Sinisalo J, Vlachopoulou E, Marchesani M, Nokelainen J, Mäyränpää MI, Lappalainen J, Paakkanen R, Wennerström A, Salli K, Niemi HJ, Männistö S, Salo P, Junttila J, Eskola M, Nikus K, Arstila TP, Perola M, Huikuri H, Karhunen PJ, Kovanen PT, Palotie A, Havulinna AS, Lluís-Ganella C, Marrugat J, Elosua R, Salomaa V, Nieminen MS, Lokki ML,

Novel 6p21.3 Risk Haplotype Predisposes to Acute Coronary Syndrome.

Circ Cardiovasc Genet 2016 Feb; 9 (1): 55-63, PMID: 26679868

The HLA-DRB1*01 allele of the human leukocyte antigen has been associated with acute coronary syndrome. Genome-wide association studies have revealed associations with human leukocyte antigen and non-human leukocyte antigen genes of 3 major histocompatibility complex gene classes but not at allelic level.We conducted a large-scale genetic analysis on a case-control cohort comprising 5376 acute coronary syndrome cases and 4852 unrelated controls from 4 populations of 2 European countries. We analyzed the risk candidate allele of HLA-DRB1*01 by genomic real-time polymerase chain reaction together with high-density single nucleotide polymorphisms of the major histocompatibility complex to precisely identify risk loci for acute coronary syndrome with effective clinical implications. We found a risk haplotype for the disease containing single nucleotide polymorphisms from BTNL2 and HLA-DRA genes and the HLA-DRB1*01 allele. The association of the haplotype appeared in 3 of the 4 populations, and the direction of the effect was consistent in the fourth. Coronary samples from subjects homozygous for the disease-associated haplotype showed higher BTNL2 mRNA levels (r=0.760; P<0.00001).We localized, with immunofluorescence staining, BTNL2 in CD68-positive macrophages of the coronary artery plaques. In homozygous cases, BTNL2 blocking, in T-cell stimulation assays, enhanced CD4(+)FOXP3(+) regulatory T cell proliferation significantly (blocking versus nonblocking; P<0.05).In cases with the risk haplotype for acute coronary syndrome, these results suggest involvement of enhanced immune reactions. BTNL2 may have an inhibitory effect on FOXP3(+) T cell proliferation, especially in patients homozygous for the risk alleles.https://www.clinicaltrials.gov; Unique Identifier: NCT00417534.

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