Dataset Information

IGF2, LEPR, POMC, PPARG, and PPARGC1 gene variants are associated with obesity-related risk phenotypes in Brazilian children and adolescents.

ABSTRACT: Association studies of genetic variants and obesity and/or obesity-related risk factors have yielded contradictory results. The aim of the present study was to determine the possible association of five single-nucleotide polymorphisms (SNPs) located in the IGF2, LEPR, POMC, PPARG, and PPARGC1 genes with obesity or obesity-related risk phenotypes. This case-control study assessed overweight (n=192) and normal-weight (n=211) children and adolescents. The SNPs were analyzed using minisequencing assays, and variables and genotype distributions between the groups were compared using one-way analysis of variance and Pearson's chi-square or Fisher's exact tests. Logistic regression analysis adjusted for age and gender was used to calculate the odds ratios (ORs) for selected phenotype risks in each group. No difference in SNP distribution was observed between groups. In children, POMC rs28932472(C) was associated with lower diastolic blood pressure (P=0.001), higher low-density lipoprotein (LDL) cholesterol (P=0.014), and higher risk in overweight children of altered total cholesterol (OR=7.35, P=0.006). In adolescents, IGF2 rs680(A) was associated with higher glucose (P=0.012) and higher risk in overweight adolescents for altered insulin (OR=10.08, P=0.005) and homeostasis model of insulin resistance (HOMA-IR) (OR=6.34, P=0.010). PPARG rs1801282(G) conferred a higher risk of altered insulin (OR=12.31, P=0.003), and HOMA-IR (OR=7.47, P=0.005) in overweight adolescents. PARGC1 rs8192678(A) was associated with higher triacylglycerols (P=0.005), and LEPR rs1137101(A) was marginally associated with higher LDL cholesterol (P=0.017). LEPR rs1137101(A) conferred higher risk for altered insulin, and HOMA-IR in overweight adolescents. The associations observed in this population suggested increased risk for cardiovascular diseases and/or type 2 diabetes later in life for individuals carrying these alleles.

SUBMITTER: Queiroz EM

PROVIDER: S-EPMC4512097 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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IGF2, LEPR, POMC, PPARG, and PPARGC1 gene variants are associated with obesity-related risk phenotypes in Brazilian children and adolescents.

Queiroz E M EM Cândido A P C AP Castro I M IM Bastos A Q A AQ Machado-Coelho G L L GL Freitas R N RN

Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 20150428 7

Association studies of genetic variants and obesity and/or obesity-related risk factors have yielded contradictory results. The aim of the present study was to determine the possible association of five single-nucleotide polymorphisms (SNPs) located in the IGF2, LEPR, POMC, PPARG, and PPARGC1 genes with obesity or obesity-related risk phenotypes. This case-control study assessed overweight (n=192) and normal-weight (n=211) children and adolescents. The SNPs were analyzed using minisequencing ass ...[more]

PMID: 25923461

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Project description:Abstract Background The melanocortin-4 receptor (MC4R) pathway is a key regulator of energy balance. Heterozygous variants of the genes for proopiomelanocortin (POMC), leptin receptor (LEPR), and proprotein convertase subtilisin/kexin type 1 (PCSK1) upstream of MC4R can result in impaired signaling in the MC4R pathway. This impaired signaling can lead to hyperphagia and early-onset, severe obesity. Setmelanotide (SET), an MC4R agonist, reduced weight and hunger after 3 months in patients with obesity due to these heterozygous variants in an earlier Phase 2 study. The current analysis is the first to assess continued efficacy of an additional year of SET treatment in patients with obesity due to heterozygous affectation of POMC, PCSK1, and LEPR. Methods Patients aged ≥6 years with obesity due to heterozygous variants in POMC, PCSK1, and LEPR were eligible for this long-term extension (LTE) trial (NCT03651765) after completing an index trial in which they received SET and demonstrated clinical benefit and acceptable safety as determined by the investigator. Patients received a minimum of 4 months of SET treatment in the index trial and began the LTE immediately following the completion of the index trial. Study visits occurred every 3 months and evaluated changes in body weight measures and assessed safety and tolerability. The current analysis reports outcomes after 1 year total of SET treatment across the index and LTE trials, relative to index trial baseline. Results As of October 29, 2021, 35 patients with obesity heterozygous for POMC, PCSK1, and LEPR had enrolled in the index trial, with 16, 17, and 17 patients continuing into the LTE trial and receiving at least 6, 9, and 12 months of treatment with SET, respectively. At index trial baseline, mean (standard deviation [SD]) body mass index (BMI) for all index trial patients was 50.26 (9.41) kg/m2, body weight in patients ≥18 years old was 142.97 (28.70) kg, and BMI Z score in patients <18 years old was 4.04 (0.65). Mean (SD) percent change in BMI was −6.93% (9.13%; n=16), −8.14% (10.13%; n=17), and −7.83% (9.69%; n=17) after 6, 9, and 12 months of treatment, respectively. Of 15 patients ≥18 years old, the mean (SD) percent change in body weight was −10.24% (7.90%; n=15) after 12 months. For the 1 patient <18 years old, mean change in BMI Z score was 0.64 after 12 months. No new safety concerns emerged during the LTE and 1 patient discontinued due to an adverse event, likely unrelated to treatment. Conclusions Treatment with SET had continued efficacy in patients with obesity due to heterozygous variants in POMC, PCSK1, and LEPR after 1 year of treatment. These data support the continued investigation of SET in these patients, which is underway in the Phase 3 EMANATE trial (NCT05093634). Presentation: Sunday, June 12, 2022 11:00 a.m. - 11:15 a.m.

