title: Interactive effects of a common γ-glutamyltransferase 1 variant and low high-density lipoprotein-cholesterol on diabetic macro- and micro-angiopathy.
abstract: BACKGROUND
  We investigated the clinical relevance of a common variant, rs4820599, in the γ-glutamyltransferase (GGT)1 gene, associated with the serum GGT level, in Japanese type 2 diabetes mellitus (T2DM) subjects.
  
  
  METHODS
  We conducted a retrospective longitudinal study (4.9 ± 2.5 years) including 352 T2DM patients (T2DM subjects) and a cross-sectional study including 796 health screening program participants (general subjects). A real-time TaqMan allelic discrimination assay was used to identify the genotypes. Risk factors for a high brachial-ankle pulse wave velocity (baPWV) (≥1750 cm/sec) or diabetic retinopathy (DR) were determined using a generalized estimating equations approach, receiver operating characteristic (ROC) analysis or Cox proportional hazards model, etc.
  
  
  RESULTS
  The frequency of the GGT1 G allele was 20.8% in the T2DM subjects, and no associations were found between the GGT1 genotype and risk of T2DM. The mean log GGT values in the T2DM and general subjects were significantly higher among G allele carriers than non-carriers. The G allele and a low HDL-C level were identified to be risk factors for a high baPWV in the T2DM subjects [odds ratio (OR) 1.80, P = 0.008; OR 1.71, P = 0.03; respectively), and a significant interactive effect between these factors was found on the risk of a high baPWV and DR. The HDL-C level at baseline was a significant predictor of a high baPWV only in G allele carriers according to the ROC analysis. This result regarding baPWV in the T2DM subjects was replicated in the general population. Meanwhile, the GGT1 genotype was not associated with the risk of DR, although it affected the principal factors involved in the risk of DR, and a low HDL-C level was also found to be a risk factor for DR only in G allele carriers.
  
  
  CONCLUSIONS
  We herein describe for the first time the significant interactive effects of the GGT1 G allele and a low HDL-C level on a high baPWV and DR. These findings may encourage future clinical trials comparing the efficacy of agents increasing the HDL-C levels among the GGT1 genotypes. However, well-designed studies in larger cohorts are needed to confirm our results.
authors.affiliation: Division of Preventive Cardiology, Department of Cardiovascular Medicine, Kumamoto University Hospital, Kumamoto, Japan. hideaki@jinnouchi.or.jp.|Jinnouchi Clinic, Diabetes Care Center, Kumamoto, Japan. hideaki@jinnouchi.or.jp.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Jinnouchi
authors.affiliation: Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, 862-0973, Kumamoto, Japan. 133y3107@st.kumamoto-u.ac.jp.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Morita
authors.affiliation: Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, 862-0973, Kumamoto, Japan. 102p1027@st.kumamoto-u.ac.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, 862-0973, Kumamoto, Japan. 132y3102@st.kumamoto-u.ac.jp.
authors.forename: Ayami
authors.initials: A
authors.lastname: Kajiwara
authors.affiliation: Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, 862-0973, Kumamoto, Japan. 109p1015@st.kumamoto-u.ac.jp.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kawata
authors.affiliation: Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, 862-0973, Kumamoto, Japan. oniken@kumamoto-u.ac.jp.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Oniki
authors.affiliation: Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, 862-0973, Kumamoto, Japan. junsaru@gpo.kumamoto-u.ac.jp.
authors.forename: Junji
authors.initials: J
authors.lastname: Saruwatari
authors.affiliation: Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, 862-0973, Kumamoto, Japan. kazukon@gpo.kumamoto-u.ac.jp.|Center for Clinical Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan. kazukon@gpo.kumamoto-u.ac.jp.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Nakagawa
authors.affiliation: Japanese Red Cross Kumamoto Health Care Center, Kumamoto, Japan. 101p1022@st.kumamoto-u.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Otake
authors.affiliation: Japanese Red Cross Kumamoto Health Care Center, Kumamoto, Japan. 103p1035@st.kumamoto-u.ac.jp.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ogata
authors.affiliation: Jinnouchi Clinic, Diabetes Care Center, Kumamoto, Japan. akira.y@jinnouchi.or.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Yoshida
authors.affiliation: Division of Preventive Cardiology, Department of Cardiovascular Medicine, Kumamoto University Hospital, Kumamoto, Japan. shokimot@kumamoto-u.ac.jp.|Department of Cardiovascular Medicine, Faculty of Life Sciences, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. shokimot@kumamoto-u.ac.jp.
authors.forename: Seiji
authors.initials: S
authors.lastname: Hokimoto
authors.affiliation: Division of Preventive Cardiology, Department of Cardiovascular Medicine, Kumamoto University Hospital, Kumamoto, Japan. ogawah@kumamoto-u.ac.jp.|Department of Cardiovascular Medicine, Faculty of Life Sciences, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. ogawah@kumamoto-u.ac.jp.
authors.forename: Hisao
authors.initials: H
authors.lastname: Ogawa
mesh_terms: D000368:Aged; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*; D003925:Diabetic Angiopathies / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D005723:gamma-Glutamyltransferase / Q000235:genetics*
chemical_list: D008075:Lipoproteins, HDL; D005723:gamma-Glutamyltransferase; C554782:gamma-glutamyltransferase, human