Obesity Characteristics Are Poor Predictors of Genetic Mutations Associated with Obesity

Ahmed W Al-Humadi; Khaled Alabduljabbar; Moath S Alsaqaaby; Hani Talaee; Carel W le Roux

doi:10.3390/jcm12196396

Obesity Characteristics Are Poor Predictors of Genetic Mutations Associated with Obesity

J Clin Med. 2023 Oct 7;12(19):6396. doi: 10.3390/jcm12196396.

Authors

Ahmed W Al-Humadi^{1

2}, Khaled Alabduljabbar^{1

3}, Moath S Alsaqaaby^{1

4}, Hani Talaee¹, Carel W le Roux¹

Affiliations

¹ Diabetes Complications Research Centre, Conway Institute, University College Dublin, D04V1W8 Dublin, Ireland.
² Department of Dentistry, Hilla University College, Babylon 510001, Iraq.
³ Department of Family Medicine and Polyclinics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
⁴ Obesity, Endocrine and Metabolism Centre, King Fahad Medical City, Riyadh 11525, Saudi Arabia.

Abstract

Background: The genetic contribution to obesity is substantial and may underpin the altered pathophysiology. One such pathway involves melanocortin signaling in the hypothalamus. Genetic variants can cause dysregulation in the central melanocortin pathway that can result in early onset of hyperphagia and obesity. Clinically identifying patients who are at risk of known genetic mutations is challenging. The main purpose of this study was to identify associations between the clinico-demographical characteristics and the presence of a genetic mutation associated with obesity.

Methods: We tested samples from 238 adult patients with class III obesity between October 2021 to February 2023 using next-generation sequencing (NGS) (Illumina, NovaSeq 6000 Sequencing System). The results were classified as "no variant identified" or "variant identified".

Results: 107 patients (45%) had one or more gene mutation in the leptin-melanocortin pathway. All variants were heterozygous. The patients with a gene mutation had a BMI of 48.4 ± 0.8 kg/m² (mean ± SEM), and those without a gene mutation had a BMI of 49.4 ± 0.7 kg/m² (p = 0.4). The mean age of onset of obesity in patients with a gene mutation was 13.9 ± 1.3 years and for those without gene mutations was 11.5 ± 0.9 years (p = 0.1). The incidence of hyperphagia as a child was also not predictive (p = 0.4).

Conclusions: Gene mutations associated with obesity in patients with a BMI > 40 kg/m² are common. However, a patient's BMI, age of onset of obesity, or age of onset of hyperphagia did not help to differentiate which patients may be more likely to have genetic mutations associated with obesity.

Keywords: POMC; genetic mutations; genetic obesity; leptin–melanocortin pathway; obesity.

Grants and funding

The logistics and cost of the genetic testing was supported by Rhythm Pharmaceuticals Inc. (Boston, USA) as part of their Rare Obesity Advanced Diagnosis (ROAD) program. The authors declare not receiving any compensation for conducting the study from Rhythm Pharmaceuticals.