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

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

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.

Keywords: ANDIS; Chronic kidney disease; Galectin-1; Human; Malmö Diet Cancer; Mendelian randomisation; Population-based; Prospective; Type 2 diabetes.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
A flow chart of participants of the MDCS-CC with circulating levels of galectin-1 who were included in the cross-sectional and longitudinal analyses and in GWAS and MR analyses.T2D, type 2 diabetes
Fig. 2
Fig. 2
Genome-wide analyses for fasting serum concentration of galectin-1 in the MDCS-CC. (a) Manhattan plot of SNPs with p values <0.10 based on genome-wide analysis (chromosomes 1–22) in n = 4086 participants from the MDCS-CC. Red line indicates the genome-wide significant p value of 5 × 10−8. (b) Quantile–quantile (QQ) plot. (c) Regional locus zoom plot of associations at/near the galectin-1 gene (LGALS1). The purple diamond indicates the sentinel SNP (rs7285699; p = 2.4 × 10−11), and all identified SNPs within different degrees of perfect linkage disequilibrium are also shown (r2 ≥ 0.80 [red], <0.8–0.6 [orange], <0.6–0.4 [green], <0.4–0.2 [light blue] and ≤0.2 [dark blue]) at this locus. cM, centimorgans; Mb, megabase
Fig. 3
Fig. 3
Two-sample MR analyses for the association of genetically predicted serum galectin-1 levels with (a) CKD and type 2 diabetes and (b) creatinine-based eGFR, overall and stratified by diabetes mellitus status. aWuttke et al (2019) [25]; bPattaro et al (2016) [26]; cANDIS cohort. T2D, type 2 diabetes; WR, Wald ratio

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Source: PubMed

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