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

Abstract

BackgroundRecent 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.ResultsWe 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 × 10-7) and women (p = 9.45 × 10-5), as well as higher total cholesterol levels in men (p = 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.ConclusionsThis work suggests that a structural variation at the LEPR gene locus is functionally associated with complex metabolic traits and the risk of T2DM.

Implications of gene copy-number variation in health and diseases

“…In a recent study, the association of the LEPR gene locus encompassing B200 kb on chromosome 1 was studied in the Korean population using the genome-wide SNP array data and it was found that CNV at the LEPR gene locus is significantly associated with metabolic traits and the risk to type 2 diabetes mellitus. 55 Overweight and obesity People with body mass index of 25 kg m À2 are considered overweight and those with body mass index of 30 kg m À2 are considered obese. As per one estimate 66% of the US population is overweight and among them about 30% are obese.…”

Genetic and environmental factors associated with type 2 diabetes and diabetic vascular complications

“…For example, a DNA copy number variation at the leptin receptor (LEPR) gene locus is associated with metabolic syndrome-related traits and risk of T2D. Lower LEPR copy numbers related to higher fasting glucose; and LEPR expression in lymphoblastoid cell lines correlated with the number of CNVs [48]. However, a role for common CNVs in the risk of T2D remains unclear.…”

Gene polymorphisms of adiponectin and leptin receptor are associated with early onset of type 2 diabetes mellitus in the Taiwanese population

“…Additionally, leptin and its receptor inhibit insulin secretion by pancreatic b-cells. 22 Homozygous autosomal mutations in the leptin receptor gene (LEPR) in mice lead to obesity and insulin resistance, which can be reversed by the introduction of a neuron-specific LEPR-B transgene. 23 In agreement with these findings, common genetic variants at LEPR, located in chromosomal region 1p31, have been associated with obesity, 24 insulin resistance, T2DM 25 and variations in leptin levels 26,27 in different populations.…”