title: Two novel functional single nucleotide polymorphisms of ADRB3 are associated with type 2 diabetes in the Chinese population.
abstract: OBJECTIVE
  The purpose of this study was to investigate the association of two novel β3-adrenergic receptor (ADRB3) gene polymorphisms (Ser165Pro and Ser257Pro) with type 2 diabetes (T2DM) in the Chinese population.
  
  
  METHODS
  A total of 650 patients with T2DM and 1337 health volunteers were enrolled to conduct the association study. Two candidate polymorphisms were recreated by site-directed mutagenesis and tested for their effect on ADRB3 expression and function in stable transfected human embryonic kidney 293 and Chinese hamster ovary-K1 cells. Real-time PCR, Western blot, confocal microscopy, and cAMP assay were used to determine mRNA, protein expression, trafficking, and ADRB3 function, respectively.
  
  
  RESULTS
  We found that both polymorphisms were significantly associated with T2DM (odds ratio = 2.060 and 95% confidence interval = 1.303-3.258 for Ser165Pro and odds ratio = 7.588, 95% confidence interval = 1.639-35.138 for Ser257Pro). Patients with T2DM with the Ser165Pro C allele had higher hemoglobin A1c, fasting plasma glucose and postprandial plasma glucose values than those in TT genotypes. We also found that patients with T2DM with the Ser257Pro C allele had lower fasting serum insulin, postprandial serum insulin, and homeostasis model assessment for insulin resistance levels than TT genotype carriers. Further in vitro study indicated that cell lines stably expressing Ser165Pro and Ser257Pro mutants of the ADRB3 gene showed impaired cAMP accumulation activity. However, both polymorphisms had no effect on ADRB3 expression and trafficking.
  
  
  CONCLUSIONS
  Ser165Pro and Ser257Pro polymorphisms affected ADRB3 function and were significantly associated with susceptibility to and development of T2DM.
authors: Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, People's Republic of China.
authors: Qiong
authors: Q
authors: Huang
authors: Tian-Lun
authors: TL
authors: Yang
authors: Bei-Sha
authors: BS
authors: Tang
authors: Xiang
authors: X
authors: Chen
authors: Xi
authors: X
authors: Huang
authors: Xiang-Hang
authors: XH
authors: Luo
authors: Yuan-Shan
authors: YS
authors: Zhu
authors: Xiao-Ping
authors: XP
authors: Chen
authors: Ping-Cheng
authors: PC
authors: Hu
authors: Juan
authors: J
authors: Chen
authors: Wei
authors: W
authors: Wei
authors: Hong-Hao
authors: HH
authors: Zhou
authors: Ji-Ye
authors: JY
authors: Yin
authors: Zhao-Qian
authors: ZQ
authors: Liu
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D016466:CHO Cells; D002681:China; D006224:Cricetinae; D003412:Cricetulus; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics; D006946:Hyperinsulinism / Q000235:genetics; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: C568534:ADRB3 protein, human; D050505:Mutant Proteins; D022702:Receptors, Adrenergic, beta-3; D011994:Recombinant Proteins