Heterozygous rare genetic variants in non-syndromic early-onset obesity.

Autor: Serra-Juhé C; Genetics Unit, Universitat Pompeu Fabra, Hospital del Mar Research Institute (IMIM), C/Doctor Aiguader, 8, 08003, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, C/Sinesio Delgado, 4, 28029, Madrid, Spain., Martos-Moreno GÁ; Hospital Infantil Universitario Niño Jesús, Department of Endocrinology, Instituto de Investigación La Princesa, Universidad Autónoma de Madrid, Department of Pediatrics, Avenida Menéndez Pelayo, 65, 28009, Madrid, Spain.; CIBER de Fisiopatología de la Obesidad y Nutriciόn (CIBEROBN), Instituto de Salud Carlos III, C/Sinesio Delgado, 4, 28029, Madrid, Spain., Bou de Pieri F; Genetics Unit, Universitat Pompeu Fabra, Hospital del Mar Research Institute (IMIM), C/Doctor Aiguader, 8, 08003, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, C/Sinesio Delgado, 4, 28029, Madrid, Spain., Flores R; Genetics Unit, Universitat Pompeu Fabra, Hospital del Mar Research Institute (IMIM), C/Doctor Aiguader, 8, 08003, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, C/Sinesio Delgado, 4, 28029, Madrid, Spain., Chowen JA; Hospital Infantil Universitario Niño Jesús, Department of Endocrinology, Instituto de Investigación La Princesa, Universidad Autónoma de Madrid, Department of Pediatrics, Avenida Menéndez Pelayo, 65, 28009, Madrid, Spain.; CIBER de Fisiopatología de la Obesidad y Nutriciόn (CIBEROBN), Instituto de Salud Carlos III, C/Sinesio Delgado, 4, 28029, Madrid, Spain., Pérez-Jurado LA; Genetics Unit, Universitat Pompeu Fabra, Hospital del Mar Research Institute (IMIM), C/Doctor Aiguader, 8, 08003, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, C/Sinesio Delgado, 4, 28029, Madrid, Spain.; Women's and Children's Hospital, South Australia Medical and Health Research Institute (SAMHRI) and University of Adelaide, 72 King William Road, North Adelaide, SA, 5006, Australia., Argente J; Hospital Infantil Universitario Niño Jesús, Department of Endocrinology, Instituto de Investigación La Princesa, Universidad Autónoma de Madrid, Department of Pediatrics, Avenida Menéndez Pelayo, 65, 28009, Madrid, Spain. jesus.argente@uam.es.; CIBER de Fisiopatología de la Obesidad y Nutriciόn (CIBEROBN), Instituto de Salud Carlos III, C/Sinesio Delgado, 4, 28029, Madrid, Spain. jesus.argente@uam.es.; IMDEA Food Institute, CEIUAM + CSI, Crta. de Cantoblanco, 8, 28049, Madrid, Spain. jesus.argente@uam.es.
Jazyk: angličtina
Zdroj: International journal of obesity (2005) [Int J Obes (Lond)] 2020 Apr; Vol. 44 (4), pp. 830-841. Date of Electronic Publication: 2019 Mar 29.
DOI: 10.1038/s41366-019-0357-5
Abstrakt: Background: Obesity is a very heterogeneous disorder at both the clinical and molecular levels and with high heritability. Several monogenic forms and genes with strong effects have been identified for non-syndromic severe obesity. Novel therapeutic interventions are in development for some genetic forms, emphasizing the importance of determining genetic contributions.
Objective: We aimed to define the contribution of rare single-nucleotide genetic variants (RSVs) in candidate genes to non-syndromic severe early-onset obesity (EOO; body mass index (BMI) >+3 standard deviation score, <3 years).
Methods: Using a pooled DNA-sequencing approach, we screened for RSVs in 15 obesity candidate genes in a series of 463 EOO patients and 480 controls. We also analysed exome data from 293 EOO patients from the "Viva la Familia" (VLF) study as a replication dataset.
Results: Likely or known pathogenic RSVs were identified in 23 patients (5.0%), with 7 of the 15 genes (BDNF, FTO, MC3R, MC4R, NEGR1, PPARG and SIM1) harbouring RSVs only in cases (3.67%) and none in controls. All were heterozygous changes, either de novo (one in BDNF) or inherited from obese parents (seven maternal, three paternal), and no individual carried more than one variant. Results were replicated in the VLF study, where 4.10% of probands carried RSVs in the overrepresented genes. RSVs in five genes were either absent (LEP) or more common in controls than in cases (ADRB3, LEPR, PCSK1 and PCSK2) in both obese datasets.
Conclusions: Heterozygous RSVs in several candidate genes of the melanocortin pathway are found in ~5.0% patients with EOO. These results support the clinical utility of genetic testing to identify patients who might benefit from targeted therapeutic intervention.
Databáze: MEDLINE
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