title: Novel 6p21.3 Risk Haplotype Predisposes to Acute Coronary Syndrome.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  https://www.clinicaltrials.gov; Unique Identifier: NCT00417534.
authors.forename: Juha
authors.initials: J
authors.lastname: Sinisalo
authors.forename: Efthymia
authors.initials: E
authors.lastname: Vlachopoulou
authors.forename: Marja
authors.initials: M
authors.lastname: Marchesani
authors.forename: Johanna
authors.initials: J
authors.lastname: Nokelainen
authors.forename: Mikko I
authors.initials: MI
authors.lastname: Mäyränpää
authors.forename: Jani
authors.initials: J
authors.lastname: Lappalainen
authors.forename: Riitta
authors.initials: R
authors.lastname: Paakkanen
authors.forename: Annika
authors.initials: A
authors.lastname: Wennerström
authors.forename: Krista
authors.initials: K
authors.lastname: Salli
authors.forename: Heikki J
authors.initials: HJ
authors.lastname: Niemi
authors.forename: Satu
authors.initials: S
authors.lastname: Männistö
authors.forename: Perttu
authors.initials: P
authors.lastname: Salo
authors.forename: Juhani
authors.initials: J
authors.lastname: Junttila
authors.forename: Markku
authors.initials: M
authors.lastname: Eskola
authors.forename: Kjell
authors.initials: K
authors.lastname: Nikus
authors.forename: T Petteri
authors.initials: TP
authors.lastname: Arstila
authors.forename: Markus
authors.initials: M
authors.lastname: Perola
authors.forename: Heikki
authors.initials: H
authors.lastname: Huikuri
authors.forename: Pekka J
authors.initials: PJ
authors.lastname: Karhunen
authors.forename: Petri T
authors.initials: PT
authors.lastname: Kovanen
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.forename: Aki S
authors.initials: AS
authors.lastname: Havulinna
authors.forename: Carla
authors.initials: C
authors.lastname: Lluis-Ganella
authors.forename: Jaume
authors.initials: J
authors.lastname: Marrugat
authors.forename: Roberto
authors.initials: R
authors.lastname: Elosua
authors.forename: Veikko
authors.initials: V
authors.lastname: Salomaa
authors.forename: Markku S
authors.initials: MS
authors.lastname: Nieminen
authors.forename: Marja-Liisa
authors.initials: ML
authors.lastname: Lokki
mesh_terms: D054058:Acute Coronary Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D000071797:Butyrophilins; D015331:Cohort Studies; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D005260:Female; D059811:HLA-DRB1 Chains / Q000235:genetics / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D018418:Th2 Cells / Q000378:metabolism / Q000473:pathology
chemical_list: C408263:BTNL2 protein, human; D000071797:Butyrophilins; D059811:HLA-DRB1 Chains; D008562:Membrane Glycoproteins
keywords: BTNL2; MHC; acute coronary syndrome; association studies; expression experiments; genetics; haplotype; human leukocyte antigen; regulatory T cell; single nucleotide polymorphism