Genetic analysis implicates ERAP1 and HLA as risk factors for severe Puumala virus infection

Hele Haapaniemi; Satu Strausz; Anniina Tervi; Samuel E Jones; Mari Kanerva; FinnGen, Estonian Biobank Research Team; Erik Abner; Anne-Marie Fors Connolly; Hanna M Ollila

doi:10.1093/hmg/ddae158

Genetic analysis implicates ERAP1 and HLA as risk factors for severe Puumala virus infection

Hum Mol Genet. 2024 Nov 13:ddae158. doi: 10.1093/hmg/ddae158. Online ahead of print.

Authors

Hele Haapaniemi¹, Satu Strausz^{1

2

3

4}, Anniina Tervi¹, Samuel E Jones¹, Mari Kanerva⁵; FinnGen, Estonian Biobank Research Team; Erik Abner⁶, Anne-Marie Fors Connolly⁷, Hanna M Ollila^{1

4

8

9}

Affiliations

¹ Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Tukholmankatu 8, 00290 Helsinki, Finland.
² Department of Oral and Maxillofacial Diseases, Helsinki University Hospital and University of Helsinki, Haartmaninkatu 1, 00290 Helsinki, Finland.
³ Department of Plastic Surgery, Cleft Palate and Craniofacial Center, Helsinki University Hospital and University of Helsinki, Stenbäckinkatu 11, 00290 Helsinki, Finland.
⁴ Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, United States.
⁵ Department of Hospital Hygiene and Infection Control, TYKS Turku University Hospital, Kiinamyllynkatu 4-8, 20521 Turku, Finland.
⁶ Estonian Genome Centre, Institute of Genomics, University of Tartu, Riia tn 23b, 51010 Tartu, Estonia.
⁷ Department of Clinical Microbiology, Umeå University, Biologihuset, 90187 Umeå, Sweden.
⁸ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, GRB 444 Boston, MA, United States.
⁹ Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, United States.

PMID: 39533856
DOI: 10.1093/hmg/ddae158

Abstract

Puumala virus (PUUV) infections can cause severe illnesses such as Hemorrhagic Fever with Renal Syndrome in humans. However, human genetic risk factors contributing to disease severity are still poorly understood. Our goal was to elucidate genetic factors contributing to PUUV infections and understand the biological mechanisms underlying individual vulnerability to PUUV infections. Leveraging data from the FinnGen study, we conducted a genome-wide association study on severe Hemorrhagic Fever with Renal Syndrome caused by PUUV with 2227 cases. We identified associations at the Human Leukocyte Antigen (HLA) locus and ERAP1 with severe PUUV infection. HLA molecules are canonical mediators for immune recognition and response. ERAP1 facilitates immune system recognition and activation by cleaving viral proteins into smaller peptides which are presented to the immune system via HLA class I molecules. Notably, we identified that the lead variant (rs26653, OR = 0.84, P = 2.9 × 10-8) in the ERAP1 gene was a missense variant changing amino acid arginine to proline. From the HLA region, we showed independent and significant associations with both HLA class I and II genes. Furthermore, we showed independent associations with four HLA alleles with severe PUUV infection using conditional HLA fine mapping. The strongest association was found with the HLA-C*07:01 allele (OR = 1.54, P = 4.0 × 10-24) followed by signals at HLA-B*13:02, HLA-DRB1*01:01, and HLA-DRB1*11:01 alleles (P < 5 × 10-8). Our findings suggest an association of viral peptide processing with ERAP1 and antigen presentation through HLA alleles that may contribute to the development of severe PUUV disease.

Keywords: GWAS; HLA; Puumala virus; fine-mapping.

Abstract

Grants and funding