This review aims to present current information on genes underlying severe obesity, with the main emphasis on the three genes LEP, LEPR and MC4R. There is a substantial amount of evidence that variants in at least ten different genes are the cause of severe monogenic obesity. The majority of these are involved in the leptin-melanocortin signalling pathway. Due to the frequency of some of the identified variants, it is clear that monogenic variants also make a significant contribution to common obesity. The artificial distinction between rare monogenic obesity and common polygenic obesity is now obsolete with the identification of MC4R variants of strong effect in the general population.

/pdf/genetics-of-severe-obesity-xwz9jhpioq.pdf

Genetics of Severe Obesity

6550 Background: Multidrug resistance (MDR) is one of the important mechanisms of treatment failure of acute myeloid leukemia (AML). Recently, MDR-1 gene single nucleotide polymorphism (SNP) has be...

Multidrug resistance-1 gene polymorphism associated with the treatment outcomes in de novo acute myeloid leukemia

Association of interleukin-6 polymorphisms with obesity: A systematic review and meta-analysis

Despite the fact that insertions/deletions (INDELs) are the second most common type of genetic variations and variable number tandem repeats (VNTRs) represent a large portion of the human genome, they have received far less attention than single nucleotide polymorphisms (SNPs) and larger forms of structural variation like copy number variations (CNVs), especially in genome-wide association studies (GWAS) of complex diseases like polygenic obesity. This is exemplified by the vast amount of review papers on the role of SNPs and CNVs in obesity, its related traits (like anthropometric measurements, biochemical variables, and eating behavior), and its related complications (like hypertension, hypertriglyceridemia, hypercholesterolemia, and insulin resistance—collectively known as metabolic syndrome). Hence, this paper reviews the types of INDELs and VNTRs that have been studied for association with obesity and its related traits and complications. These INDELs and VNTRs could be found in the obesity loci or genes from the earliest GWAS and candidate gene association studies, like FTO, genes in the leptin–proopiomelanocortin pathway, and UCP2/3. Given the important role of the brain serotonergic and dopaminergic reward system in obesity susceptibility, the association of INDELs and VNTRs in these neurotransmitters’ metabolism and transport genes with obesity is also reviewed. Next, the role of INS VNTR in obesity and its related traits is questionable, since recent large-scale studies failed to replicate the earlier positive associations. As obesity results in chronic low-grade inflammation of the adipose tissue, the proinflammatory cytokine gene IL1RA and anti-inflammatory cytokine gene IL4 have VNTRs that are implicated in obesity. A systemic proinflammatory state in combination with activation of the renin–angiotensin system and decreased nitric oxide bioavailability as found in obesity leads to endothelial dysfunction. This explains why VNTR and INDEL in eNOS and ACE, respectively, could be predisposing factors of obesity. Finally, two novel genes, DOCK5 and PER3, which are involved in the regulation of the Akt/MAPK pathway and circadian rhythm, respectively, have VNTRs and INDEL that might be associated with obesity. In conclusion, INDELs and VNTRs could have important functional consequences in the pathophysiology of obesity, and research on them should be continued to facilitate obesity prediction, prevention, and treatment.

/pdf/the-association-of-insertions-deletions-indels-and-variable-23tjufup9o.pdf

The association of insertions/deletions (INDELs) and variable number tandem repeats (VNTRs) with obesity and its related traits and complications.

Leptin is a principal adipose-derived hormone mostly implicated in the regulation of energy balance through the activation of anorexigenic neuronal pathways. Comprehensive studies have established that the maintenance of certain concentrations of circulating leptin is essential to avoid an imbalance in nutrient intake. Indeed, genetic modifications of the leptin/leptin receptor axis and the obesogenic environment may induce changes in leptin levels or action in a manner that accelerates metabolic dysfunctions, resulting in a hyperphagic status and adipose tissue expansion. As a result, a vicious cycle begins wherein hyperleptinaemia and leptin resistance occur, in turn leading to increased food intake and fat enlargement, which is followed by leptin overproduction. In addition, in the context of obesity, a defective thermoregulatory response is associated with impaired leptin signalling overall within the ventromedial nucleus of the hypothalamus. These recent findings highlight the role of leptin in the regulation of adaptive thermogenesis, thus suggesting leptin to be potentially considered as a new thermolipokine. This review provides new insight into the link between obesity, hyperleptinaemia, leptin resistance and leptin deficiency, focusing on the ability to restore leptin sensitiveness by way of enhanced thermogenic responses and highlighting novel anti-obesity therapeutic strategies.

https://www.mdpi.com/1422-0067/22/12/6445/pdf

Impaired Leptin Signalling in Obesity: Is Leptin a New Thermolipokine?

