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Expression-based genome-wide association study links the receptor CD44 in adipose tissue with type 2 diabetes
Open accessAbstract
Type 2 diabetes (T2D) is a complex, polygenic disease affecting nearly 300 million people worldwide. T2D is primarily characterized by insulin resistance, and growing evidence has indicated the causative link between adipose tissue inflammation and the development of insulin resistance. Genetic association studies have successfully revealed a number of important genes consistently associated with T2D to date. However, these robust T2D-associated genes do not fully elucidate the mechanisms underlying the development and progression of the disease. Here, we report an alternative approach, gene expression-based genome-wide association study (eGWAS): searching for genes repeatedly implicated in functional microarray experiments (often publicly available). We performed an eGWAS across 130 independent experiments (totally 1,175 T2D case-control microarrays) to find additional genes implicated in the molecular pathogenesis of T2D and identified the immune-cell receptor CD44 as our top candidate ( P = 8.5 × 10 −20 ). We found CD44 deficiency in a diabetic mouse model ameliorates insulin resistance and adipose tissue inflammation and also found that anti-CD44 antibody treatment decreases blood glucose levels and adipose tissue macrophage accumulation in a high-fat, diet-fed mouse model. Further, in humans, we observed CD44 is expressed in inflammatory cells in obese adipose tissue and discovered serum CD44 levels were positively correlated with insulin resistance and glycemic control. CD44 likely plays a causative role in the development of adipose tissue inflammation and insulin resistance in rodents and humans. Genes repeatedly implicated in publicly available experimental data may have unique functionally important roles in T2D and other complex diseases.
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“CD44, the main hyaluronan cell surface receptor is associated with T2DM, as shown by expression-based genome-wide association studies.”
From The Vasculature in Prediabetes (2018) · cites this paper as [176]
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Metadata
- Authors
- Kodama, K., Horikoshi, M., Toda, K., Yamada, S., Hara, K., Irie, J., Sirota, M., Morgan, A. A., Chen, R., Ohtsu, H., Maeda, S., Kadowaki, T., & Butte, A. J.
- Affiliations
- Lucile Packard Children's Hospital (US)
- The University of Tokyo (JP)
- Kitasato Institute Hospital (JP)
- Keio University (JP)
- RIKEN (JP)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-04-12
- Volume
- 109
- Issue
- 18
- Pages
- 7049-7054
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3344989
- OpenAlex
- W2044994793
- Cited by
- 171
- References
- 43
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 16 · 2023: 18 · 2022: 9 · 2021: 10 · 2020: 14 · 2019: 8 · 2018: 17 · 2017: 10 · 2016: 10 · 2015: 20 · 2014: 11 · 2013: 14 · 2012: 7
- FWCI
- 12.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Lunds Universitet
- Kitasato University
- School of Medicine, Stanford University
- Japan Society for the Promotion of Science (20229008)
- U.S. National Library of Medicine (K22LM008261, R01LM009719, T15LM007033)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- type 2 diabetes, CD44, insulin resistance, adipose tissue inflammation, adipose tissue macrophages, obesity, diabetic mouse model, anti-CD44 antibody, glycemic control
- MeSH terms
- Adipose Tissue, Aged, Animals, Blood Glucose, Diabetes Mellitus, Type 2, Dietary Fats, Female, Humans, Insulin Resistance, Macrophages, Male, Mice, Inbred C57BL, Middle Aged, Obesity, Panniculitis, Gene Expression, Case-Control Studies, Mice, Knockout, Hyaluronan Receptors, Oligonucleotide Array Sequence Analysis, Mice, Genome-Wide Association Study
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