rs3197999 — MST1 R689C

A Genetic Crossroads Between Gut Immunity and Inflammatory Disease

Your MST1 gene encodes macrophage-stimulating protein (MSP), a critical regulator of innate immune responses¹¹ innate immune responses
The first-line defense system that responds to pathogens without prior exposure to bacterial challenges in the gut. The rs3197999 variant causes an arginine-to-cysteine substitution at position 689 (R689C) in the protein, located within a critical receptor-binding domain that determines how effectively MSP activates immune cells.

This variant sits at the intersection of immune surveillance and inflammatory disease. It's one of the most consistently replicated genetic risk factors²² It's one of the most consistently replicated genetic risk factors
Confirmed across multiple populations and study designs for inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC), appearing in genome-wide association studies with odds ratios of 1.20 for IBD and 1.51 for PSC. Unlike many genetic variants that simply reduce protein function, the Cys689 variant actually enhances certain aspects of macrophage activity—a gain of function that paradoxically increases inflammation risk.

The Mechanism

MSP is secreted primarily by the liver and circulates in blood as an inactive precursor. When cleaved by proteases at sites of tissue injury or bacterial invasion, it becomes biologically active and binds to the RON receptor tyrosine kinase on macrophages, epithelial cells, and other immune cells³³ epithelial cells, and other immune cells
RON is expressed in tissues throughout the body but especially abundant in gut-associated immune cells. This triggers signaling cascades that regulate chemotaxis (cell migration toward infection sites), phagocytosis (engulfment of bacteria), and cytokine production.

The R689C substitution occurs in the serine protease homology domain⁴⁴ occurs in the serine protease homology domain
This domain forms the receptor-binding surface but is catalytically inactive—MSP is a "dead" protease that retained its binding structure of the MSP β-chain. Functional studies using macrophage-like cell lines showed that the Cys689 variant significantly increases the stimulatory effect⁵⁵ significantly increases the stimulatory effect
Enhanced chemotaxis and proliferation compared to wild-type Arg689 of MSP on chemotaxis and proliferation. This gain of function suggests the variant creates a hyperactive immune response—macrophages migrate more aggressively and respond more vigorously to bacterial signals.

Paradoxically, individuals with the AA genotype have approximately 10-fold lower MSP binding affinity⁶⁶ approximately 10-fold lower MSP binding affinity
Measured in receptor-binding assays to RON and profoundly decreased serum MSP levels. The mechanism appears to involve altered protein stability or secretion efficiency. So the variant simultaneously increases cellular responsiveness when MSP binds but reduces overall circulating MSP—a complex functional profile that may dysregulate normal immune homeostasis in the gut.

The Evidence

The initial discovery came from gene-centric mapping⁷⁷ The initial discovery came from gene-centric mapping
Rather than unbiased GWAS, this study specifically targeted chromosome 3p21 based on prior linkage evidence of the 3p21 IBD linkage region in 2008. Fisher and colleagues identified rs3197999 with P=3.62×10⁻⁶ in a combined screen of 1,020 IBD patients and replication in 745 additional cases. The variant showed association with both Crohn's disease and ulcerative colitis.

A 2008 meta-analysis⁸⁸ A 2008 meta-analysis
Barrett et al., combining data from three studies with 3,230 Crohn's cases and 4,829 controls confirmed the association with genome-wide significance (P=1.15×10⁻¹², OR=1.20). A parallel study in 3,133 ulcerative colitis patients and 4,494 controls replicated the finding (combined P=3.8×10⁻⁹).

The variant's role extends beyond classic IBD. A 2011 genome-wide association study in primary sclerosing cholangitis⁹⁹ A 2011 genome-wide association study in primary sclerosing cholangitis
Melum et al., 715 Scandinavian and German PSC cases vs 2,962 controls identified rs3197999 as one of two non-HLA susceptibility loci with P=1.1×10⁻¹⁶ and OR=1.51. PSC is a chronic cholestatic liver disease characterized by bile duct inflammation and frequently co-occurs with IBD. Homozygous AA carriers also show increased risk¹⁰¹⁰ Homozygous AA carriers also show increased risk
OR=1.97 for overall cholangiocarcinoma, OR=1.84 for PSC-unrelated biliary tract cancer of cholangiocarcinoma, the feared cancer complication of chronic bile duct inflammation.

