rs10515237 — PCSK1 PCSK1 A/G (rs10515237)

The Prohormone Scissor: How PCSK1 Variants Shape Insulin and Appetite

Every time your pancreas detects rising blood sugar, it doesn't release insulin directly — it releases proinsulin, a folded precursor that needs to be cut open before it becomes active. The enzyme doing that cutting is prohormone convertase 1/3 (PC1/3)¹¹ prohormone convertase 1/3 (PC1/3)
Encoded by the PCSK1 gene on chromosome 5; cleaves inactive prohormone precursors at specific paired basic amino acid sites to generate active peptide hormones, the protein encoded by PCSK1. But PC1/3 doesn't work on proinsulin alone — it also cleaves POMC into α-melanocyte-stimulating hormone (α-MSH), a key satiety signal in the brain, and proglucagon into GLP-1, the incretin that amplifies insulin release after meals. A single enzyme sits at the convergence of insulin processing, appetite regulation, and incretin signaling.

The rs10515237 variant sits within an intron of PCSK1 and is in [strong linkage disequilibrium | LD r² ≈ 0.84 in Europeans; variants that are tightly co-inherited — measuring one reliably predicts the other] with rs6234 and rs6235, the non-synonymous variants encoding the Q665E-S690T haplotype in the C-terminal domain of PC1/3. When you carry the G allele at rs10515237, you very likely also carry the functional haplotype that partially reduces PC1/3 activity. This is what makes rs10515237 clinically meaningful despite being intronic itself.

The Mechanism

The Q665E-S690T amino acid pair encoded by the rs6234-rs6235 haplotype alters the C-terminal propeptide region of PC1/3. This region acts as an intramolecular chaperone that guides proper protein folding — changes to it reduce the enzyme's catalytic efficiency without abolishing function entirely. The result is a partial loss-of-function²² partial loss-of-function
Not as severe as the rare biallelic null mutations that cause severe early-onset obesity and malabsorptive diarrhea; common heterozygous variants reduce activity modestly that propagates through three downstream pathways: slower proinsulin→insulin conversion (raising the proinsulin-to-insulin ratio), reduced POMC cleavage to α-MSH (blunting melanocortin-mediated satiety), and potentially altered proglucagon processing to GLP-1 (modifying incretin responses).

The Evidence

The founding study, Benzinou et al. 2008 (Nature Genetics)³³ Benzinou et al. 2008 (Nature Genetics)
13,659 individuals of European ancestry across 8 independent cohorts; the Q665E-S690T haplotype was the strongest association signal at p = 2.31 × 10⁻¹², established common PCSK1 variants as genuine obesity risk loci. The rs6234-rs6235 haplotype — which rs10515237 tags — conferred a 22% increased risk of obesity per risk haplotype in the original cohorts. A companion functional experiment confirmed that the N221D mutation (rs6232) significantly impaired PC1/3 catalytic activity in cell-based assays.

The largest meta-analysis to date, Nead et al. 2015 (Human Molecular Genetics)⁴⁴ Nead et al. 2015 (Human Molecular Genetics)
Up to 331,175 individuals from GWAS consortia; systematic review combining literature and custom array data from diverse ethnic backgrounds, quantified the effect more precisely: the rs6234/rs6235 haplotype carries OR = 1.07 (95% CI 1.04–1.10, p = 3.00 × 10⁻⁷) for obesity, and rs6232 carries OR = 1.15 (95% CI 1.06–1.24, p = 6.08 × 10⁻⁶). These are modest effect sizes consistent with a polygenic contribution to a complex trait. A HuGE review and meta-analysis by Stijnen et al. 2014⁵⁵ HuGE review and meta-analysis by Stijnen et al. 2014
Comprehensive systematic review of all published PCSK1 association studies; examined associations with BMI, obesity, waist circumference confirmed the associations and identified that rs6232 effects were stronger in childhood obesity than adult obesity — consistent with the enzyme's role in early growth and metabolic programming.

The metabolic consequence of reduced PC1/3 activity was directly measured by Heni et al. 2010 (BMC Medical Genetics)⁶⁶ Heni et al. 2010 (BMC Medical Genetics)
1,498 German subjects with detailed OGTT and clamp studies; rs6235 minor allele frequency 25.8%: carriers of the rs6235 risk allele had 8% higher proinsulin area-under-the-curve and elevated proinsulin-to-insulin ratio, confirming that the functional haplotype measurably impairs prohormone processing in vivo.

Practical Implications

Carriers of the G allele at rs10515237 have a modestly elevated proinsulin-to-insulin ratio — their pancreatic beta cells are secreting more precursor and less active hormone per stimulus. Over time, this can translate into reduced beta-cell efficiency and elevated long-term diabetes risk. The satiety pathway impairment compounds this: if POMC-to-α-MSH conversion is reduced, the melanocortin-4 receptor pathway fires less robustly after meals, potentially raising the threshold at which fullness signals terminate eating. This combination — less effective insulin per secretory event plus blunted satiety — is the proposed mechanism linking PCSK1 variants to excess adiposity.

From a dietary standpoint, the primary lever is glycemic load. When meals generate rapid postprandial glucose peaks, beta cells secrete larger proinsulin pulses — and in PCSK1 G-allele carriers, those pulses are converted less efficiently. Spreading glucose load across the day by choosing lower-glycemic foods reduces the secretory burden on an already less-efficient processing system. Monitoring fasting proinsulin (where available) and the standard proinsulin:insulin ratio can detect beta-cell stress before HbA1c rises.

Interactions

The rs10515237/rs6234-rs6235 haplotype interacts additively with rs6232 (the N221D missense variant) within the same gene. Individuals carrying both the rs6232 risk allele and the rs6235 haplotype have two independently acting reductions in PC1/3 activity — compound heterozygosity within PCSK1 is plausible and would confer greater proinsulin accumulation. The melanocortin pathway interaction is also relevant: variants in MC4R (rs17782313) and POMC itself further modify satiety signaling downstream of PC1/3 cleavage, creating a polygenic appetite-regulation score that several GWAS consortia have begun characterizing.