Genetics of Severe Obesity

Purpose of Review This review aims to present current information on genes underlying severe obesity, with the main emphasis on the three genes LEP, LEPR and MC4R. Recent Findings 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. Summary 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. Keywords Obesity Leptin Melanocortin-4 receptor GWAS BM

No Association between Single-Nucleotide Polymorphisms of The S1PR1 Gene or Interleukin-17 Levels with Fingolimod Response in A Small Group of Iranian Relapsing-Remitting Multiple Sclerosis Patients: A Case-Control Study

Objective: Multiple sclerosis (MS) has a multi-factorial etiology involving genetic factors. Fingolimod (Gilenya ®, FTY720) modulates the G-protein-coupled sphingosine 1-phosphate (S1P) receptors, S1PR1, 2, 3, 4 and 5. Variation in the human S1PR1 coding sequence results in heterogeneity in the function of the receptor. Interleukin-17, producing CD4+ T cells, tends to be increased after treatment with Fingolimod. The aim of the study was to investigate single-nucleotide polymorphisms (SNPs) in the S1PR1 gene or interleukin-17 (IL-17) levels in a small group of Iranian relapsing-remitting MS patients treated with Fingolimod. Materials and Methods: In this case-control study, the genomic DNA of 94 MS patients treated with Fingolimod was extracted and Sanger sequencing was performed on polymerase chain reaction (PCR) products to detect variants in the S1PR1 gene. Quantification of IL-17 from the serum of the patients was performed using a commercially available enzyme-linked immunosorbent assay (ELISA). Results: Among 94 relapsing-remitting MS patients treated with Fingolimod, 69 (73.4%) were responders and 25 (26.6%) were non-responders. There were four novel and five common SNPs in the S1PR1 gene and no significant association between SNP genotype and drug response was detected. In a subset of 34 patients, there was no significant difference in IL-17 serum concentrations before or after treatment and no association with S1PR1 polymorphisms was determined. Conclusion: This study is the first in Iran to investigate association between SNPs of the S1PR1 gene or IL-17 levels with fingolimod response in a small group of Iranian relapsing remitting MS patients. There was no association with S1PR1 gene SNPs or IL-17 levels before or after treatment

Possible relationship between common genetic variation and white matter development in a pilot study of preterm infants

Background The consequences of preterm birth are a major public health concern with high rates of ensuing multisystem morbidity, and uncertain biological mechanisms. Common genetic variation may mediate vulnerability to the insult of prematurity and provide opportunities to predict and modify risk. Objective To gain novel biological and therapeutic insights from the integrated analysis of magnetic resonance imaging and genetic data, informed by prior knowledge. Methods We apply our previously validated pathway-based statistical method and a novel network-based method to discover sources of common genetic variation associated with imaging features indicative of structural brain damage. Results Lipid pathways were highly ranked by Pathways Sparse Reduced Rank Regression in a model examining the effect of prematurity, and PPAR (peroxisome proliferator-activated receptor) signaling was the highest ranked pathway once degree of prematurity was accounted for. Within the PPAR pathway, five genes were found by Graph Guided Group Lasso to be highly associated with the phenotype: aquaporin 7 (AQP7), malic enzyme 1, NADP(+)-dependent, cytosolic (ME1), perilipin 1 (PLIN1), solute carrier family 27 (fatty acid transporter), member 1 (SLC27A1), and acetyl-CoA acyltransferase 1 (ACAA1). Expression of four of these (ACAA1, AQP7, ME1, and SLC27A1) is controlled by a common transcription factor, early growth response 4 (EGR-4). Conclusions This suggests an important role for lipid pathways in influencing development of white matter in preterm infants, and in particular a significant role for interindividual genetic variation in PPAR signaling

Choice of gDNA isolation method has a significant impact on average murine Telomere Length estimates.

Telomere Length (TL) and integrity is significantly associated with age-related disease, multiple genetic and environmental factors. We observe mouse genomic DNA (gDNA) isolation methods to have a significant impact on average TL estimates. The canonical qPCR method does not measure TL directly but via the ratio of telomere repeats to a single copy gene (SCG) generating a T/S ratio. We use a monochromatic-multiplex-qPCR (mmqPCR) method which multiplexes the PCR and enables quantification of the target and the single copy gene within the same qPCR reaction. We demonstrate that TL measurements, from murine gDNA, isolated via Spin Columns (SC) and Magnetic Beads (MB), generate significantly smaller T/S ratios compared to gDNA isolated via traditional phenol/chloroform methods. The former methods may impede correct TL estimation by producing non representative fragment sets and reducing qPCR efficacy. This work highlights discrepancies in TL measurements due to different extraction techniques. We recommend the use of gDNA isolation methods that are shown to preserve DNA length and integrity, such as phenol/chloroform isolation. We propose that widely used high throughput DNA isolation methodologies can create spurious associations within a sample set, thus creating misleading data. We suggest that published TL associations should be revisited in the light of these data

