Analyses of Non-Synonymous Obesity Risk Alleles in SH2B1 (rs7498665) and APOB48R (rs180743) in Obese Children and Adolescents Undergoing a 1-year Lifestyle Intervention

Volckmar, Anna‐Lena; Pütter, Carolin; Song, Jun‐Yeob; Graniger, J.; Knoll, Nadja; Wolters, Barbara; Scherag, André; Reinehr, Thomas

doi:10.1055/s-0033-1334875

Cited by 13 publications

(9 citation statements)

References 19 publications

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“…Several studies have examined the effects of single adulthood or childhood BMI and/or obesity susceptibility SNPs or loci on obesity intervention outcome. However, these studies have generally been performed in smaller study populations, and the durations of the applied interventions have been limited (26,27,(30)(31)(32)(33)(34)(35).…”

Section: Discussionmentioning

confidence: 99%

Genetic Susceptibility for Childhood BMI has no Impact on Weight Loss Following Lifestyle Intervention in Danish Children

Hollensted

Fogh

Schnurr

et al. 2018

Obesity

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Objective This study aimed to investigate the effect of a genetic risk score (GRS) comprising 15 single‐nucleotide polymorphisms, previously shown to associate with childhood BMI, on the baseline cardiometabolic traits and the response to a lifestyle intervention in Danish children and adolescents. Methods Children and adolescents with overweight or obesity (n = 920) and a population‐based control sample (n = 698) were recruited. Anthropometric and biochemical measures were obtained at baseline and in a subgroup of children and adolescents with overweight or obesity again after 6 to 24 months of lifestyle intervention (n = 754). The effects of the GRS were examined by multiple linear regressions using additive genetic models. Results At baseline, the GRS associated with BMI standard deviation score (SDS) both in children and adolescents with overweight or obesity (β = 0.033 [SE = 0.01]; P = 0.001) and in the population‐based sample (β = 0.065 [SE = 0.02]; P = 0.001). No associations were observed for cardiometabolic traits. The GRS did not influence changes in BMI SDS or cardiometabolic traits following lifestyle intervention. Conclusions A GRS for childhood BMI was associated with BMI SDS but not with other cardiometabolic traits in Danish children and adolescents. The GRS did not influence treatment response following lifestyle intervention.

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Section: Discussionmentioning

confidence: 99%

Genetic Susceptibility for Childhood BMI has no Impact on Weight Loss Following Lifestyle Intervention in Danish Children

Hollensted

Fogh

Schnurr

et al. 2018

Obesity

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“…SH2B1 rs7498665 risk allele encodes a nonsynonymous substitution of Thr484Ala [92] . However, Thr484Ala substitution alone is not sufficient to cause obesity [117] , raising the possibility that other unidentified SH2B1 mutations, which co-segregate with rs7498665, may increase risk for obesity. Several SH2B1 missense mutations (P90H, T175N, P322S and F344LfsX20) were reported to be genetically linked to obesity and insulin resistance in mixed European descents [118] .…”

