rs72613567 — HSD17B13 Splice Variant (;A)

HSD17B13 — The Liver's Hidden Shield Against Fat-Driven Inflammation

Deep inside your liver cells, tiny fat droplets accumulate when caloric intake, alcohol, or metabolic stress overwhelm the liver's processing capacity. Coating the surface of these fat droplets is a lipid droplet–associated enzyme called HSD17B13¹¹ HSD17B13
Hydroxysteroid 17-beta dehydrogenase 13, a member of the short-chain dehydrogenase/reductase enzyme family exclusively expressed in hepatocytes. In most people, this enzyme is fully active — and paradoxically, its activity appears to drive inflammation, fibrosis, and liver disease progression. One of the most striking discoveries in liver genetics over the past decade is that losing HSD17B13 function is protective: a naturally occurring insertion variant that silences the enzyme is associated with dramatically reduced risk of nonalcoholic steatohepatitis (NASH), alcoholic liver disease, cirrhosis, and hepatocellular carcinoma.

The Mechanism

The rs72613567 variant consists of an adenine insertion (;A) immediately adjacent to the donor splice site²² donor splice site
The nucleotide sequence at the exon-intron boundary where the spliceosome cuts to remove the intron; disruption here causes aberrant or skipped splicing of intron 6 in HSD17B13. This insertion disrupts normal mRNA processing, producing an alternative transcript (termed isoform D) that is frameshifted and encodes a truncated, enzymatically inactive protein. The truncated protein is also unstable — HSD17B13 protein levels in liver biopsies decrease proportionally to the number of insertion alleles carried.

HSD17B13 normally functions as a retinol dehydrogenase and lipid droplet–associated oxidoreductase, and it appears to modulate hepatic lipogenesis and lipid droplet expansion. Its loss alters the liver's phospholipid composition and suppresses inflammation-related gene expression pathways. Whole-transcriptome profiling of carriers shows downregulation of 274 genes, predominantly in immune response and inflammatory pathways — explaining why the loss-of-function state protects against the inflammatory cascade that drives NASH and fibrosis.

Critically, the variant does not protect against simple steatosis³³ steatosis
Fat accumulation in liver cells without inflammation; the earliest stage of fatty liver disease. The protection is specific to the progression from steatosis to steatohepatitis (inflammation) and fibrosis — meaning the enzyme's activity is particularly harmful during the transition to aggressive liver disease.

The Evidence

The landmark study from Abul-Husn et al. (NEJM 2018) analyzed 46,544 participants in the Geisinger Health System cohort: protective effect on alcoholic liver disease: 42% reduction in heterozygotes, 53% in homozygotes; on nonalcoholic liver disease: 17% and 30% reduction; on alcoholic cirrhosis: 42% and 73% reduction⁴⁴ protective effect on alcoholic liver disease: 42% reduction in heterozygotes, 53% in homozygotes; on nonalcoholic liver disease: 17% and 30% reduction; on alcoholic cirrhosis: 42% and 73% reduction
Abul-Husn NS et al. N Engl J Med 2018;378:1096-1106. These associations were replicated in independent cohorts totaling over 37,000 additional participants.

At the histology level, Pirola et al. (2019) examined 356 biopsy-proven NAFLD patients and found that each insertion allele reduces the odds of NASH (OR 0.61), ballooning degeneration (OR 0.47), and lobular inflammation (OR 0.48) — all hallmarks of progressive liver disease: Pirola CJ et al. Splice variant rs72613567 prevents worst histologic outcomes in patients with NAFLD. J Lipid Res, 2019⁵⁵ Pirola CJ et al. Splice variant rs72613567 prevents worst histologic outcomes in patients with NAFLD. J Lipid Res, 2019.

A 2020 meta-analysis pooling over 564,000 participants confirmed protection across all liver disease categories: pooled OR 0.73 for any liver disease, 0.81 for cirrhosis, 0.64 for hepatocellular carcinoma⁶⁶ pooled OR 0.73 for any liver disease, 0.81 for cirrhosis, 0.64 for hepatocellular carcinoma
Wang P et al. HSD17B13 rs72613567 protects against liver diseases and histological progression of NAFLD: a systematic review and meta-analysis. Eur Rev Med Pharmacol Sci, 2020.

In alcoholic liver disease specifically, a multicenter study of 3,315 European patients found that TA carriers have significantly lower HCC risk (OR 0.73 in ALD patients, and OR 0.64 for HCC development among those with ALD): Yang J, Nault JC et al. Hepatology 2019;71:1099-1108⁷⁷ Yang J, Nault JC et al. Hepatology 2019;71:1099-1108.

The protective effect also modifies the impact of the major liver-risk variant PNPLA3 rs738409⁸⁸ PNPLA3 rs738409
The strongest common genetic risk factor for NAFLD and alcoholic liver disease — an I148M missense variant in adiponutrin/patatin-like phospholipase domain-containing protein 3: the HSD17B13 TA allele substantially attenuates the liver injury associated with the PNPLA3 G (risk) allele, demonstrating that these two variants interact within the same lipid droplet biology pathway.

One important nuance: in patients who have already progressed to portal hypertension and advanced cirrhosis, the protective effect appears attenuated — the variant protects against developing severe liver disease more than it improves outcomes once severe disease is established.

Practical Implications

For carriers of one or two insertion alleles, the evidence supports that your liver has a meaningful biological buffer against alcohol-induced inflammation and metabolic liver disease progression. However, this protection is not absolute — it operates on a spectrum and can be overwhelmed by sufficient stressor load (heavy alcohol use, severe obesity, or co-inherited liver-risk variants like PNPLA3 GG).

For non-carriers (DD genotype), the absence of this protection means that alcohol, metabolic syndrome risk factors, and other liver stressors carry a higher baseline risk for inflammatory liver disease progression. Periodic liver function monitoring (ALT/AST, GGT) and abdominal imaging is particularly valuable for informing decisions about alcohol consumption and metabolic management.

Interactions

The most important genetic interaction is with PNPLA3 rs738409 (I148M): the GG high-risk genotype at PNPLA3 markedly amplifies liver disease risk, but HSD17B13 TA carriers show attenuated ALT levels and less severe histology even when carrying PNPLA3 risk alleles. The ALT-lowering benefit of HSD17B13 TA is greatest among individuals with three or four steatogenic alleles across PNPLA3 and TM6SF2 (rs58542926).

TM6SF2 rs58542926 (E167K) impairs hepatic VLDL secretion and elevates liver triglycerides; like PNPLA3, its risk effect operates in the same lipid droplet biology axis where HSD17B13 exerts protection, making these three variants key components of any comprehensive liver genetic risk assessment.