Project description:IntroductionIndividuals with proopiomelanocortin (POMC) or leptin receptor (LEPR) deficiency are young and experience severe obesity, hyperphagia, and comorbidities, which can impair quality of life (QOL).MethodsTwo pivotal Phase 3 trials explored the effect of setmelanotide on body weight and hunger in individuals with obesity due to POMC (NCT02896192) or LEPR (NCT03287960) deficiency. QOL and depression were investigated in parallel using the disease-specific, age-appropriate Impact of Weight on Quality of Life-Lite (IWQOL-Lite), Pediatric Quality of Life Inventory (PedsQL), and Patient Health Questionnaire-9 (PHQ-9).ResultsIn total, the POMC and LEPR trials enrolled 21 patients. Adults (≥ 18 years old; n = 7) had moderate-to-severe impairment in QOL at baseline, with mean (standard deviation [SD]) IWQOL-Lite total score 60.3 (13.2; maximum IWQOL-Lite total score = 100). The effect of setmelanotide on IWQOL-Lite total score was observed as soon as Week 5. Among those with scores at Week 52, 5 of 6 adults experienced a clinically meaningful improvement, with mean (SD) total scores increased from baseline by 24.2 (12.1) points. Children (6-12 years old; n = 2) and adolescents (13-17 years old; n = 4) had impaired QOL at baseline, with mean (SD) self-reported PedsQL total scores 53.3 (6.2) and 63.3 (29.1), respectively (maximum PedsQL total score = 100). Three of 5 patients experienced clinically meaningful improvement in PedsQL, with 2 children whose PedsQL total score increased by 28.3 and 3.3 points and 3 adolescents whose mean (SD) total score increased from baseline by 5.8 (18.3) points. Baseline mean (SD) PHQ-9 score (in those ≥ 12 years old) was 5.3 (3.8) and was generally maintained through Week 52.ConclusionsPatients with POMC or LEPR deficiency had impaired, and in some cases severely impaired, QOL before setmelanotide treatment. Setmelanotide improved QOL in patients as early as Week 5, with some patients no longer experiencing impaired QOL at Week 52. Improvements in QOL may be related to a reduction in hunger and body weight associated with setmelanotide. Because of the highly complex psychological consequences of rare genetic diseases of obesity, some patients may require a long period of treatment to improve QOL and benefit from interdisciplinary care.

Project description:PURPOSE:In this study we investigated a set of 100 sentence contexts and their cloze probabilities to develop a database of linguistic stimuli for Brazilian Portuguese children and adolescents. The study also examined age-related changes on cloze probabilities, and specified the predictor effects of age and cloze probabilities on idiosyncratic responses and errors (semantic, syntactic, and other errors). Finally, the study also aimed to shed light on cultural effects on word generation by comparing Brazilian and Portuguese sentence databases. METHOD:361 typically developing monolingual Brazilian speakers, with ages ranging from 7 to 18 years, participated in the study. The cloze task was composed by 100 sentence contexts, grounded on the European Portuguese database. Responses were classified as valid (correct) or invalid (semantic, syntactic, and other-type errors). Statistical analyses were based on mixed-effects logistic models. RESULTS:Sixty-three sentences met criteria for high cloze probabilities, 30 for medium cloze, and 7 for low cloze. Age was a significant predictor of idiosyncratic responses, semantic and syntactic errors: older participants were less likely to produce idiosyncratic responses, as well as semantic and syntactic errors. Cloze probability values were concordant in the Brazilian and Portuguese databases for 31 out of 49 (83.7%) high-cloze sentences and for 7 low-cloze sentences. CONCLUSION:In this study we have provided a database with cloze probability values for a set of 100 sentence-final word contexts for Brazilian Portuguese children and adolescents. Results showed that both age and sentence contextual level predicted sentence final word completion. Older participants were more likely to choose more consistently the same final word, with the contextual level of a given sentence also contributing to the final word selection. Age should be controlled for in future studies probing semantic processing with this set of sentences.

Dataset Information

IGF2, LEPR, POMC, PPARG, and PPARGC1 gene variants are associated with obesity-related risk phenotypes in Brazilian children and adolescents.

Publications

IGF2, LEPR, POMC, PPARG, and PPARGC1 gene variants are associated with obesity-related risk phenotypes in Brazilian children and adolescents.

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