Effects of Heterozygous Variants in the Leptin-Melanocortin Pathway on Roux-en-Y Gastric Bypass Outcomes: a 15-Year Case-Control Study

Introduction: Heterozygous variants in the leptin-melanocortin pathway are associated with obesity. However, their effect on the long-term outcomes after Roux-en-Y gastric bypass (RYGB) is still unknown.

Methods: In this matched case-control study, 701 participants from the Mayo Clinic Biobank with a history of RYGB were genotyped. Sixty-three patients had a heterozygous variant in the leptin-melanocortin pathway. After excluding patients with potential confounders, carriers were randomly matched (on sex, age, body mass index [BMI], and years since surgery) with two non-carrier controls. The electronic medical record of carriers and matched non-carriers was reviewed for up to 15 years after RYGB.

Results: A total of 50 carriers and 100 matched non-carriers with a history of RYGB were included in the study. Seven different genes (LEPR, PCSK1, POMC, SH2B1, SRC1, MC4R, and SIM1) in the leptin-melanocortin pathway were identified. At the time of surgery, the mean age was 50.8 ± 10.6 years, BMI 45.6 ± 7.3 kg/m², and 79% women. There were no differences in postoperative years of follow-up, Roux limb length, or gastric pouch size between groups. Fifteen years after RYGB, the percentage of total body weight loss (%TBWL) in carriers was - 16.6 ± 10.7 compared with - 28.7 ± 12.9 in non-carriers (diff = 12.1%; 95% CI, 4.8 to 19.3) and the percentage of weight regain after maximum weight loss was 52.7 ± 29.7 in carriers compared with 29.8 ± 20.7 in non-carriers (diff = 22.9%; 95% CI, 5.3 to 40.5). The nadir %TBWL was lower - 32.1 ± 8.1 in carriers compared with - 36.8 ± 10.4 in non-carriers (diff = 4.8%; 95% CI 1.8 to 7.8).

Conclusions: Carriers of a heterozygous variant in the leptin-melanocortin pathway have a progressive and significant weight regain in the mid- and long-term after RYGB. Genotyping patients experiencing significant weight regain after RYGB could help implement multidisciplinary and individualized weight loss interventions to improve weight maintenance after surgery.