title: Copy number variation at leptin receptor gene locus associated with metabolic traits and the risk of type 2 diabetes mellitus.
abstract: BACKGROUND
  Recent efforts have been made to link complex human traits and disease susceptibility to DNA copy numbers. The leptin receptor (LEPR) has been implicated in obesity and diabetes. Mutations and genetic variations of LEPR gene have been discovered in rodents and humans. However, the association of DNA copy number variations at the LEPR gene locus with human complex diseases has not been reported. In an attempt to study DNA copy number variations associated with metabolic traits and type 2 diabetes mellitus (T2DM), we targeted the LEPR gene locus in DNA copy number analyses.
  
  
  RESULTS
  We identified DNA copy number variations at the LEPR gene locus among a Korean population using genome-wide SNP chip data, and then quantified copy numbers of the E2 DNA sequence in the first two exons overlapped between LEPR and LEPROT genes by the quantitative multiplex PCR of short fluorescent fragment (QMPSF) method. Among the non-diabetic subjects (n = 1,067), lower E2 DNA copy numbers were associated with higher fasting glucose levels in men (p = 1.24 x 10(-7)) and women (p = 9.45 x 10(-5)), as well as higher total cholesterol levels in men (p = 9.96 x 10(-7)). In addition, the significant association between lower E2 DNA copy numbers and lower level of postprandial 2 hr insulin was evident only in non-diabetic women, whereas some obesity-related phenotypes and total cholesterol level exhibited significant associations only in non-diabetic men. Logistic regression analysis indicated that lower E2 DNA copy numbers were associated with T2DM (odds ratio, 1.92; 95% CI, 1.26-2.96; p < 0.003) in our nested case-control study. Interestingly, the E2 DNA copy number exhibited a negative correlation with LEPR gene expression, but a positive correlation with LEPROT gene expression.
  
  
  CONCLUSIONS
  This work suggests that a structural variation at the LEPR gene locus is functionally associated with complex metabolic traits and the risk of T2DM.
authors.affiliation: Division of Biobank for Health Sciences, Korea National Institute of Health, Korea Centers for Disease Control and Prevention, 194 Tongil Ro, Seoul, 122-701, Korea. jaepiljeon@hanmail.net
authors.forename: Jae-Pil
authors.initials: JP
authors.lastname: Jeon
authors.forename: Sung-Mi
authors.initials: SM
authors.lastname: Shim
authors.forename: Hye-Young
authors.initials: HY
authors.lastname: Nam
authors.forename: Gil-Mi
authors.initials: GM
authors.lastname: Ryu
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Hong
authors.forename: Hyung-Lae
authors.initials: HL
authors.lastname: Kim
authors.forename: Bok-Ghee
authors.initials: BG
authors.lastname: Han
mesh_terms: D001786:Blood Glucose / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D007723:Korea; D008297:Male; D054411:Receptors, Leptin / Q000235:genetics*
chemical_list: D001786:Blood Glucose; D054411:Receptors, Leptin; D002784:Cholesterol