title: Single nucleotide polymorphisms associated with abnormal coronary microvascular function.
abstract: BACKGROUND
  Single nucleotide polymorphisms (SNPs) are the most common source of genetic variation. Although microvascular pathology is associated with cardiovascular events, genetic phenotypes causing microvascular disease remain largely unknown. This study identifies sex-specific SNPs associated with coronary microvascular dysfunction.
  
  
  RESULTS
  Six hundred and forty-three patients without significant obstructive coronary heart disease were enrolled, referred for cardiac catheterization, and underwent invasive coronary microcirculatory assessment. Patient data were collected from 1529 autosomal SNPs and seven X chromosome SNPs, which were selected to represent the variability from 76 candidate genes with published associations with coronary vasoreactivity, angiogenesis, inflammation, vascular calcification, atherosclerosis risk factors, female hormones, blood coagulation, or coronary heart disease. Coronary flow reserve (CFR) was assessed by an intracoronary injection of adenosine. Patients were categorized according to a CFR above or below 2.5 and were stratified by sex.After adjusting for age, sex, and BMI, this study shows that SNPs within VEGFA and CDKN2B-AS1 are associated with abnormal CFR (P<0.005). SNPs within MYH15, VEGFA, and NT5E are associated with abnormal CFR in men. No SNPs were associated with abnormal CFR in women.
  
  
  CONCLUSIONS
  Genetic variations within defined regions of VEGFA and CDKN2B-AS1 genes are associated with coronary microvascular dysfunction. Furthermore, sex-specific allelic variants within MYH15, VEGFA, and NT5E are associated with an increased risk of coronary microvascular dysfunction in men.
authors.affiliation: aDepartment of Cardiovascular Medicine and Hypertension, Kagoshima University Hospital, Sakuragaoka, Kagoshima, Japan bDepartment of Internal Medicine, Division of Cardiovascular Diseases cDepartment of Health Sciences Research, Division of Biomedical Statistics and Informatics dDepartment of Experimental Pathology and Laboratory Medicine, Division of Genomics Shared Resource eDepartment of Internal Medicine, Division of Nephrology, Mayo Clinic and College of Medicine, Rochester, Minnesota, USA fDepartment of Cardiology, Ajou University Medical Center, Suwon, Korea.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yoshino
authors.forename: Rebecca
authors.initials: R
authors.lastname: Cilluffo
authors.forename: Patricia J M
authors.initials: PJ
authors.lastname: Best
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Atkinson
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Aoki
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: Mariza
authors.initials: M
authors.lastname: de Andrade
authors.forename: Byoung-Joo
authors.initials: BJ
authors.lastname: Choi
authors.forename: Lilach O
authors.initials: LO
authors.lastname: Lerman
authors.forename: Amir
authors.initials: A
authors.lastname: Lerman
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D041321:Chromosomes, Human, X; D003326:Coronary Circulation / Q000235:genetics*; D003327:Coronary Disease / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D003430:Cross-Sectional Studies; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008833:Microcirculation / Q000235:genetics*; D008875:Middle Aged; D018995:Myosin Heavy Chains / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D062085:RNA, Long Noncoding / Q000235:genetics; D012307:Risk Factors; D012737:Sex Factors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D055815:Young Adult
chemical_list: C561518:CDKN2B antisense RNA, human; D058851:GPI-Linked Proteins; D062085:RNA, Long Noncoding; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D015720:5'-Nucleotidase; C548241:NT5E protein, human; D018995:Myosin Heavy Chains
references.citation: Vasc Med. 2005 Feb;10(1):37-44
references.pmid: 15920999
references.citation: J Am Coll Cardiol. 2000 May;35(6):1654-60
references.pmid: 10807473
references.citation: N Engl J Med. 2011 Dec 1;365(22):2098-109
references.pmid: 22129254
references.citation: Invest Ophthalmol Vis Sci. 2009 Dec;50(12):5552-8
references.pmid: 19553626
references.citation: Circulation. 1997 Nov 18;96(10):3390-5
references.pmid: 9396432
references.citation: Hum Mol Genet. 2008 Mar 15;17(6):806-14
references.pmid: 18048406
references.citation: J Am Coll Cardiol. 1995 Oct;26(4):1068-79
references.pmid: 7560601
references.citation: N Engl J Med. 2011 Feb 3;364(5):432-42
references.pmid: 21288095
references.citation: J Am Coll Cardiol. 1999 Feb;33(2):463-70
references.pmid: 9973027
references.citation: Cardiovasc Res. 2011 Apr 1;90(1):9-17
references.pmid: 21159671
references.citation: Eur Heart J. 1993 Sep;14(9):1158-62
references.pmid: 8223728
references.citation: J Am Coll Cardiol. 2006 Feb 7;47(3 Suppl):S21-9
references.pmid: 16458167
references.citation: Mol Genet Metab. 2011 May;103(1):44-50
references.pmid: 21371928
references.citation: Biotechniques. 2002 Jun;Suppl:56-8, 60-1
references.pmid: 12083399
references.citation: J Am Coll Cardiol. 1995 Jul;26(1):41-9
references.pmid: 7797774
references.citation: Curr Probl Cardiol. 2011 Aug;36(8):291-318
references.pmid: 21723447
references.citation: PLoS Genet. 2010 Oct 28;6(10):e1001184
references.pmid: 21060863
references.citation: Stroke. 2009 Feb;40(2):363-8
references.pmid: 19023099
references.citation: N Engl J Med. 2010 May 6;362(18):1736-7
references.pmid: 20445187
references.citation: Trans Am Clin Climatol Assoc. 1999;110:107-16; discussion 117-8
references.pmid: 10344011
references.citation: Eur Heart J. 2008 Jun;29(11):1359-69
references.pmid: 18424787
references.citation: J Am Coll Cardiol. 2001 May;37(6):1523-8
references.pmid: 11345360
references.citation: Circulation. 1995 Nov 1;92(9):2426-31
references.pmid: 7586341
references.citation: Circulation. 2000 Mar 7;101(9):948-54
references.pmid: 10704159
references.citation: J Med Genet. 2011 Jan;48(1):38-47
references.pmid: 20978019
references.citation: Anesthesiology. 2001 Feb;94(2):372-5
references.pmid: 11176110
references.citation: J Am Coll Cardiol. 2007 Aug 21;50(8):760-7
references.pmid: 17707181
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901
references.citation: Nature. 2011 Feb 10;470(7333):264-8
references.pmid: 21307941
references.citation: Am Heart J. 2007 Dec;154(6):1035-42
references.pmid: 18035072
references.citation: J Neurosci. 2013 Jul 3;33(27):11314-22
references.pmid: 23825434