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

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.

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.

University Hospital, Finland.

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).

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.

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.