Causality Between Serum Uric Acid and Diabetic Microvascular Complications - a Mendelian Randomization Study

Overview

Journal Diabetol Metab Syndr

Publisher Biomed Central

Specialty Endocrinology

Date 2024 Jun 18

PMID 38890685

Authors

Hongli Wu

Xuefeng Li

Wenning Zhang

Huifang Peng

Hongwei Jiang

Affiliations

Soon will be listed here.

Abstract

Background: The aim of this study was to investigate whether a causal relationship exists between serum uric acid (SUA) and diabetic microvascular complications using a two-sample Mendelian randomization (MR) method.

Methods: We used the MR approach, utilizing genome-wide association study (GWAS) summary statistics, to estimate the causal effect of SUA on diabetic microvascular complications in European individuals. The summary statistical data of SUA were obtained from the open database (IEU OPEN GWAS PROJECT) (p < 5 × 10), and data on diabetic microvascular complications (diabetic nephropathy, diabetic neuropathy, diabetic retinopathy) were obtained from the FinnGen consortium. F-statistics were calculated to assess the correlation between instrumental variables (IVs) and SUA, and single nucleotide polymorphisms (SNPs) associated with confounders or outcomes were excluded by consulting the PhenoScanner database. Inverse variance weighting (IVW) was used for primary estimation, and MR‒Egger, weighted median (WM), and Mendelian randomization pleiotropy residuals sum and outliers (MR-PRESSO) were used for additional assessment. Heterogeneity was assessed using the Cochran's Q test, and polytropy was assessed using the MR‒Egger intercept.

Results: MR analysis revealed a causal relationship between a genetically predicted increase in SUA and diabetic nephropathy [OR = 1.32, 95%(CI) = 1.07-1.63, p = 0.008]. The results were consistent with those after MR-PRESSO [OR = 1.30, 95%(CI) = 1.07-1.58, p = 0.008]. There was a causal relationship between type 2 diabetes mellitus (T2DM) and renal complication IVW [OR = 1.27, 95%(CI) = 1.00-1.62, p = 0.049]. These results were consistent with those after MR-PRESSO [OR = 1.27, 95%(CI) = 1.00-1.62, p = 0.050]. There was no significant causal relationship between the genetically predicted increase in SUA and diabetic retinopathy [OR 1.09, 95%(CI) = 0.94-1.26, p = 0.249] or diabetic neuropathy [OR = 1.08, 95%(CI) = 0.84-1.40, p = 0.549].

Conclusions: This MR analysis suggests a causal relationship between genetically predicted uric acid increases and diabetic microvascular complications. A significant causal relationship exists between SUA and diabetic nephropathy but not between SUA and diabetic retinopathy or diabetic neuropathy.

Citing Articles

Correlation between Chinese visceral adiposity index and serum uric acid levels in type 2 diabetes mellitus patients.

Araujo Intchasso Adotey S, Zhang Q, Chen M, Jiao Y, Zhang Y, Butoyi C Front Endocrinol (Lausanne). 2025; 16:1479662.

PMID: 39917540 PMC: 11798813. DOI: 10.3389/fendo.2025.1479662.

References

Jalal D, Rivard C, Johnson R, Maahs D, McFann K, Rewers M . Serum uric acid levels predict the development of albuminuria over 6 years in patients with type 1 diabetes: findings from the Coronary Artery Calcification in Type 1 Diabetes study. Nephrol Dial Transplant. 2010; 25(6):1865-9. PMC: 2902891. DOI: 10.1093/ndt/gfp740. View

Crawley W, Jungels C, Stenmark K, Fini M . U-shaped association of uric acid to overall-cause mortality and its impact on clinical management of hyperuricemia. Redox Biol. 2022; 51:102271. PMC: 8889273. DOI: 10.1016/j.redox.2022.102271. View

Lytvyn Y, Skrtic M, Yang G, Yip P, Perkins B, Cherney D . Glycosuria-mediated urinary uric acid excretion in patients with uncomplicated type 1 diabetes mellitus. Am J Physiol Renal Physiol. 2014; 308(2):F77-83. DOI: 10.1152/ajprenal.00555.2014. View

Zhuang Y, Huang H, Hu X, Zhang J, Cai Q . Serum uric acid and diabetic peripheral neuropathy: a double-edged sword. Acta Neurol Belg. 2022; 123(3):857-863. PMC: 10238292. DOI: 10.1007/s13760-022-01978-1. View

