title: Candidate gene association study of coronary artery calcification in chronic kidney disease: findings from the CRIC study (Chronic Renal Insufficiency Cohort).
abstract: OBJECTIVE
  This study sought to identify loci for coronary artery calcification (CAC) in patients with chronic kidney disease (CKD).
  
  
  BACKGROUND
  CKD is associated with increased CAC and subsequent coronary heart disease (CHD), but the mechanisms remain poorly defined. Genetic studies of CAC in CKD may provide a useful strategy for identifying novel pathways in CHD.
  
  
  METHODS
  We performed a candidate gene study (∼2,100 genes; ∼50,000 single nucleotide polymorphisms [SNPs]) of CAC within the CRIC (Chronic Renal Insufficiency Cohort) study (N = 1,509; 57% European, 43% African ancestry). SNPs with preliminary evidence of association with CAC in CRIC were examined for association with CAC in the PennCAC (Penn Coronary Artery Calcification) (N = 2,560) and AFCS (Amish Family Calcification Study) (N = 784) samples. SNPs with suggestive replication were further analyzed for association with myocardial infarction (MI) in the PROMIS (Pakistan Risk of Myocardial Infarction Study) (N = 14,885).
  
  
  RESULTS
  Of 268 SNPs reaching p < 5 × 10(-4) for CAC in CRIC, 28 SNPs in 23 loci had nominal support (p < 0.05 and in same direction) for CAC in PennCAC or AFCS. Besides chr9p21 and COL4A1, known loci for CHD, these included SNPs having reported genome-wide association study association with hypertension (e.g., ATP2B1). In PROMIS, 4 of the 23 suggestive CAC loci (chr9p21, COL4A1, ATP2B1, and ABCA4) had significant associations with MI, consistent with their direction of effect on CAC.
  
  
  CONCLUSIONS
  We identified several loci associated with CAC in CKD that also relate to MI in a general population sample. CKD imparts a high risk of CHD and may provide a useful setting for discovery of novel CHD genes and pathways.
authors.affiliation: Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Jane F
authors.initials: JF
authors.lastname: Ferguson
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Matthews
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Townsend
authors.forename: Dominic S
authors.initials: DS
authors.lastname: Raj
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kanetsky
authors.forename: Matthew
authors.initials: M
authors.lastname: Budoff
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Fischer
authors.forename: Sylvia E
authors.initials: SE
authors.lastname: Rosas
authors.forename: Radhika
authors.initials: R
authors.lastname: Kanthety
authors.forename: Mahboob
authors.initials: M
authors.lastname: Rahman
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Master
authors.forename: Atif
authors.initials: A
authors.lastname: Qasim
authors.forename: Mingyao
authors.initials: M
authors.lastname: Li
authors.forename: Nehal N
authors.initials: NN
authors.lastname: Mehta
authors.forename: Haiqing
authors.initials: H
authors.lastname: Shen
authors.forename: Braxton D
authors.initials: BD
authors.lastname: Mitchell
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: O'Connell
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
authors.forename: Weang Kee
authors.initials: WK
authors.lastname: Ho
authors.forename: Robin
authors.initials: R
authors.lastname: Young
authors.forename: Asif
authors.initials: A
authors.lastname: Rasheed
authors.forename: John
authors.initials: J
authors.lastname: Danesh
authors.forename: Jiang
authors.initials: J
authors.lastname: He
authors.forename: John W
authors.initials: JW
authors.lastname: Kusek
authors.forename: Akinlolu O
authors.initials: AO
authors.lastname: Ojo
authors.forename: John
authors.initials: J
authors.lastname: Flack
authors.forename: Alan S
authors.initials: AS
authors.lastname: Go
authors.forename: Crystal A
authors.initials: CA
authors.lastname: Gadegbeku
authors.forename: Jackson T
authors.initials: JT
authors.lastname: Wright
authors.forename: Danish
authors.initials: D
authors.lastname: Saleheen
authors.forename: Harold I
authors.initials: HI
authors.lastname: Feldman
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Foulkes
authors.forename: Muredach P
authors.initials: MP
authors.lastname: Reilly
mesh_terms: D000328:Adult; D000368:Aged; D044383:Black People / Q000235:genetics; D015331:Cohort Studies; D003331:Coronary Vessels; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000453:epidemiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D051436:Renal Insufficiency, Chronic / Q000150:complications*; D012307:Risk Factors; D061205:Vascular Calcification / Q000209:etiology / Q000235:genetics*; D044465:White People / Q000235:genetics
keywords: AA; African ancestry; CAC; CHD; CKD; Chronic Renal Insufficiency Cohort Study (CRIC); EA; European ancestry; GWAS; HDL; HTN; LD; LDL; MAF; MI; OR; PC; SNP; candidate genes; chronic kidney disease; chronic kidney disease (CKD); coronary artery calcification; coronary artery calcification (CAC); coronary heart disease; eGFR; estimated glomerular filtration rate; genome-wide association study/studies; high-density lipoprotein cholesterol; hypertension; linkage disequilibrium; low-density lipoprotein; minor allele frequency; myocardial infarction; myocardial infarction (MI); odds ratio; principal component; risk factors; single nucleotide polymorphism; single nucleotide polymorphisms (SNPs)