Expression-based genome-wide association study links the receptor CD44 in adipose tissue with type 2 diabetes

Keiichi Kodama, Momoko Horikoshi, Kyoko Toda, Satoru Yamada, Kazuo Hara, Junichiro Irie, Marina Sirota, Alexander A. Morgan, Rong Chen, Hiroshi Ohtsu, Shiro Maeda, Takashi Kadowaki, Atul J. Butte

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)7049-7054
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number18
DOIs
Publication statusPublished - 2012 May 1

Fingerprint

Genome-Wide Association Study
Type 2 Diabetes Mellitus
Adipose Tissue
Insulin Resistance
Genes
Inflammation
Genetic Association Studies
High Fat Diet
Disease Progression
Blood Glucose
Anti-Idiotypic Antibodies
Rodentia
Macrophages
Gene Expression
Serum

Keywords

  • Bioinformatics
  • Hyperglycemia
  • Integration
  • Meta-analysis
  • Obesity

ASJC Scopus subject areas

  • General

Cite this

Expression-based genome-wide association study links the receptor CD44 in adipose tissue with type 2 diabetes. / Kodama, Keiichi; Horikoshi, Momoko; Toda, Kyoko; Yamada, Satoru; Hara, Kazuo; Irie, Junichiro; Sirota, Marina; Morgan, Alexander A.; Chen, Rong; Ohtsu, Hiroshi; Maeda, Shiro; Kadowaki, Takashi; Butte, Atul J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 18, 01.05.2012, p. 7049-7054.

Research output: Contribution to journalArticle

Kodama, K, Horikoshi, M, Toda, K, Yamada, S, Hara, K, Irie, J, Sirota, M, Morgan, AA, Chen, R, Ohtsu, H, Maeda, S, Kadowaki, T & Butte, AJ 2012, 'Expression-based genome-wide association study links the receptor CD44 in adipose tissue with type 2 diabetes', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 18, pp. 7049-7054. https://doi.org/10.1073/pnas.1114513109
Kodama, Keiichi ; Horikoshi, Momoko ; Toda, Kyoko ; Yamada, Satoru ; Hara, Kazuo ; Irie, Junichiro ; Sirota, Marina ; Morgan, Alexander A. ; Chen, Rong ; Ohtsu, Hiroshi ; Maeda, Shiro ; Kadowaki, Takashi ; Butte, Atul J. / Expression-based genome-wide association study links the receptor CD44 in adipose tissue with type 2 diabetes. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 18. pp. 7049-7054.
@article{4fc0d6089d5a48dd9df4aaa9ae001d1a,
title = "Expression-based genome-wide association study links the receptor CD44 in adipose tissue with type 2 diabetes",
abstract = "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.",
keywords = "Bioinformatics, Hyperglycemia, Integration, Meta-analysis, Obesity",
author = "Keiichi Kodama and Momoko Horikoshi and Kyoko Toda and Satoru Yamada and Kazuo Hara and Junichiro Irie and Marina Sirota and Morgan, {Alexander A.} and Rong Chen and Hiroshi Ohtsu and Shiro Maeda and Takashi Kadowaki and Butte, {Atul J.}",
year = "2012",
month = "5",
day = "1",
doi = "10.1073/pnas.1114513109",
language = "English",
volume = "109",
pages = "7049--7054",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "18",

}

TY - JOUR

T1 - Expression-based genome-wide association study links the receptor CD44 in adipose tissue with type 2 diabetes

AU - Kodama, Keiichi

AU - Horikoshi, Momoko

AU - Toda, Kyoko

AU - Yamada, Satoru

AU - Hara, Kazuo

AU - Irie, Junichiro

AU - Sirota, Marina

AU - Morgan, Alexander A.

AU - Chen, Rong

AU - Ohtsu, Hiroshi

AU - Maeda, Shiro

AU - Kadowaki, Takashi

AU - Butte, Atul J.

PY - 2012/5/1

Y1 - 2012/5/1

N2 - 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.

AB - 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.

KW - Bioinformatics

KW - Hyperglycemia

KW - Integration

KW - Meta-analysis

KW - Obesity

UR - http://www.scopus.com/inward/record.url?scp=84860791012&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84860791012&partnerID=8YFLogxK

U2 - 10.1073/pnas.1114513109

DO - 10.1073/pnas.1114513109

M3 - Article

VL - 109

SP - 7049

EP - 7054

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 18

ER -