Ahola A, Sandholm N, Forsblom C, Harjutsalo V, Dahlstrom E, Groop P . The serum uric acid concentration is not causally linked to diabetic nephropathy in type 1 diabetes. Kidney Int. 2017; 91(5):1178-1185. DOI: 10.1016/j.kint.2016.11.025. View

Kaewput W, Thongprayoon C, Rangsin R, Jindarat S, Narindrarangkura P, Bathini T . The Association between Serum Uric Acid and Peripheral Neuropathy in Patients with Type 2 Diabetes Mellitus: A Multicenter Nationwide CrossSectional Study. Korean J Fam Med. 2020; 41(3):189-194. PMC: 7272369. DOI: 10.4082/kjfm.18.0205. View

Xia Q, Zhang S, Yang S, Zhu X, Su S, Hu A . Serum uric acid is independently associated with diabetic nephropathy but not diabetic retinopathy in patients with type 2 diabetes mellitus. J Chin Med Assoc. 2020; 83(4):350-356. DOI: 10.1097/JCMA.0000000000000285. View

Cui J, Ren J, Chen D, Xin Z, Yuan M, Xu J . Prevalence and associated factors of diabetic retinopathy in Beijing, China: a cross-sectional study. BMJ Open. 2017; 7(8):e015473. PMC: 5724071. DOI: 10.1136/bmjopen-2016-015473. View

Kuwata H, Okamura S, Hayashino Y, Tsujii S, Ishii H . Serum uric acid levels are associated with increased risk of newly developed diabetic retinopathy among Japanese male patients with type 2 diabetes: A prospective cohort study (diabetes distress and care registry at Tenri [DDCRT 13]). Diabetes Metab Res Rev. 2017; 33(7). DOI: 10.1002/dmrr.2905. View

10.

Burgess S, Butterworth A, Thompson S . Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013; 37(7):658-65. PMC: 4377079. DOI: 10.1002/gepi.21758. View

11.

Yu S, Chen Y, Hou X, Xu D, Che K, Li C . Serum Uric Acid Levels and Diabetic Peripheral Neuropathy in Type 2 Diabetes: a Systematic Review and Meta-analysis. Mol Neurobiol. 2015; 53(2):1045-1051. DOI: 10.1007/s12035-014-9075-0. View

12.

Guo Y, Liu S, Xu H . Uric Acid and Diabetic Retinopathy: A Systematic Review and Meta-Analysis. Front Public Health. 2022; 10:906760. PMC: 9197488. DOI: 10.3389/fpubh.2022.906760. View

13.

Huang T, Hao D, Wu B, Mao L, Zhang J . Uric acid demonstrates neuroprotective effect on Parkinson's disease mice through Nrf2-ARE signaling pathway. Biochem Biophys Res Commun. 2017; 493(4):1443-1449. DOI: 10.1016/j.bbrc.2017.10.004. View

14.

Burgess S, Thompson S . Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017; 32(5):377-389. PMC: 5506233. DOI: 10.1007/s10654-017-0255-x. View

15.

Becker B . Towards the physiological function of uric acid. Free Radic Biol Med. 1993; 14(6):615-31. DOI: 10.1016/0891-5849(93)90143-i. View

16.

Skrivankova V, Richmond R, Woolf B, Yarmolinsky J, Davies N, Swanson S . Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: The STROBE-MR Statement. JAMA. 2021; 326(16):1614-1621. DOI: 10.1001/jama.2021.18236. View

17.

Fayazi H, Yaseri M, Mortazavi S, Sharifhassan Z, Assadinia A . The relation between serum uric acid levels and diabetic peripheral neuropathy in type 2 diabetes in Guilan, north of Iran. BMC Endocr Disord. 2022; 22(1):39. PMC: 8840027. DOI: 10.1186/s12902-022-00952-5. View

18.

Kurki M, Karjalainen J, Palta P, Sipila T, Kristiansson K, Donner K . FinnGen provides genetic insights from a well-phenotyped isolated population. Nature. 2023; 613(7944):508-518. PMC: 9849126. DOI: 10.1038/s41586-022-05473-8. View

19.

Davey Smith G, Hemani G . Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet. 2014; 23(R1):R89-98. PMC: 4170722. DOI: 10.1093/hmg/ddu328. View

20.

Ficociello L, Rosolowsky E, Niewczas M, Maselli N, Weinberg J, Aschengrau A . High-normal serum uric acid increases risk of early progressive renal function loss in type 1 diabetes: results of a 6-year follow-up. Diabetes Care. 2010; 33(6):1337-43. PMC: 2875450. DOI: 10.2337/dc10-0227. View