A genomewide scan for early-onset coronary artery disease in 438 families: the GENECARD Study.
A family history of coronary artery disease (CAD), especially when the disease occurs at a young age, is a potent risk factor for CAD. DNA collection in families in which two or more siblings are affected at an early age allows identification of genetic factors for CAD by linkage analysis. We performed a genomewide scan in 1,168 individuals from 438 families, including 493 affected sibling pairs with documented onset of CAD before 51 years of age in men and before 56 years of age in women. We prospectively defined three phenotypic subsets of families: (1) acute coronary syndrome in two or more siblings; (2) absence of type 2 diabetes in all affected siblings; and (3) atherogenic dyslipidemia in any one sibling. Genotypes were analyzed for 395 microsatellite markers. Regions were defined as providing evidence for linkage if they provided parametric two-point LOD scores >1.5, together with nonparametric multipoint LOD scores >1.0. Regions on chromosomes 3q13 (multipoint LOD = 3.3; empirical P value <.001) and 5q31 (multipoint LOD = 1.4; empirical P value <.081) met these criteria in the entire data set, and regions on chromosomes 1q25, 3q13, 7p14, and 19p13 met these criteria in one or more of the subsets. Two regions, 3q13 and 1q25, met the criteria for genomewide significance. We have identified a region on chromosome 3q13 that is linked to early-onset CAD, as well as additional regions of interest that will require further analysis. These data provide initial areas of the human genome where further investigation may reveal susceptibility genes for early-onset CAD.
Hauser
Elizabeth R
ER
Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA. Elizabeth.Hauser@duke.edu
Crossman
David C
DC
Granger
Christopher B
CB
Haines
Jonathan L
JL
Jones
Christopher J H
CJ
Mooser
Vincent
V
McAdam
Brendan
B
Winkelmann
Bernhard R
BR
Wiseman
Alan H
AH
Muhlestein
J Brent
JB
Bartel
Alan G
AG
Dennis
Charles A
CA
Dowdy
Elaine
E
Estabrooks
Susan
S
Eggleston
Karen
K
Francis
Sheila
S
Roche
Kath
K
Clevenger
Paula W
PW
Huang
Liling
L
Pedersen
Bonnie
B
Shah
Svati
S
Schmidt
Silke
S
Haynes
Carol
C
West
Sandra
S
Asper
Donny
D
Booze
Michael
M
Sharma
Sanjay
S
Sundseth
Scott
S
Middleton
Lefkos
L
Roses
Allen D
AD
Hauser
Michael A
MA
Vance
Jeffery M
JM
Pericak-Vance
Margaret A
MA
Kraus
William E
WE
D000328:Adult; D017668:Age of Onset; D002874:Chromosome Mapping; D003324:Coronary Artery Disease / Q000235:genetics*; D004247:DNA / Q000378:metabolism; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D016678:Genome; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008957:Models, Genetic; D010641:Phenotype
D005819:Genetic Markers; D004247:DNA