Abstract
Abstract
Aims/hypothesis
Galectin-1 modulates inflammation and angiogenesis, and cross-sectional studies indicate that galectin-1 may be a uniting factor between obesity, type 2 diabetes and kidney function. We examined whether circulating galectin-1 can predict incidence of chronic kidney disease (CKD) and type 2 diabetes in a middle-aged population, and if Mendelian randomisation (MR) can provide evidence for causal direction of effects.
Methods
Participants (n = 4022; 58.6% women) in the Malmö Diet and Cancer Study–Cardiovascular Cohort enrolled between 1991 and 1994 (mean age 57.6 years) were examined. eGFR was calculated at baseline and after a mean follow-up of 16.6 ± 1.5 years. Diabetes status was ascertained through registry linkage (mean follow-up of 18.4 ± 6.1 years). The associations of baseline galectin-1 with incident CKD and type 2 diabetes were assessed with Cox regression, adjusting for established risk factors. In addition, a genome-wide association study on galectin-1 was performed to identify genetic instruments for two-sample MR analyses utilising the genetic associations obtained from the Chronic Kidney Disease Genetics (CKDGen) Consortium (41,395 cases and 439,303 controls) and the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (74,124 cases and 824,006 controls). One genome-wide significant locus in the galectin-1 gene region was identified (sentinel SNP rs7285699; p = 2.4 × 10−11). The association between galectin-1 and eGFR was also examined in individuals with newly diagnosed diabetes from the All New Diabetics In Scania (ANDIS) cohort.
Results
Galectin-1 was strongly associated with lower eGFR at baseline (p = 2.3 × 10−89) but not with incident CKD. However, galectin-1 was associated with increased risk of type 2 diabetes (per SD increase, HR 1.12; 95% CI 1.02, 1.24). Two-sample MR analyses could not ascertain a causal effect of galectin-1 on CKD (OR 0.92; 95% CI 0.82, 1.02) or type 2 diabetes (OR 1.05; 95% CI 0.98, 1.14) in a general population. However, in individuals with type 2 diabetes from ANDIS who belonged to the severe insulin-resistant diabetes subgroup and were at high risk of diabetic nephropathy, genetically elevated galectin-1 was significantly associated with higher eGFR (p = 5.7 × 10−3).
Conclusions/interpretation
Galectin-1 is strongly associated with lower kidney function in cross-sectional analyses, and two-sample MR analyses suggest a causal protective effect on kidney function among individuals with type 2 diabetes at high risk of diabetic nephropathy. Future studies are needed to explore the mechanisms by which galectin-1 affects kidney function and whether it could be a useful target among individuals with type 2 diabetes for renal improvement.
Graphical abstract
Funder
Diabetesfonden
Svenska Sällskapet för Medicinsk Forskning
The Swedish ALF agreement
Pfizer
Crafoordska Stiftelsen
Linnéuniversitetet
Hjärt-Lungfonden
Direktör Albert Påhlssons Stiftelse
Olink Proteomics
Dr P Håkanssons Stiftelse
Stiftelsen för Strategisk Forskning
Insamlingsstiftelsen Diabetes Wellness Network Sverige
Novo Nordisk Fonden
Vetenskapsrådet
H2020 European Research Council
Knut och Alice Wallenbergs Stiftelse
Publisher
Springer Science and Business Media LLC
Subject
Endocrinology, Diabetes and Metabolism,Internal Medicine
Cited by
7 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献