Rare gene variants and weight loss at 10 years after sleeve gastrectomy and gastric bypass - a randomized clinical trial

Abstract

<div><h3><br></h3><h3>Background<br></h3><div>Genetic background of severe obesity is inadequately understood. The effect of genetic factors on weight loss after metabolic bariatric surgery (MBS) has shown inconclusive results.</div></div><div><h3>Objectives</h3><div>To determine the prevalence of rare obesity-associated gene variants in a secondary analysis of a randomized clinical trial (RCT) comparing laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB) for the treatment of severe obesity and examine their association with long-term weight loss at 10 years.</div></div><div><h3>Setting</h3><div>University Hospital, Finland.</div></div><div><h3>Methods</h3><div>Targeted sequencing panel was used to examine variants in 79 obesity-associated genes and 16p11.2 copy number variants. Weight loss was evaluated by percentage total weight loss (%TWL).</div></div><div><h3><br></h3><h3>Results<br></h3><div>Out of 240 patients, 113 patients [mean body mass index 48.4 kg/m², (6.8 standard deviation [SD]) kg/m² and median age 49 (range 26–64) years, LSG n = 60, LRYGB n = 53] were available for this post-hoc study. We identified 7 rare heterozygous likely/suspected pathogenic (LP/SP) variants in <em>SH2B1</em>, <em>PCSK1</em>, <em>DNMT3A</em>, <em>BDNF,</em> and <em>AFF4</em> in 6 patients (5.3%), 5 heterozygous variants of uncertain significance in <em>PLXNA4</em>, <em>PLXNA2</em>, <em>NRP1,</em> and <em>SEMA3D</em> in 5 patients (4.4%), heterozygous Bardet-Biedl syndrome variants in 3 patients (2.7%), and <em>PCKS1</em> risk allele p.Asn221Asp in 9 patients (8.0%). The patients with LP/SP variants had earlier age of obesity onset (<em>P</em> = .0089) and higher %TWL (<em>P</em> = .0446) compared with patients without LP/SP variants.</div></div><div><h3>Conclusions</h3><div>There were LP/SP pathogenic variants in 5% of the patients supporting the potential benefits of genetic testing to optimize targeted therapies in the future. Despite deleterious gene defects the long-term MBS outcome can be favorable.</div></div>