A functional polymorphism in the SPINK5 gene is associated with asthma in a Chinese Han Population

<p>Abstract</p> <p>Background</p> <p>Mutation in <it>SPINK5 </it>causes Netherton syndrome, a rare recessive skin disease that is accompanied by severe atopic manifestations including atopic dermatitis, allergic rhinitis, asthma, high serum IgE and hypereosinophilia. Recently, single nucleotide polymorphism (SNP) of the <it>SPINK5 </it>was shown to be significantly associated with atopy, atopic dermatitis, asthma, and total serum IgE. In order to determine the role of the <it>SPINK5 </it>in the development of asthma, a case-control study including 669 asthma patients and 711 healthy controls in Han Chinese was conducted.</p> <p>Methods</p> <p>Using PCR-RFLP assay, we genotyped one promoter SNP, -206G>A, and four nonsynonymous SNPs, 1103A>G (Asn368Ser), 1156G>A (Asp386Asn), 1258G>A (Glu420Lys), and 2475G>T (Glu825Asp). Also, we analyzed the functional significance of -206G>A using the luciferase reporter assay and electrophoresis mobility shift assay.</p> <p>Results</p> <p>we found that the G allele at SNP -206G>A was associated with increased asthma susceptibility in our study population (p = 0.002, odds ratio 1.34, 95% confidence interval 1.11–1.60). There was no significant association between any of four nonsynonymous SNPs and asthma. The A allele at -206G>A has a significantly higher transcriptional activity than the G allele. Electrophoresis mobility shift assay also showed a significantly higher binding efficiency of nuclear protein to the A allele compared with the G allele.</p> <p>Conclusion</p> <p>Our findings indicate that the -206G>A polymorphism in the <it>SPINK5 </it>is associated with asthma susceptibility in a Chinese Han population.</p

Nurse led, primary care based antiretroviral treatment versus hospital care: a controlled prospective study in Swaziland

<p>Abstract</p> <p>Background</p> <p>Antiretroviral treatment services delivered in hospital settings in Africa increasingly lack capacity to meet demand and are difficult to access by patients. We evaluate the effectiveness of nurse led primary care based antiretroviral treatment by comparison with usual hospital care in a typical rural sub Saharan African setting.</p> <p>Methods</p> <p>We undertook a prospective, controlled evaluation of planned service change in Lubombo, Swaziland. Clinically stable adults with a CD4 count > 100 and on antiretroviral treatment for at least four weeks at the district hospital were assigned to either nurse led primary care based antiretroviral treatment care or usual hospital care. Assignment depended on the location of the nearest primary care clinic. The main outcome measures were clinic attendance and patient experience.</p> <p>Results</p> <p>Those receiving primary care based treatment were less likely to miss an appointment compared with those continuing to receive hospital care (RR 0·37, <it>p </it>< 0·0001). Average travel cost was half that of those receiving hospital care (<it>p </it>= 0·001). Those receiving primary care based, nurse led care were more likely to be satisfied in the ability of staff to manage their condition (RR 1·23, <it>p </it>= 0·003). There was no significant difference in loss to follow-up or other health related outcomes in modified intention to treat analysis. Multilevel, multivariable regression identified little inter-cluster variation.</p> <p>Conclusions</p> <p>Clinic attendance and patient experience are better with nurse led primary care based antiretroviral treatment care than with hospital care; health related outcomes appear equally good. This evidence supports efforts of the WHO to scale-up universal access to antiretroviral treatment in sub Saharan Africa.</p

The gene encoding interleukin-13: a susceptibility locus for asthma and related traits

Asthma is a complex inflammatory disorder controlled by both genetic and environmental influences. Multiple genetic analyses have identified the T helper type 2 (Th2) cytokine gene cluster on chromosome 5q as a susceptibility locus for asthma. Recently, the Th2 cytokine interleukin-13 has been shown to be a critical mediator of the asthma phenotype in murine models. In this commentary we discuss several recent studies that have identified polymorphisms in the gene encoding interleukin-13. The consistent genetic associations of interleukin-13 with asthma and related traits across diverse ethnic populations in these studies provides strong support for the candidacy of this cytokine as a susceptibility locus for asthma and atopy on chromosome 5q31