Contribution of heterozygous PCSK1 variants to obesity and implications for precision medicine: a case-control study

Folon, L; Baron, M; Toussaint, B; Vaillant, E; Boissel, M; Scherrer, V; Loiselle, H; Leloire, A; Badreddine, A; Balkau, B; Charpentier, G; Franc, S; Marre, M; Aboulouard, S; Salzet, M; Canouil, M; Derhourhi, M; Froguel, P; Bonnefond, A

doi:10.1016/s2213-8587(22)00392-8

Obesity

Contribution of heterozygous PCSK1 variants to obesity and implications for precision medicine: a case-control study

Lancet Diabetes EndocrinolPublished March 2023Case-control study

Main finding · ObesityResultOdds ratio 9.3 95% CI 1.5–177.4

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Authors' conclusion

Only carriers of heterozygous, null, or complete loss-of-function PCSK1 variants cause monogenic obesity and, therefore, might be eligible for setmelanotide. In silico tests were unable to accurately detect these variants, which suggests that in vitro assays are necessary to determine the variant pathogenicity for genetic diagnosis and precision medicine purposes.

Study context

Population: Participants with overweight/obesity (cases) or healthy weight (controls) from the RaDiO study (three community-based and one hospital-based cohort, France, 1995–2000); adults and children/adolescentsPCSK1 sequenced
Participants: 9,320 participants

Comparison: Carriers of complete loss-of-function or null heterozygous PCSK1 variants vs non-carriers
Carriersn = seven
Non-carriersn = 4,395reference
Outcome: Obesity (and BMI) by cluster of PCSK1 variants

Methodological detailsfunctional genomic study, in vitro functional assessment, machine-learning clustering of variants

Functional genomic study
In vitro functional assessment
Machine-learning clustering of variants

Main finding

Obesity

Odds ratio

9.3

95% CI 1.5–177.4

P = 0.014

Events by group

Carriers86%six of seven

Non-carriers35%1518 of 4395

Carriersvs Non-carriers

OR 9.3 (95% CI 1.5–177.4); P = 0.014

As reported in the abstract

Observational data: associations, not effects.

Further findings

BMI · SE 1.95; higher BMI in carriers

mean effect π 6.94 · P = 0.00029

Carriers32.0 kg/m²SD 9.3

Non-carriers27.3 kg/m²SD 6.5

Partial or neutral PCSK1 variant clusters

No effect on obesity or overweight and on BMI

Rare exome variant ensemble learner (REVEL) in silico prediction vs in vitro function

False positives: 15 (25%)
False negatives: four (7%)

Rare heterozygous PCSK1 variants detected

Rare heterozygous variants: 65
Null variants: four
Missense variants: 61
Missense variants with complete PC1/3 loss of function: 15

Original publication

Contribution of heterozygous PCSK1 variants to obesity and implications for precision medicine: a case-control study. Lancet Diabetes Endocrinol. Published March 2023. doi:10.1016/s2213-8587(22)00392-8

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