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- Title
Rare Heterozygous PCSK1 Variants in Human Obesity: The Contribution of the p.Y181H Variant and a Literature Review.
- Authors
Van Dijck, Evelien; Beckers, Sigri; Diels, Sara; Huybrechts, Tammy; Verrijken, An; Van Hoorenbeeck, Kim; Verhulst, Stijn; Massa, Guy; Van Gaal, Luc; Van Hul, Wim
- Abstract
Recently, it was reported that heterozygous PCSK1 variants, causing partial PC1/3 deficiency, result in a significant increased risk for obesity. This effect was almost exclusively generated by the rare p.Y181H (rs145592525, GRCh38.p13 NM_000439.5:c.541T>C) variant, which affects PC1/3 maturation but not enzymatic capacity. As most of the identified individuals with the heterozygous p.Y181H variant were of Belgian origin, we performed a follow-up study in a population of 481 children and adolescents with obesity, and 486 lean individuals. We identified three obese (0.62%) and four lean (0.82%) p.Y181H carriers (p = 0.506) through sanger sequencing and high resulting melting curve analysis, indicating no association with obesity. Haplotype analysis was performed in 13 p.Y181H carriers, 20 non-carriers (10 with obesity and 10 lean), and two p.Y181H families, and showed identical haplotypes for all heterozygous carriers (p < 0.001). Likewise, state-of-the-art literature concerning the role of rare heterozygous PCSK1 variants implies them to be rarely associated with monogenic obesity, as first-degree carrier relatives of patients with PC1/3 deficiency are mostly not reported to be obese. Furthermore, recent meta-analyses have only indicated a robust association for scarce disruptive heterozygous PCSK1 variants with obesity, while clinical significance is less or sometimes lacking for most nonsynonymous variants.
- Subjects
GENETIC variation; OBESITY; OVERWEIGHT children; ADOLESCENT obesity; LITERATURE reviews; HAPLOTYPES; CHILDHOOD obesity
- Publication
Genes, 2022, Vol 13, Issue 10, pN.PAG
- ISSN
2073-4425
- Publication type
Article
- DOI
10.3390/genes13101746