DOI: 10.1097/hc9.0000000000001026 ISSN: 2471-254X

HLA and non-HLA genetic analyses reveal suggestive variants associated with statin-induced liver injury

Callie Jo Zaborenko, Tae-Hwi Schwantes-An, Yi-Ju Li, Andrew Dellinger, Paola Nicoletti, Ann K. Daly, Guruprasad Aithal, Naga Chalasani,
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Background:

Statins are widely prescribed for cardiovascular risk reduction and are generally well tolerated. However, they can cause drug-induced liver injury (DILI), and the genetic factors contributing to statin-DILI remain poorly understood.

Methods:

HLA association and genome-wide association (GWAS) studies were conducted to identify genetic variants associated with statin-DILI. High-confidence cases (n=71) were identified from the Drug-Induced Liver Injury Network (DILIN) and compared with statin-exposed controls without liver injury (n=551) from the Indiana Biobank. Association testing was performed across ancestries and within ancestry, adjusting for age, sex, and three principal components of genotypes. Top variants were further evaluated in non-statin DILI cases and unexposed controls. In addition, we investigated the frequency of candidate variants among a comprehensive list of pharmacogenetic variants related to statins.

Results:

HLA-DQA1*03:01 was significantly associated with increased risk of statin-DILI (OR=3.49, 95% CI 2.21–5.51, p -value=1.27×10 −7 ), with enrichment observed across multiple ancestry groups, particularly non-Hispanic Black and Hispanic individuals. From the GWAS, three loci showed suggestive associations ( p -value <5×10 −06 ) with statin-DILI, including rs35197737 in RGS1 (OR=5.03, 95% CI 1.11–3.66, p =1.14×10 −7 ), rs75629598 in FRMD4A (OR=4.4, 95% CI=2.33–8.12, p =3.97×10 −6 ), and rs7658630 in the intergenic region on chromosome 4 (OR=4.86, 95% CI 2.66–8.85, p =2.68×10 −7 ). No pharmacogenetic variants revealed statistical significance.

Conclusion:

We identified HLA and non- HLA genetic variants associated with statin DILI. Future studies with larger sample sizes should confirm these observations.

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