title: Single nucleotide polymorphisms in genes encoding LKB1 (STK11), TORC2 (CRTC2) and AMPK alpha2-subunit (PRKAA2) and risk of type 2 diabetes.
abstract: The LKB1-AMPK-TORC2 signaling pathway controls glucose homeostasis in the liver, and mediates therapeutic effects of insulin-sensitizing antidiabetic agents. To examine whether genetic variations in genes encoding components of this signaling pathway contribute to increased susceptibility to type 2 diabetes, we screened STK11 (LKB1) and CRTC2 (TORC2) genes for genetic variants and conducted a case-control study in 1787 unrelated Japanese individuals. Additionally, the previously described association between the PRKAA2 (AMPK alpha2-subunit) haplotype and type 2 diabetes was tested for replication. We observed associations of nominal significance with two SNPs, an intronic SNP in the STK11 (rs741765; OR 1.33, 95% CI 1.05-1.67, p=0.017, under a recessive genetic model), and a non-synonymous SNP in the CRTC2 (6909C>T: Arg379Cys; OR 3.01, 95% CI 1.18-7.66, p=0.016, under a dominant model), although neither withstood correction for multiple testing. We were unable to replicate the association between the PRKAA2 haplotype and type 2 diabetes: however, in the single SNP evaluation, an intronic PRKAA2 SNP (rs1418442) that had previously been reported to be associated with serum cholesterol levels in Caucasian females showed a weak association (OR 0.62, 95% CI 0.40-0.96, p=0.030, under a recessive model). Among the three genes investigated herein, gene-gene (SNP-SNP) interaction studies provided evidence for an interaction between STK11 and CRTC2 influencing susceptibility to type 2 diabetes. Our findings suggest that genetic variants of LKB1-AMPK-TORC2 pathway components may exert a weak influence on the occurrence of type 2 diabetes in Japanese.
authors.affiliation: Division of Genetic Information, Institute for Genome Research, The University of Tokushima, 3-18-15, Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Parvaneh
authors.initials: P
authors.lastname: Keshavarz
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.forename: Naoto
authors.initials: N
authors.lastname: Nakamura
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Toshihito
authors.initials: T
authors.lastname: Tanahashi
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Itakura
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000328:Adult; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007564:Japan; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012307:Risk Factors; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C493245:CRTC2 protein, human; D009097:Multienzyme Complexes; D014157:Transcription Factors; C526181:PRKAA2 protein, human; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases