title: Genetic, epigenetic and protein analyses of intercellular adhesion molecule 1 in Malaysian subjects with type 2 diabetes and diabetic nephropathy.
abstract: OBJECTIVE
  Recent research has implicated that the inflammation may be a key pathophysiological mechanism in diabetic nephropathy (DN). Intercellular adhesion molecule 1 (ICAM-1) is an acute phase marker of inflammation. In the present study, we carried out genetic, epigenetic and protein analyses of ICAM-1 in a Malaysian population, including normal glucose tolerance (NGT) subjects and type 2 diabetes (T2D) patients with or without DN in order to evaluate its role in DN.
  
  
  METHODS
  Analyses of DNA polymorphism and methylation in the ICAM1 gene were performed with TaqMan allelic discrimination and pyrosequencing, respectively. Plasma ICAM-1 levels were determined using an enzyme-linked immune-sorbent assay kit.
  
  
  RESULTS
  We found that the ICAM1 K469E(A/G) polymorphism (rs5498) was significantly associated with DN. Particularly, 86.1% of T2D patients with DN carried heterozygous genotype compared to the patients without DN (68.6%). Furthermore, plasma ICAM-1 levels were increased from NGT subjects to T2D patients without and with DN (P<0.001). The NGT subjects carrying heterozygous genotype had significantly lower plasma ICAM-1 levels compared to the K469(A/A) genotype carriers (P=0.009). In the ICAM1 gene promoter, DNA methylation levels of CpG sites were low, and no association of the ICAM1 DNA methylation alteration with DN was detected.
  
  
  CONCLUSIONS
  The present study provided evidence that the ICAM1 K469E(A/G) polymorphism with high heterozygous index and elevation of plasma ICAM-1 levels were associated with DN in a Malaysian population. Further prospective study of ICAM-1 protein according to the ICAM1 K469E(A/G) genotypes is necessary for predicting the susceptibility to T2D and DN.
authors.affiliation: Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden; Cardiovascular, Diabetes and Nutrition Research Centre, Institute for Medical Research, Kuala Lumpur, Malaysia.
authors.forename: Norhashimah
authors.initials: N
authors.lastname: Abu Seman
authors.affiliation: Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska University Hospital, Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Anderstam
authors.affiliation: Cardiovascular, Diabetes and Nutrition Research Centre, Institute for Medical Research, Kuala Lumpur, Malaysia.
authors.forename: Wan Nazaimoon
authors.initials: WN
authors.lastname: Wan Mohamud
authors.affiliation: Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Claes-Göran
authors.initials: CG
authors.lastname: Östenson
authors.affiliation: Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Brismar
authors.affiliation: Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden. Electronic address: Harvest.Gu@ki.se.
authors.forename: Harvest F
authors.initials: HF
authors.lastname: Gu
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D015331:Cohort Studies; D019175:DNA Methylation; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D008296:Malaysia; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D015854:Up-Regulation
chemical_list: D006442:Glycated Hemoglobin; D018799:Intercellular Adhesion Molecule-1; C573420:ICAM1 protein, human; C517652:hemoglobin A1c protein, human
keywords: DNA methylation; Diabetic nephropathy; Intercellular adhesion molecule 1; Single nucleotide polymorphism; Type 2 diabetes