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Photo: KG Pressfoto

Marju Orho-Melander

Professor

Photo: KG Pressfoto

The role of circulating galectin-1 in type 2 diabetes and chronic kidney disease : evidence from cross-sectional, longitudinal and Mendelian randomisation analyses

Author

  • Isabel Drake
  • Emanuel Fryk
  • Lena Strindberg
  • Annika Lundqvist
  • Anders H. Rosengren
  • Leif Groop
  • Emma Ahlqvist
  • Jan Borén
  • Marju Orho-Melander
  • Per Anders Jansson

Summary, in English

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: [Figure not available: see fulltext.]

Department/s

  • Diabetes - Cardiovascular Disease
  • EpiHealth: Epidemiology for Health
  • EXODIAB: Excellence of Diabetes Research in Sweden
  • Diabetes - Islet Patophysiology
  • Genomics, Diabetes and Endocrinology

Publishing year

2022

Language

English

Pages

128-139

Publication/Series

Diabetologia

Volume

65

Issue

1

Document type

Journal article

Publisher

Springer

Topic

  • Urology and Nephrology

Keywords

  • ANDIS
  • Chronic kidney disease
  • Galectin-1
  • Human
  • Malmö Diet Cancer
  • Mendelian randomisation
  • Population-based
  • Prospective
  • Type 2 diabetes

Status

Published

Research group

  • Diabetes - Cardiovascular Disease
  • Diabetes - Islet Patophysiology
  • Genomics, Diabetes and Endocrinology

ISBN/ISSN/Other

  • ISSN: 0012-186X