Genome-wide Association Study Identifies HLA-DPB1 as a Significant Risk Factor for Severe Aplastic Anemia

Area of Science:

• Immunogenetics
• Hematology
• Genomics

Background:

• Severe aplastic anemia (SAA) is a rare, life-threatening condition characterized by bone marrow failure and pancytopenia.
• The exact causes of acquired SAA are unknown but are suspected to involve immune dysregulation and environmental factors.

Purpose of the Study:

• To investigate the genetic underpinnings of severe aplastic anemia (SAA) through a genome-wide association study (GWAS).
• To identify specific genetic variants within the major histocompatibility complex (MHC) associated with SAA susceptibility.

Main Methods:

• Conducted a genome-wide association study (GWAS) with discovery and validation cohorts, comparing SAA cases to healthy controls.
• Utilized SNP analysis within the MHC region on chromosome 6p21, focusing on HLA class II (HLA-DPB1) and class I (HLA-B) genes.
• Performed phylogenetic analysis and imputed HLA-DPB1 alleles to assess the functional impact of identified genetic variations.

Main Results:

• Identified significant single nucleotide polymorphisms (SNPs) in HLA-DPB1, including rs1042151 (p.Met76Val), strongly associated with SAA risk (p = 1.94 × 10^-13).
• The Met76Val substitution in HLA-DPB1 was linked to altered HLA-DP cell surface expression and increased SAA risk with specific alleles (DPB1^∗03:01, DPB1^∗10:01, DPB1^∗01:01).
• A second SNP near HLA-B (rs28367832) also reached genome-wide significance, suggesting a potential role for HLA class I genes in SAA pathogenesis.

Conclusions:

• Genetic variations in HLA-DPB1 and potentially HLA-B are associated with an increased risk of developing severe aplastic anemia.
• The identified HLA-DPB1 variants, particularly those encoding the p.Met76Val substitution, may influence SAA risk through altered peptide binding specificity or expression levels.
• These findings highlight the role of immune response genes in the etiology of SAA and offer potential targets for future research.