Objective. Obesity is a complex heterogeneous disease that is caused by genes, environmental factors, and the interaction between the two. The leptin (LEP) and leptin receptor (LEPR) genes have been evaluated for polymorphisms that could potentially be related to the pathophysiology of obesity and its complications. The aim of this study was to investigate the role of LEP G2548A and LEPR 668A/G polymorphisms in the pathogenesis of obesity. Subjects. The study included 127 patients with obesity and 105 healthy controls. Polymerase chain reaction and restriction fragment length analysis for LEP G2548A and LEPR 668A/G polymorphisms were applied. Results. There was no statistically significant difference in the genotype frequencies of the LEP gene polymorphism between patients and control groups (). We found a difference in the LEPR genotypes between patients and controls, but this was not statistically significant (). Additionally, we found an increased risk of obesity in the LEP/LEPR GG/GG combined genotype (). Conclusion. Our findings indicate that the LEP G2548A polymorphism is not a relevant obesity marker and that the LEPR 668A/G polymorphism may be related to obesity in a Turkish population. Further researches with larger patient population are necessary to ascertain the implications of LEP and LEPR polymorphisms in obesity.

https://downloads.hindawi.com/journals/dm/2013/216279.pdf

Investigation of associations between obesity and LEP G2548A and LEPR 668A/G polymorphisms in a Turkish population.

1. Familial Mediterranean fever (FMF) is considered an autosomal recessive disorder, associated with a single gene named Mediterranean fever (MEFV). The aim of this study was to perform genotyping and haplotyping analysis of the multidrug resistance (ATP-binding cassette, subfamily B, member 1 – ABCB1) gene in FMF patients.2. Three ABCB1 gene polymorphisms (C1236T, G2677T/A and C3435T) were analyzed in 309 FMF patients and 250 healthy control subjects. All subjects were genotyped by PCR–restriction fragment length polymorphism analysis, and statistical analysis was performed using the Arlequin 3.1.1 and SPSS 16.0 software packages.3. The CT genotype frequency of the C3435T polymorphism (p = 0.003), the CT–GT–CT (C1236T–G2677T/A–C3435T) triple genotype (p = 0.001) and the C–G (C1236T–G2677T/A) haplotype (p = 0.030) were more common in the FMF patients. The CT–GG–CC triple genotype and T–G–C, C–T–T and T–G–T haplotypes (C1236T–G2677T/A–C3435T) were higher in the control subjects (p = 0.011, 0.001, 0...

Association analysis of three ABCB1 (MDR1) gene variants (C1236T, G2677A/T and C3435T) and their genotype/haplotype combinations with the familial Mediterranean fever

KEYWORDS Obesity. Cytokines. IL-4 Gene. IL-6 Gene. Polymorphism ABSTRACT Obesity results in a proinflammatory state starting within the metabolic cells as adipocyte, monocyte. The bioactive system, including cytokines as IL-4 and IL-6, contributes to the pathogenesis of conditions associated with obesity and favors inflammation. This study aimed to investigate the role of IL-4 gene intron 3 VNTR and IL-6 gene - 597G/A polymorphisms in the pathogenesis of obesity. The study included 127 patients with obesity (BMI>30kg/m2) and 110 healthy controls. Genomic DNA was isolated and genotyped using polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) analysis for IL-4 gene and IL-6 gene polymorphisms. There was no statistical significant difference in the allele and genotype frequencies of both genes polymorphism in obesity patients and control groups (p>0.05). Additionally, there was no statistical significant difference in the combine genotype analysis of IL-4 gene intron 3 VNTR and IL-6 gene -597G/A polymorphism (p>0.05). These findings showed that there are not any associations of IL-4 gene intron 3 VNTR and IL-6 gene -597G/A polymorphisms with susceptibility of a person for development of obesity. This is the first report that investigates the relationships between susceptibility of obesity and IL- 4 gene intron 3 VNTR, IL-6 gene -597G/A polymorphisms.

http://www.krepublishers.com/02-Journals/IJHG/IJHG-13-0-000-13-Web/IJHG-13-4-000-13-Abst-Pdf/IJHG-13-4-209-13-547-Tekcan-A/IJHG-13-4-209-13-547-Tekcan-A-Tt.pdf

The Investigation of Obesity Susceptibility with IL-4 Gene Intron 3 VNTR and IL-6 Gene -597G/A Polymorphisms in a Turkish Population

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Papers

Investigation of associations between obesity and LEP G2548A and LEPR 668A/G polymorphisms in a Turkish population.

Association analysis of three ABCB1 (MDR1) gene variants (C1236T, G2677A/T and C3435T) and their genotype/haplotype combinations with the familial Mediterranean fever

The Investigation of Obesity Susceptibility with IL-4 Gene Intron 3 VNTR and IL-6 Gene -597G/A Polymorphisms in a Turkish Population