study. |
| Publication Type | Journal Article |
| Year of Publication | 2019 |
| Authors | Jordan, DM, Choi, HK, Verbanck, M, Topless, R, Won, H-H, Nadkarni, G, Merriman, TR, Do, R |
| Journal | PLoS Med |
| Volume | 16 |
| Issue | 1 |
| Pagination | e1002725 |
| Date Published | 2019 01 |
| ISSN | 1549-1676 |
| Keywords | Adult, Age Factors, Female, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Male, Mendelian Randomization Analysis, Renal Insufficiency, Chronic, Sex Factors, Uric Acid, Young Adult |
| Abstract | <p><b>BACKGROUND: </b>Studies have shown strong positive associations between serum urate (SU) levels and chronic kidney disease (CKD) risk; however, whether the relation is causal remains uncertain. We evaluate whether genetic data are consistent with a causal impact of SU level on the risk of CKD and estimated glomerular filtration rate (eGFR).</p><p><b>METHODS AND FINDINGS: </b>We used Mendelian randomization (MR) methods to evaluate the presence of a causal effect. We used aggregated genome-wide association data (N = 110,347 for SU, N = 69,374 for gout, N = 133,413 for eGFR, N = 117,165 for CKD), electronic-medical-record-linked UK Biobank data (N = 335,212), and population-based cohorts (N = 13,425), all in individuals of European ancestry, for SU levels and CKD. Our MR analysis showed that SU has a causal effect on neither eGFR level nor CKD risk across all MR analyses (all P > 0.05). These null associations contrasted with our epidemiological association findings from the 4 population-based cohorts (change in eGFR level per 1-mg/dl [59.48 μmol/l] increase in SU: -1.99 ml/min/1.73 m2; 95% CI -2.86 to -1.11; P = 8.08 × 10(-6); odds ratio [OR] for CKD: 1.48; 95% CI 1.32 to 1.65; P = 1.52 × 10(-11)). In contrast, the same MR approaches showed that SU has a causal effect on the risk of gout (OR estimates ranging from 3.41 to 6.04 per 1-mg/dl increase in SU, all P < 10-3), which served as a positive control of our approach. Overall, our MR analysis had >99% power to detect a causal effect of SU level on the risk of CKD of the same magnitude as the observed epidemiological association between SU and CKD. Limitations of this study include the lifelong effect of a genetic perturbation not being the same as an acute perturbation, the inability to study non-European populations, and some sample overlap between the datasets used in the study.</p><p><b>CONCLUSIONS: </b>Evidence from our series of causal inference approaches using genetics does not support a causal effect of SU level on eGFR level or CKD risk. Reducing SU levels is unlikely to reduce the risk of CKD development.</p> |
| DOI | 10.1371/journal.pmed.1002725 |
| Alternate Journal | PLoS Med. |
| PubMed ID | 30645594 |
| PubMed Central ID | PMC6333326 |
| Grant List | MC_QA137853 / / Medical Research Council / United Kingdom R01 AR056291 / AR / NIAMS NIH HHS / United States R01 AR065944 / AR / NIAMS NIH HHS / United States P50 AR060772 / AR / NIAMS NIH HHS / United States K23 DK107908 / DK / NIDDK NIH HHS / United States R35 GM124836 / GM / NIGMS NIH HHS / United States R01 HL139865 / HL / NHLBI NIH HHS / United States R01 HL087641 / HL / NHLBI NIH HHS / United States R01 HL086694 / HL / NHLBI NIH HHS / United States U01 HG004402 / HG / NHGRI NIH HHS / United States UL1 RR025005 / RR / NCRR NIH HHS / United States HHSN268201200036C / HL / NHLBI NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States R01 AG023629 / AG / NIA NIH HHS / United States |
ePub date:
19/01