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.
authors.affiliation: Division of Systems Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kodama
authors.forename: Momoko
authors.initials: M
authors.lastname: Horikoshi
authors.forename: Kyoko
authors.initials: K
authors.lastname: Toda
authors.forename: Satoru
authors.initials: S
authors.lastname: Yamada
authors.forename: Kazuo
authors.initials: K
authors.lastname: Hara
authors.forename: Junichiro
authors.initials: J
authors.lastname: Irie
authors.forename: Marina
authors.initials: M
authors.lastname: Sirota
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Morgan
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohtsu
authors.forename: Shiro
authors.initials: S
authors.lastname: Maeda
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Atul J
authors.initials: AJ
authors.lastname: Butte
mesh_terms: D000273:Adipose Tissue / Q000276:immunology* / Q000473:pathology; D000368:Aged; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000235:genetics* / Q000276:immunology*; D004041:Dietary Fats / Q000008:administration & dosage; D005260:Female; D015870:Gene Expression; D055106:Genome-Wide Association Study; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics* / Q000378:metabolism; D007333:Insulin Resistance / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009765:Obesity / Q000150:complications / Q000235:genetics / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D015434:Panniculitis / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000473:pathology
chemical_list: D001786:Blood Glucose; C497483:CD44 protein, human; C476399:Cd44 protein, mouse; D004041:Dietary Fats; D018960:Hyaluronan Receptors