Abstract
Objectives
To study the prevalence and influence on metabolic profile of the prohormone-convertase-1 (PCSK1) N221D variant in childhood obesity, proven its role in the leptin-melanocortin signaling pathway as in proinsulin and other prohormone cleavage.
Methods
Transversal study of 1066 children with obesity (mean age and BMI Z-score 10.38 ± 3.44 years and +4.38 ± 1.77, respectively), 51.4 % males, 54.4 % prepubertal, 71.5 % Caucasians and 20.8 % Latinos. Anthropometric and metabolic features were compared between patients carrying the N221D variant in PCSK1 and patients with no variants found after next generation sequencing analysis of 17 genes (CREBBP, CPE, HTR2C, KSR2, LEP, LEPR, MAGEL2, MC3R, MC4R, MRAP2, NCOA1, PCSK1, POMC, SH2B1, SIM1, TBX3 and TUB) involved in the leptin-melanocortin pathway.
Results
No variants were found in 531 patients (49.8 %), while 68 patients carried the PCSK1 N221D variant (42 isolately, and 26 with at least one additional gene variant). Its prevalence was higher in Caucasians vs. Latinos (χ2 7.81; p<0.01). Patients carrying exclusively the PCSK1 N221D variant (n=42) showed lower insulinemia (p<0.05), HOMA index (p<0.05) and area under the curve for insulin in the oral glucose tolerance test (p<0.001) and higher WBISI (p<0.05) than patients with no variants, despite similar obesity severity, age, sex and ethnic distribution.
Conclusions
The N221D variant in PCSK1 is highly prevalent in childhood obesity, influenced by ethnicity. Indirect estimation of insulin resistance, based on insulinemia could be byassed in these patients and underestimate their type 2 diabetes mellitus risk.
Funding source: Fondo de Investigación Sanitaria. ISCIII
Award Identifier / Grant number: FIS: PI09/91060, PI10/00747, PI13/02195, PI16/0048
Funding source: Instituto de Salud Carlos III.
Award Identifier / Grant number: CIBER FisiopatologÃ-a de la Obesidad y Nutrición
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Research ethics: The project was approved by the Medical Ethical Committee at the Hospital Infantil Universitario Niño Jesús (local ID R0014/10) and is in accordance with the “Ethical Principles for Medical Research Involving Human Subjects” adopted in the Declaration of Helsinki by the World Medical Association (64th WMA General Assembly, Fortaleza, Brazil, October 2013).
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Informed consent: Written informed consent was obtained from all parents or their legal guardian, and patients over 12 years of age granted their informed assent, after the study and the procedures included had been fully explained.
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Author contributions: JA and GAMM designed the study and performed the clinical workup with the patients. All authors were involved in data compilation, analysis, result discussion and manuscript writing. All three authorsave accepted responsibility for the content of this submitted manuscript and approved submission.
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Competing interests: The authors state no conflicts of interest.
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Research funding: CIBER Fisiopatología de la Obesidad y Nutrición (CB06/03). Instituto de Salud Carlos III, Fondo de Investigación Sanitaria (FIS: PI09/91060, PI10/00747, PI13/02195, PI16/00485, PI 19/00166 & PI 22/01820).
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Data availability: “The raw data can be obtained on request from the corresponding author.”
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