Gene-gene interaction analysis¹¹¹¹ Gene-gene interaction analysis
In a Chinese Crohn's disease cohort of 1,590 cases and 1,478 controls identified significant interactions between MST1 and JAK2, IL23R, and PTGER4—all genes involved in inflammatory signaling pathways. This suggests MST1 participates in broader networks regulating mucosal immunity rather than acting in isolation.

A 2024 pediatric study¹²¹² A 2024 pediatric study
367 pediatric IBD patients (197 Crohn's, 170 ulcerative colitis) found the CC genotype was positively associated with systemic steroid use in Crohn's disease and more common in female CD patients, suggesting the variant may influence disease severity or treatment requirements beyond simple susceptibility.

Practical Actions

If you carry one or two copies of the A allele, your genetic profile suggests a heightened inflammatory response to gut bacterial challenges. This doesn't guarantee you'll develop IBD—most carriers remain healthy—but it warrants attention to gut barrier health and inflammatory triggers.

Dietary patterns matter significantly¹³¹³ Dietary patterns matter significantly
Multiple studies show Mediterranean diet adherence reduces IBD risk and disease activity. The Mediterranean diet's benefits likely operate through multiple mechanisms: omega-3 fatty acids modulate inflammatory signaling, polyphenols reduce oxidative stress, and fiber feeds beneficial bacteria that produce short-chain fatty acids (SCFAs) like butyrate, which strengthen gut barrier integrity. Higher adherence to Mediterranean diet¹⁴¹⁴ Higher adherence to Mediterranean diet
In first-degree relatives of Crohn's patients, a population already at higher genetic risk was associated with reduced intestinal inflammation and lower risk of later-onset Crohn's disease.

Monitoring inflammatory markers can catch subclinical inflammation before symptoms appear. C-reactive protein (CRP) and fecal calprotectin¹⁵¹⁵ C-reactive protein (CRP) and fecal calprotectin
Calprotectin is more specific for intestinal inflammation and correlates better with endoscopic findings than CRP are the most validated biomarkers in IBD. Fecal calprotectin <250 μg/g identifies mucosal healing with 94% sensitivity, and rising levels can predict relapse earlier than clinical symptoms.

Probiotics have mixed evidence in IBD. For ulcerative colitis specifically¹⁶¹⁶ For ulcerative colitis specifically
Not for Crohn's disease, where most studies show no benefit over placebo, certain strains show promise: Escherichia coli Nissle 1917 for maintenance of remission, and VSL#3 (a multi-strain probiotic) for inducing remission in mild to moderately active UC. VSL#3 is the only probiotic with strong evidence¹⁷¹⁷ VSL#3 is the only probiotic with strong evidence
Particularly for pouchitis, an inflammatory condition of the surgically created intestinal pouch in common IBD practice.

Interactions

The rs3197999 variant lies in a complex genomic region on chromosome 3p21 that contains 10 genes within a 336 kb associated interval. Notably, it's in linkage disequilibrium¹⁸¹⁸ Notably, it's in linkage disequilibrium
Almost complete cosegregation of minor alleles, D'=0.60, r²=0.35 with rs1050450 in GPX1 (glutathione peroxidase 1), which causes a Pro198Leu substitution that reduces GPx-1 antioxidant enzyme activity. Some researchers have proposed that GPX1, rather than MST1, might be the pathophysiologically relevant gene at this locus.

The functional distinction is important: MST1 R689C affects innate immune activation (macrophage chemotaxis and bacterial response), while GPX1 Pro198Leu affects antioxidant capacity (ability to neutralize reactive oxygen species produced during inflammation). Both mechanisms could plausibly contribute to IBD pathogenesis. It's possible that the true causal variant is neither rs3197999 nor rs1050450 but another variant in linkage disequilibrium with both, or that both variants independently contribute to disease risk through complementary pathways. Given the proximity and LD structure, individuals with the MST1 A allele often also carry the GPX1 Leu198 allele, potentially compounding inflammatory susceptibility through both enhanced immune activation and reduced antioxidant defense.

Gene-gene interaction studies have identified significant epistasis between MST1 and several inflammatory pathway genes. The MST1–JAK2 interaction was replicated across original and validation datasets, and MST1 showed consistent interactions with IL23R (interleukin-23 receptor, a validated IBD susceptibility gene targeted by biologics like ustekinumab) and PTGER4 (prostaglandin E receptor 4, involved in inflammatory signaling). These interactions suggest that MST1 genetic effects may be amplified or modified by variation in other immune genes, and that personalized risk assessment should eventually incorporate multi-locus profiles rather than single-SNP analysis.