The role of circulating galectin-1 in type 2 diabetes and chronic kidney disease : evidence from cross-sectional, longitudinal and Mendelian randomisation analyses
(2022) In Diabetologia 65(1). p.128-139- 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... (More)
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.]
(Less)
- author
- Drake, Isabel LU ; Fryk, Emanuel ; Strindberg, Lena ; Lundqvist, Annika ; Rosengren, Anders H. LU ; Groop, Leif LU ; Ahlqvist, Emma LU ; Borén, Jan ; Orho-Melander, Marju LU and Jansson, Per Anders
- organization
- publishing date
- 2022
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- ANDIS, Chronic kidney disease, Galectin-1, Human, Malmö Diet Cancer, Mendelian randomisation, Population-based, Prospective, Type 2 diabetes
- in
- Diabetologia
- volume
- 65
- issue
- 1
- pages
- 128 - 139
- publisher
- Springer
- external identifiers
-
- pmid:34743218
- scopus:85118535343
- ISSN
- 0012-186X
- DOI
- 10.1007/s00125-021-05594-1
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © 2021, The Author(s).
- id
- 0b249d22-dc62-45ee-a8dd-dc0eb4231066
- date added to LUP
- 2021-12-02 12:13:29
- date last changed
- 2024-06-15 21:57:47
@article{0b249d22-dc62-45ee-a8dd-dc0eb4231066,
abstract = {{<p>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<sup>−11</sup>). 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<sup>−89</sup>) 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<sup>−3</sup>). 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.]</p>}},
author = {{Drake, Isabel and Fryk, Emanuel and Strindberg, Lena and Lundqvist, Annika and Rosengren, Anders H. and Groop, Leif and Ahlqvist, Emma and Borén, Jan and Orho-Melander, Marju and Jansson, Per Anders}},
issn = {{0012-186X}},
keywords = {{ANDIS; Chronic kidney disease; Galectin-1; Human; Malmö Diet Cancer; Mendelian randomisation; Population-based; Prospective; Type 2 diabetes}},
language = {{eng}},
number = {{1}},
pages = {{128--139}},
publisher = {{Springer}},
series = {{Diabetologia}},
title = {{The role of circulating galectin-1 in type 2 diabetes and chronic kidney disease : evidence from cross-sectional, longitudinal and Mendelian randomisation analyses}},
url = {{http://dx.doi.org/10.1007/s00125-021-05594-1}},
doi = {{10.1007/s00125-021-05594-1}},
volume = {{65}},
year = {{2022}},
}