rs2228603 — NCAN T130M (Pro92Ser)

Missense variant in neurocan associated with hepatic steatosis, liver inflammation and fibrosis progression, and altered lipid metabolism in the context of NAFLD.

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NCAN — The Liver Fat and Fibrosis Gene

Neurocan (NCAN)11 Neurocan (NCAN)
Neurocan is a chondroitin sulfate proteoglycan (also called CSPG3) originally characterised in the brain, where it modulates cell adhesion and migration in the central nervous system is one of the surprises of liver genetics. A variant at the 19p13.11 locus was identified in a genome-wide scan not because of NCAN's neural role, but because of unexpected expression in human liver tissue — expression that appears to influence how the liver handles fat and resists fibrotic injury.

The rs2228603 T allele (historically called "T130M" in older isoform numbering, canonical HGVS: p.Pro92Ser) carries two opposing effects: it increases the risk of hepatic steatosis progressing toward inflammation and fibrosis, yet it is also associated with lower circulating LDL, total cholesterol, and triglycerides in individuals who already have NAFLD — and with reduced carotid atherosclerosis in a prospective observational study. This combination of signals makes NCAN one of the more nuanced variants in liver metabolism genetics.

The Mechanism

NCAN encodes a large extracellular matrix proteoglycan. In the brain it anchors the perineuronal net around synapses. In the liver its role is less well characterised, but Nischalke et al.22 Nischalke et al.
Nischalke HD et al. A common polymorphism in the NCAN gene is associated with hepatocellular carcinoma in alcoholic liver disease. J Hepatol, 2014 were the first to localise NCAN protein expression to human liver tissue, revealing that the variant has a tissue-context it was not expected to have. The p.Pro92Ser change alters a conserved proline in the N-terminal domain of the neurocan core protein; proline-to-serine substitutions often affect local protein folding and extracellular matrix scaffold assembly. How this translates into altered hepatic lipid handling is not yet fully established at the molecular level, but the epidemiological signal is replicated across multiple independent cohorts.

The Evidence

The original GWAS by Speliotes et al.33 original GWAS by Speliotes et al.
Speliotes EK et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet, 2011 identified the NCAN locus among variants reaching genome-wide significance (p<5×10⁻⁸) for CT-quantified hepatic steatosis, alongside PNPLA3 and PPP1R3B. The study used 7,176 individuals in the discovery stage and 592 histology-confirmed NAFLD cases for validation.

Gorden et al.44 Gorden et al.
Gorden A et al. Genetic variation at NCAN locus is associated with inflammation and fibrosis in non-alcoholic fatty liver disease in morbid obesity. Hum Hered, 2013 extended this in 1,092 bariatric surgery patients, showing that the T allele associates with hepatic inflammation and fibrosis — a progression beyond simple steatosis — and with lower serum LDL, total cholesterol, and triglycerides, with the lipid associations present specifically in the NAFLD subgroup.

The hepatocellular carcinoma risk was documented by Nischalke et al.55 Nischalke et al.
Nischalke HD et al. A common polymorphism in the NCAN gene is associated with hepatocellular carcinoma in alcoholic liver disease. J Hepatol, 2014: T allele frequency was 15.1% in alcoholic HCC patients versus 9.3% in cirrhosis without HCC, with a validated OR of 2.53 (95% CI 1.36–4.68; p=0.0025) for HCC in the alcoholic liver disease context specifically.

A more recent prospective study by Ikezaki et al.66 Ikezaki et al.
Ikezaki H et al. Impact of NAFLD-related SNPs on the carotid atherosclerosis development; a five-year prospective observational study. Atheroscler Plus, 2024 found that NCAN CT/TT carriers had substantially lower carotid atherosclerosis incidence over 5 years (4.7% vs 13.9%; p=0.04), suggesting the lipid-lowering effect in people with liver pathology may confer a cardiovascular benefit.

Evidence for NAFLD susceptibility in Asian populations has been mixed: Wu et al.77 Wu et al.
Wu MJ et al. Role of NCAN rs2228603 polymorphism in the incidence of nonalcoholic fatty liver disease: a case-control study. Lipids Health Dis, 2016 found no significant association with NAFLD incidence in a Chinese cohort (n=377), though CT carriers showed elevated HDL and alkaline phosphatase — consistent with dual hepatoprotective and hepatotoxic signals.