Section: Sh2b1 Regulates Reproduction In Micementioning

confidence: 99%

SH2B1 regulation of energy balance, body weight, and glucose metabolism

Rui

2014

WJD

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The Src homology 2B (SH2B) family members (SH2B1, SH2B2 and SH2B3) are adaptor signaling proteins containing characteristic SH2 and PH domains. SH2B1 (also called SH2-B and PSM) and SH2B2 (also called APS) are able to form homo-or hetero-dimers via their N-terminal dimerization domains. Their C-terminal SH2 domains bind to tyrosyl phosphorylated proteins, including Janus kinase 2 (JAK2), TrkA, insulin receptors, insulin-like growth factor-1 receptors, insulin receptor substrate-1 (IRS1), and IRS2. SH2B1 enhances leptin signaling by both stimulating JAK2 activity and assembling a JAK2/ IRS1/2 signaling complex. SH2B1 promotes insulin signaling by both enhancing insulin receptor catalytic activity and protecting against dephosphorylation of IRS proteins. Accordingly, genetic deletion of SH2B1 results in severe leptin resistance, insulin resistance, hyperphagia, obesity, and type 2 diabetes in mice. Neuronspecific overexpression of SH2B1β transgenes protects against diet-induced obesity and insulin resistance. SH2B1 in pancreatic β cells promotes β cell expansion and insulin secretion to counteract insulin resistance in obesity. Moreover, numerous SH2B1 mutations are genetically linked to leptin resistance, insulin resistance, obesity, and type 2 diabetes in humans. Unlike SH2B1, SH2B2 and SH2B3 are not required for the maintenance of normal energy and glucose homeostasis. The metabolic function of the SH2B family is conserved from insects to humans. Key words: Obesity; Type 2 diabetes; Leptin resistance; Insulin resistance; Glucose intolerance; Hypothalamus; Energy balance; Food intake; Hyperphagia; Nonalcoholic fatty liver disease Core tip: The Src homology 2B (SH2B) family members mediate cell signaling in response to a variety of hormones, cytokines, and growth factors. In the brain, SH2B1 enhances leptin signaling and leptin's antiobesity action. In peripheral tissues, SH2B1 cell-autonomously enhances insulin signaling. In pancreatic islets, SH2B1 is required for compensatory β cell expansion in response to insulin resistance and β cell stress. SH2B1-deficiency results in severe leptin resistance, energy imbalance, obesity, and type 2 diabetes. SH2B1 mutations are linked to leptin resistance, insulin resistance, obesity, and type 2 diabetes in humans. Thus, SH2B1 is a critical metabolic regulator in mammals.Rui L. SH2B1 regulation of energy balance, body weight, and glucose metabolism. World J Diabetes 2014; 5(4): 511-526 Available from:

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“…In this study, some of these CpG-SNPs have anteriorly been associated with energy homeostasis, but almost none of them was previously linked with weight loss after an energy-restricted treatment. Interestingly, the analyzed obesity-related CpG-SNP in SH2B1 gene, rs7359397, was associated with body weight, BMI, and truncal fat mass loss, even though, Volckmar et al (2013) evaluated the impact of a non-synonymous SNP in SH2B1 in body weight reduction in overweight and obese children undergoing a 1-year lifestyle intervention, with a no strong effect on weight loss-related phenotypes [33]. However, this SNP had not been previously associated with obesity or BMI in contrast with the rs7359397 CpG-SNP analyzed in this study.…”

Section: Discussionmentioning

confidence: 99%

<b><i>SH2B1</i></b> CpG-SNP Is Associated with Body Weight Reduction in Obese Subjects Following a Dietary Restriction Program

Mansego¹,

Milagro²,

Zulet³

et al. 2014

Ann Nutr Metab

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The objective of this study was to examine whether 7 SNPs previously associated with obesity-related traits that add or remove potential sites of DNA methylation are accompanied by differential DNA methylation and subsequently affect adiposity variables or body weight reduction in WBC from obese subjects under an energy-restricted program. Material and Methods: Anthropometric measurements were assessed in 47 volunteers recruited within the RESMENA study (Spain). At baseline, DNA from white blood cells was isolated and 7 obesity-related trait CpG-SNPs were genotyped by TaqMan-PCR. Then, methylation levels of CpG-SNP sites were quantified by MassArray® EpiTyper™ or MS-HRM approaches. Results: Differential DNA methylation levels were observed by genotypes in all of the CpG-SNPs analyzed. The FTO and BDNF methylation levels were further correlated with baseline body weight and, BDNF mRNA levels and body weight change, respectively. Moreover, the rs7359397 (SH2B1) was associated with the body weight, body mass index, and truncal fat mass reduction. Conclusions: Our results reveal the interaction of epigenetic and genetic variations in CpG-SNPs, especially in BDNF and SH2B1 genes, and how allele-specific methylation may contribute to elucidate the possible molecular mechanisms as these SNPs are affecting the decrease of mRNA levels and contributing to a lower body weight reduction. © 2014 S. Karger AG, Basel

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Analyses of Non-Synonymous Obesity Risk Alleles in SH2B1 (rs7498665) and APOB48R (rs180743) in Obese Children and Adolescents Undergoing a 1-year Lifestyle Intervention

Cited by 13 publications

References 19 publications

Genetic Susceptibility for Childhood BMI has no Impact on Weight Loss Following Lifestyle Intervention in Danish Children

Genetic Susceptibility for Childhood BMI has no Impact on Weight Loss Following Lifestyle Intervention in Danish Children

SH2B1 regulation of energy balance, body weight, and glucose metabolism

<b><i>SH2B1</i></b> CpG-SNP Is Associated with Body Weight Reduction in Obese Subjects Following a Dietary Restriction Program

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