Novel 6p21.3 Risk Haplotype Predisposes to Acute Coronary Syndrome.
Circulation. Cardiovascular Genetics
|December 19, 2015
Summary
The human leukocyte antigen HLA-DRB1*01 allele is linked to acute coronary syndrome. A specific haplotype involving BTNL2 and HLA-DRA genes may increase disease risk by affecting immune responses.
Area of Science:
- Immunogenetics
- Cardiovascular Genetics
Background:
- The human leukocyte antigen (HLA) system plays a crucial role in immune responses.
- The HLA-DRB1*01 allele has been previously associated with acute coronary syndrome (ACS).
- Genome-wide association studies (GWAS) identified associations with major histocompatibility complex (MHC) genes but lacked allelic resolution.
Purpose of the Study:
- To investigate the allelic and haplotypic associations of HLA-DRB1*01 with acute coronary syndrome.
- To identify specific genetic loci within the MHC region conferring risk for ACS.
- To explore the functional role of identified genetic variants in disease pathogenesis.
Main Methods:
- Large-scale genetic analysis of a case-control cohort (5376 ACS cases, 4852 controls) from European populations.
- Genomic real-time polymerase chain reaction (PCR) for HLA-DRB1*01 allele analysis.
- High-density single nucleotide polymorphism (SNP) genotyping across the MHC region.
- Immunofluorescence staining and T-cell stimulation assays to assess gene function.
Main Results:
- A risk haplotype containing SNPs from BTNL2 and HLA-DRA, along with the HLA-DRB1*01 allele, was identified for ACS.
- This haplotype association was consistent across three of four populations studied.
- Individuals homozygous for the risk haplotype exhibited increased BTNL2 mRNA levels in coronary artery plaques.
- BTNL2 was localized to macrophages within coronary plaques.
- Blocking BTNL2 function in vitro significantly enhanced regulatory T cell (Treg) proliferation in homozygous cases.
Conclusions:
- The identified risk haplotype suggests an involvement of enhanced immune reactions in ACS pathogenesis.
- BTNL2 may exert an inhibitory effect on FOXP3-positive (Treg) cell proliferation, particularly in individuals homozygous for the risk alleles.
- These findings highlight a potential mechanism linking specific HLA and non-HLA genes to ACS through immune dysregulation.
Keywords:
BTNL2MHCacute coronary syndromeassociation studiesexpression experimentsgeneticshaplotypehuman leukocyte antigenregulatory T cellsingle nucleotide polymorphismMore Related Videos
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