The T allele is relatively uncommon overall (global frequency ~6.7%), but is rarer in people of African ancestry (~1.4%) and slightly more common in East Asian populations (~6.6%). The TT homozygous genotype is present in fewer than 1% of people of any ancestry.

Practical Actions

For CT heterozygotes (the most common at-risk genotype), the evidence suggests monitoring liver health markers — particularly if other NAFLD risk factors are present — and reducing dietary saturated fat intake, which exacerbates hepatic fat accumulation at the liver level. The NCAN T allele's association with lower LDL/TC/TG in NAFLD patients does not mean the genotype is benign with respect to liver injury: the altered lipid profile may reflect hepatic fat redistribution rather than cardioprotection. Alcohol intake amplifies risk substantially given the alcoholic HCC association.

For the rare TT homozygote, liver health surveillance with periodic ultrasound and liver enzymes (ALT, AST, GGT, alkaline phosphatase) is warranted, especially in the presence of obesity, metabolic syndrome, or significant alcohol use.

Interactions

The strongest interaction documented in the literature is with PNPLA3 rs738409 — both variants independently increase hepatic steatosis risk, and cohort studies that genotyped both confirmed additive effects on NAFLD susceptibility and severity. A paediatric GWAS (Shang et al. 2015, PMID 25522307) found that cumulative risk allele load across NAFLD-associated variants including rs2228603 and rs738409 was associated with OR 4.76 for NAFLD when 10+ risk alleles were present.

GCKR rs1260326 is another locus that commonly appears alongside NCAN in NAFLD association studies. Carriers of both GCKR and NCAN risk alleles may have compounded hepatic lipid handling impairment.

Nutrient Interactions

saturated fat altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal Normal

Common genotype — no NCAN-related liver fat risk

You carry the common CC genotype at NCAN rs2228603. About 87% of people share this genotype. You do not carry the T allele that has been associated with increased hepatic steatosis progression, liver inflammation, and elevated hepatocellular carcinoma risk in alcoholic liver disease.

CT T Carrier Intermediate

One NCAN T allele — modestly elevated liver fat and fibrosis risk

You carry one copy of the NCAN T allele, found in approximately 12–13% of people globally. Genome-wide studies have identified this allele as associated with hepatic steatosis, and follow-up studies in bariatric surgery patients linked it to liver inflammation and fibrosis progression beyond simple fat accumulation.

A paradoxical lipid-lowering effect (lower LDL, total cholesterol, and triglycerides) has been observed in NAFLD patients who carry this allele — but this appears to reflect hepatic fat redistribution in an injured liver, not cardiovascular protection in the general sense. In a five-year prospective study, CT/TT carriers had meaningfully lower carotid atherosclerosis rates, suggesting the picture is complex and context-dependent.

The risk for hepatocellular carcinoma in alcoholic liver disease is elevated in T allele carriers; alcohol intake substantially amplifies this risk.

TT T Homozygous High Risk

Two NCAN T alleles — elevated liver inflammation and HCC risk

You carry two copies of the NCAN T allele, a rare genotype present in fewer than 1% of people of any ancestry. The homozygous state magnifies the risk signals associated with a single T allele: elevated hepatic steatosis susceptibility, a greater likelihood of progression to liver inflammation and fibrosis (steatohepatitis), and a meaningfully elevated risk of hepatocellular carcinoma specifically in the context of alcohol-related liver disease.

In the validation cohort of Nischalke et al. 2014, the T allele was associated with an OR of 2.53 (95% CI 1.36–4.68) for HCC among patients with alcoholic liver cirrhosis. As a TT homozygote your allele dose doubles the exposure to this risk.

The paradoxical lipid-lowering effect (lower LDL, TC, TG) seen in NAFLD patients with the T allele may be more pronounced in the TT genotype, but this should not be mistaken for cardiovascular protection — it is more likely a marker of significant hepatic dysfunction driving altered lipoprotein secretion.