Lack of significant effects of the type 2 diabetes susceptibility loci JAZF1, CDC123/CAMK1D, NOTCH2, ADAMTS9, THADA, and TSPAN8/LGR5 on diabetes and quantitative metabolic traits

Horm Metab Res. 2010 Jan;42(1):14-22. doi: 10.1055/s-0029-1233480. Epub 2009 Aug 10.

Abstract

Recently, several novel loci reaching genome-wide significance levels for type 2 diabetes (T2D) were identified through a meta-analysis of three genome-wide scans and large-scale follow-up. The aim of our study was to investigate the association of these loci with T2D and related subphenotypes in two cohorts from Germany. We performed an association study of 9 SNPs in or around JAZF1, CDC123/ CAMK1D, NOTCH2, BCL11A, ADAMTS9, VEGFA, DCD, THADA, and TSPAN8/ LGR5 with T2D and related quantitative traits (fasting insulin and glucose, indices derived from OGTT) in the isolated population of Sorbs (205 cases and 695 controls) and in a mixed German population (Leipzig) (938 subjects with and 918 without T2D). None of the variants was associated with T2D, but the meta-analysis of both cohorts revealed a modest trend of association of rs7578597 in THADA with T2D (p=0.055). Furthermore, Sorbian subjects homozygous for the rs7578597 T-allele had lower mean 30-minute plasma insulin when compared with carriers of the C-allele (p<0.05). The T-allele was also nominally associated with higher fasting plasma glucose in the Leipzig cohort (p<0.05). Although several other SNPs showed some evidence for association with T2D-related traits the effects were not replicated within our study. Associations of the T2D-risk alleles with T2D or related subphenotypes were overall very weak in the approximately 2 700 subjects studied. This is compatible with the modest effect size of these "second sweep" variants, which will require large-scale association studies on quantitative traits to clarify their role in the pathophysiology of T2D.

MeSH terms

  • ADAM Proteins / genetics*
  • ADAMTS9 Protein
  • Adult
  • Antigens, Neoplasm / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 1 / genetics
  • Case-Control Studies
  • Cell Cycle Proteins / genetics
  • Cohort Studies
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism
  • Female
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study*
  • Germany
  • Glucose / metabolism
  • Humans
  • Insulin / metabolism
  • Male
  • Membrane Glycoproteins / genetics
  • Middle Aged
  • Neoplasm Proteins / genetics
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci*
  • Receptor, Notch2 / genetics
  • Receptors, G-Protein-Coupled / genetics
  • Tetraspanins

Substances

  • Antigens, Neoplasm
  • Cell Cycle Proteins
  • Insulin
  • JAZF1 protein, human
  • LGR5 protein, human
  • Membrane Glycoproteins
  • NOTCH2 protein, human
  • Neoplasm Proteins
  • Receptor, Notch2
  • Receptors, G-Protein-Coupled
  • THADA protein, human
  • TSPAN8 protein, human
  • Tetraspanins
  • CDC123 protein, human
  • CAMK1D protein, human
  • Calcium-Calmodulin-Dependent Protein Kinase Type 1
  • ADAM Proteins
  • ADAMTS9 Protein
  • ADAMTS9 protein, human
  • Glucose