Expressive

rs1110446 (TRIM31): HBV-linked liver cancer risk

Key takeaways

  • rs1110446 is located near TRIM31 and TRIM31-AS1 in the HLA class I region on chromosome 6p21.3
  • Carrying the risk allele is associated with roughly 79% higher odds of liver cancer in people with chronic hepatitis B infection (OR 1.79, P = 1.66 x 10^-13)
  • The association was confirmed across Japanese, Hong Kong Chinese, and Thai populations in a multi-cohort meta-analysis
  • The variant's risk signal is independent of the nearby HLA-A*33:03 allele, suggesting additional genetic factors are at work in the HLA class I region
  • GTEx data show the alternate allele increases expression of ZFP57 across multiple tissues and HCP5B in whole blood

Key takeaways

  • rs1110446 sits in the HLA class I region on chromosome 6p21.3, in proximity to the TRIM31 and TRIM31-AS1 genes
  • Among people with chronic hepatitis B virus (HBV) infection, carrying the alternate allele is linked to approximately 79% higher odds of developing hepatocellular carcinoma (a primary form of liver cancer)
  • A meta-analysis across Japanese, Hong Kong Chinese, and Thai populations confirmed the association at P = 1.66 x 10^-13
  • The variant's liver cancer risk signal is independent of the nearby HLA-A*33:03 allele, indicating distinct genetic factors are at work in this region
  • GTEx eQTL data show the alternate allele is associated with increased expression of ZFP57 across multiple tissues and HCP5B in whole blood

What the research says

A genome-wide association study (GWAS) of 473 Japanese HCC cases and 516 HBV carrier controls identified rs1110446 in the HLA class I region as a significant factor associated with hepatocellular carcinoma (HCC) - the most common type of primary liver cancer - in people with chronic HBV infection; replication in East Asian cohorts confirmed the association with an odds ratio (OR) of 1.79 at P = 1.66 x 10^-13 (Sawai H et al., Scientific Reports 2019). The nearby classical HLA allele HLA-A33:03 was also significantly associated with disease progression to HCC (OR = 1.97, P = 4.58 x 10^-4), but conditioning analysis showed that rs1110446 captures independent risk information: adjusting for HLA-A33:03 did not eliminate the rs1110446 signal, while adjusting for rs1110446 did abolish the HLA-A*33:03 association, suggesting additional non-classical genetic factors in the region contribute to HBV-related HCC risk (Sawai H et al., Scientific Reports 2019).

Reported associations

  • HBV-related hepatocellular carcinoma (liver cancer): Alternate allele associated with increased odds among chronic HBV carriers; OR = 1.79, P = 1.66 x 10^-13 in meta-analysis spanning Japanese, Hong Kong Chinese, and Thai populations (Sawai H et al., Scientific Reports 2019)
  • HBV-related HCC, HLA context: Adjacent HLA-A33:03 allele also associated with disease progression (OR = 1.97), but the two signals are not equivalent; rs1110446 signal persisted after conditioning on HLA-A33:03, while HLA-A*33:03 association did not persist after conditioning on rs1110446 (Sawai H et al., Scientific Reports 2019)

Evidence quality

The discovery cohort comprised 473 Japanese HCC cases and 516 HBV carrier controls, covering 447,830 autosomal SNPs. From 65 candidate SNPs with P < 10^-4 in the HLA class I region, three (rs2523961, rs1110446, rs3094137) were taken forward for genotyping in three independent replication sets spanning Japanese, Hong Kong Chinese, and Thai populations; all three replicated with P values at genome-wide significance in meta-analysis (Sawai H et al., Scientific Reports 2019). The authors note that prior GWAS on HBV-related HCC conducted exclusively in Chinese populations, including rs17401966 in KIF1B, had failed to replicate in non-Chinese East Asian populations; this study was designed to address that limitation through multi-population replication. No conflicting published evidence regarding rs1110446 appears in the provided source material. The complexity of the HLA region, including extensive linkage disequilibrium and many co-inherited variants, means the causal variant underlying the association signal has not been definitively established.

Tissue-specific expression effects

GTEx v11 data from 953 donors identify rs1110446 as an expression quantitative trait locus (eQTL) - meaning the allele is statistically associated with how much nearby genes are expressed in tissue samples - for two genes:

  • ZFP57: Increased expression linked to the alternate allele in visceral adipose (omentum), esophagus muscularis, esophagus mucosa, tibial artery, non-sun-exposed skin, sun-exposed skin, and whole blood GTEx Portal
  • HCP5B: Increased expression in whole blood GTEx Portal

Lifestyle considerations

No lifestyle considerations on file for this variant.

Frequently asked questions

What is rs1110446?

rs1110446 is a genetic variant in the HLA class I region on chromosome 6p21.3, located near the TRIM31 and TRIM31-AS1 genes. It was identified in a genome-wide association study of hepatitis B virus-related liver cancer in East Asian populations.

Is rs1110446 linked to liver cancer?

Yes. Research found that rs1110446 is associated with hepatocellular carcinoma in people with chronic hepatitis B virus infection, with a meta-analysis odds ratio of 1.79 and P = 1.66 x 10^-13. This means carriers showed approximately 79% higher odds of developing this form of liver cancer compared to non-carriers in the study populations.

What is the HLA class I region?

The HLA (human leukocyte antigen) class I region is a section of chromosome 6 spanning about 3.6 million base pairs that contains over 200 genes. HLA class I genes encode proteins central to immune function, including presenting peptide fragments to T cells. rs1110446 is located within this region.

What does rs1110446 do at the molecular level?

GTEx expression data show the alternate allele is associated with increased expression of ZFP57 across several tissue types including adipose tissue, esophagus, skin, and blood, and increased HCP5B expression in whole blood. Whether these expression changes explain the liver cancer association has not been established by the available research.

Was the rs1110446 finding confirmed in multiple populations?

Yes. The initial discovery was made in a Japanese cohort, then replicated in three independent cohorts covering Japanese, Hong Kong Chinese, and Thai individuals. Meta-analysis confirmed genome-wide significant association at P = 1.66 x 10^-13.