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

Abstract

Background: 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.

Objectives: 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.

Setting: University Hospital, Finland.

Methods: 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).

Results: 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 SH2B1, PCSK1, DNMT3A, BDNF, and AFF4 in 6 patients (5.3%), 5 heterozygous variants of uncertain significance in PLXNA4, PLXNA2, NRP1, and SEMA3D in 5 patients (4.4%), heterozygous Bardet-Biedl syndrome variants in 3 patients (2.7%), and PCKS1 risk allele p.Asn221Asp in 9 patients (8.0%). The patients with LP/SP variants had earlier age of obesity onset (P = .0089) and higher %TWL (P = .0446) compared with patients without LP/SP variants.

Conclusions: 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.

Keywords: Gene panel; Genetic obesity; Metabolic bariatric surgery; Weight loss.