rs10515237 — PCSK1 PCSK1 A/G (rs10515237)

Intronic variant in PCSK1 that tags the Q665E-S690T functional haplotype

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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. This is what makes rs10515237 clinically meaningful despite being intronic itself.

The Evidence

The founding study, Benzinou et al. 2008 (Nature Genetics)22 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)33 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. 201444 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.

Proinsulin was directly measured by Heni et al. 2010 (BMC Medical Genetics)55 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.

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.

Nutrient Interactions

protein increased_need
simple carbohydrates altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant.

AA Normal PC1/3 Activity Normal

Common genotype with normal prohormone convertase activity and standard insulin processing efficiency

PC1/3 (PCSK1) is expressed primarily in pancreatic beta cells, enteroendocrine cells of the gut, and neurons of the hypothalamus. In the AA genotype, PC1/3 cleaves proinsulin to insulin and C-peptide at the expected rate; cleaves POMC to α-MSH (satiety) and ACTH (cortisol regulation) normally; and processes proglucagon to GLP-1 in the gut (stimulating insulin release after meals). The AA genotype in GWAS meta-analyses (n > 300,000) carries a reference-level association with obesity — it is the baseline against which G-allele risk is measured.

AG Reduced PC1/3 Activity Intermediate

One G allele modestly reduces prohormone convertase activity, mildly elevating proinsulin and blunting satiety signals

The G allele at rs10515237 co-segregates with Q665E-S690T, two amino acid changes in the C-terminal region of PC1/3. In the 1,498-person study by Heni et al. (2010), rs6235 carriers (in LD with rs10515237) had 8% higher proinsulin AUC during an OGTT and elevated proinsulin:insulin ratios, demonstrating measurable but partial impairment.

GG Low PC1/3 Activity Reduced

Two G alleles substantially reduce prohormone convertase activity, raising proinsulin levels, impairing satiety signaling, and increasing obesity and diabetes risk

In homozygous G-allele carriers, two copies of the Q665E-S690T haplotype are present. The proinsulin:insulin ratio is highest in this genotype — elevated proinsulin itself is not metabolically inert: it has reduced biological activity compared to insulin but some receptor binding capacity, and chronically elevated proinsulin is an independent risk marker for cardiovascular events and type 2 diabetes (the "proinsulin hypothesis").