Copy number variation at leptin receptor gene locus associated with metabolic traits and the risk of type 2 diabetes mellitus

<p>Abstract</p> <p>Background</p> <p>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 <it>LEPR </it>gene have been discovered in rodents and humans. However, the association of DNA copy number variations at the <it>LEPR </it>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 <it>LEPR </it>gene locus in DNA copy number analyses.</p> <p>Results</p> <p>We identified DNA copy number variations at the <it>LEPR </it>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 <it>LEPR </it>and <it>LEPROT </it>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 (<it>p </it>= 1.24 × 10^-7) and women (<it>p </it>= 9.45 × 10^-5), as well as higher total cholesterol levels in men (<it>p </it>= 9.96 × 10^-7). In addition, the significant association between lower E2 DNA copy numbers and lower level of postprandial 2hr 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.</p> <p>Conclusions</p> <p>This work suggests that a structural variation at the <it>LEPR </it>gene locus is functionally associated with complex metabolic traits and the risk of T2DM.</p

Effect of Al–5Ti–1B Addition on Solidification Microstructure and Hot Deformation Behavior of DC-Cast Al–Zn–Mg–Cu Alloy

This study investigated the effect of adding Al–5Ti–1B grain refiner on the solidification microstructure and hot deformation behavior of direct-chill (DC) cast Al–Zn–Mg–Cu alloys. The grain refiner significantly decreased the grain size and modified the morphology. Fine-grained (FG) alloys with grain refiners exhibit coarse secondary phases with a reduced number density compared to coarse-grained (CG) alloys without grain refiners. Dynamic recrystallization (DRX) was enhanced at higher compression temperatures and lower strain rates in the CG and FG alloys. Both particle stimulated nucleation (PSN) and continuous dynamic recrystallization (CDRX) are enhanced in the FG alloys, resulting in decreased peak stress values (indicating DRX onset) at 450°C. The peak stress of the FG alloys was higher at 300-400°C than that of the CG alloys because of grain refinement hardening over softening by enhanced DRX