Plasma proteins and onset of type 2 diabetes and diabetic complications: Proteome-wide Mendelian randomization and colocalization analyses

Shuai Yuan; Fengzhe Xu; Xue Li; Jie Chen; Jie Zheng; Christos S Mantzoros; Susanna C Larsson

doi:10.1016/j.xcrm.2023.101174

Plasma proteins and onset of type 2 diabetes and diabetic complications: Proteome-wide Mendelian randomization and colocalization analyses

Cell Rep Med. 2023 Sep 19;4(9):101174. doi: 10.1016/j.xcrm.2023.101174. Epub 2023 Aug 30.

Authors

Shuai Yuan¹, Fengzhe Xu², Xue Li³, Jie Chen³, Jie Zheng⁴, Christos S Mantzoros⁵, Susanna C Larsson⁶

Affiliations

¹ Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. Electronic address: shuai.yuan@ki.se.
² Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China.
³ Department of Big Data in Health Science, School of Public Health, Center of Clinical Big Data and Analytics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁴ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁵ Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA.
⁶ Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden. Electronic address: susanna.larsson@ki.se.

Abstract

We conduct proteome-wide Mendelian randomization and colocalization analyses to decipher the associations of blood proteins with the risk of type 2 diabetes and diabetic complications. Genetic data on plasma proteome are obtained from 54,306 UK Biobank participants and 35,559 Icelanders. Summary-level data on type 2 diabetes are obtained from the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis consortium) consortium (74,124 cases) and FinnGen study (33,043 cases). Data on 10 diabetic complications are obtained from FinnGen and corresponding studies. Among 1,886 proteins, genetically predicted levels of 47 plasma proteins are associated with type 2 diabetes. Eleven of these proteins have strong support of colocalization. Seventeen proteins are associated with at least one diabetic complication, although a few have colocalization support. HLA-DRA, AGER, HSPA1A, and HSPA1B are associated with most microvascular complications. This study reveals causal proteins for the onset of type 2 diabetes and diabetic complications, which enhances the understanding of molecular etiology and development of therapeutics.

Keywords: Mendelian randomization; colocalization; diabetic complication; plasma protein; type 2 diabetes.

Publication types

Meta-Analysis

MeSH terms

Blood Proteins / genetics
Diabetes Mellitus, Type 2* / epidemiology
Diabetes Mellitus, Type 2* / genetics
Humans
Mendelian Randomization Analysis
Plasma
Proteome / genetics

Substances

Proteome
Blood Proteins