Rare Heterozygous PCSK1 Variants in Human Obesity: The Contribution of the p.Y181H Variant and a Literature Review

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.

A Inteligência Artificial E Suas Implicações No Campo Da Genética

“…MARTIN; LINDBERG, 2016). A deficiência de PCSK1 já foi observada apresentando uma herança autossômica recessiva e dominante (LÖFFLER et al, 2017;PHILIPPE et al, 2015;VAN DIJCK et al, 2022;HARTER et al, 2016). E de forma interessante, temos alguns relatos na literatura de heterozigose composta (FRANK et al, 2013;JACKSON et al, 1997;O'RAHILLY et al, 1995).…”

Integrating epistasis in genome wide association studies to improve understanding of health and disease

“…The variant of PCSK1, rs1710315, in Table 3.3.1 is also reported in available literature (Van Dijck et al, 2022), but like that of GHRL, it is only known to be associated to obesity. These two genes (PCKS1 and GHRL) in Table 3.3.3 and their associated SNPs spark somewhat of a "chicken or the egg" debate since obesity accounts for 80-85% of the risk of developing T2D (Schnurr et al, 2020).…”