TY - JOUR
T1 - A genomewide linkage study of 1,933 families affected by premature coronary artery disease
T2 - The British Heart Foundation (BHF) Family Heart Study
AU - BHF Family Heart Study Research Group
AU - Samani, Nilesh J
AU - Burton, Paul
AU - Mangino, Massimo
AU - Ball, Stephen G
AU - Balmforth, Anthony J
AU - Barrett, Jenny
AU - Bishop, Timothy
AU - Hall, Alistair
AU - Stribling, Julian
AU - de Souza, Pat
AU - Singh, Ravi
AU - Ogleby, Jenny
AU - Ridge, Cathy
AU - Logtens, Elaine
AU - Hopwood, Laura
AU - Faulkes, Julie
AU - Morrell, Christine
AU - Barthorpe, Lynne
AU - Burtonwood, Natalie
AU - Dorsch, Micha
AU - Durham, Nigel
AU - Forest, Claire
AU - Kelly, Natasha
AU - Hall, Vera
AU - Lawrance, Richard
AU - Oldham, Julia
AU - Rennie, Elizabeth
AU - Smith, Adrian
AU - Thompson, Samantha
AU - Adams , Sue
AU - Clemitson, Jenny-Rebecca
AU - Bodycote, Claire
AU - Koekemoer, Andrea
AU - Raleigh, Stuart
AU - Maqbool , Azhar
AU - Yuldasheva, Nadira
AU - Ellis, Stacey
AU - Mason, Samantha
AU - Midgley, Lynne
AU - Pleasants, Natalie
AU - Cuthbert, Richard
AU - Tooze , Peter F.
AU - Platts, Mark
AU - Fox, Joanne
AU - Dixon, Rick
AU - Sheehan, Nuala
AU - Scurrah, Katrina
AU - Pickett, Sarah
AU - Walters, Kevin
AU - Nsengimana, Jeremie
PY - 2005/12
Y1 - 2005/12
N2 - Coronary artery disease (CAD) and its most important complication, myocardial infarction (MI), are the leading cause of premature death in the Western world. CAD has a substantial genetic basis, especially when it occurs early. We investigated the genetic determinants of premature CAD by performing a genomewide linkage analysis of 4,175 affected subjects from 1,933 families recruited throughout the United Kingdom. Each family had at least two available siblings with CAD, with validated onset before age 66 years. Linkage analysis was performed using 416 microsatellite markers. We observed suggestive linkage, for both CAD and MI, to a region on chromosome 2. For CAD, a LOD score of 1.86 was observed at marker D2S2271, which, in an ordered subset analysis, increased to 2.70 in families (n=1,698) with a minimum age at diagnosis of 56 years or younger. For MI, an overlapping peak with a LOD score of 1.15 was observed at marker D2S2216, which increased to 2.1 in families (n=801) with a minimum age at diagnosis of 59 years or younger. Exclusion mapping showed that 100% of the autosomal genome could be excluded for locus-specific sibling relative risks of 1.5 and 1.6 for CAD and MI, respectively. The region identified on chromosome 2 overlaps linked regions observed in two other smaller genome scans for CAD. Together, these findings strongly suggest that there is a locus on chromosome 2 that influences coronary atherosclerosis risk. The exclusion of a common locus that increases risk of CAD to siblings by >50% has important implications for strategies for further defining the genetic basis of CAD.
AB - Coronary artery disease (CAD) and its most important complication, myocardial infarction (MI), are the leading cause of premature death in the Western world. CAD has a substantial genetic basis, especially when it occurs early. We investigated the genetic determinants of premature CAD by performing a genomewide linkage analysis of 4,175 affected subjects from 1,933 families recruited throughout the United Kingdom. Each family had at least two available siblings with CAD, with validated onset before age 66 years. Linkage analysis was performed using 416 microsatellite markers. We observed suggestive linkage, for both CAD and MI, to a region on chromosome 2. For CAD, a LOD score of 1.86 was observed at marker D2S2271, which, in an ordered subset analysis, increased to 2.70 in families (n=1,698) with a minimum age at diagnosis of 56 years or younger. For MI, an overlapping peak with a LOD score of 1.15 was observed at marker D2S2216, which increased to 2.1 in families (n=801) with a minimum age at diagnosis of 59 years or younger. Exclusion mapping showed that 100% of the autosomal genome could be excluded for locus-specific sibling relative risks of 1.5 and 1.6 for CAD and MI, respectively. The region identified on chromosome 2 overlaps linked regions observed in two other smaller genome scans for CAD. Together, these findings strongly suggest that there is a locus on chromosome 2 that influences coronary atherosclerosis risk. The exclusion of a common locus that increases risk of CAD to siblings by >50% has important implications for strategies for further defining the genetic basis of CAD.
KW - Age of Onset
KW - Chromosome Mapping
KW - Chromosomes, Human, Pair 2
KW - Coronary Artery Disease
KW - Coronary Vessels
KW - Diseases in Twins
KW - Family Health
KW - Genetic Linkage
KW - Genetic Markers
KW - Genome, Human
KW - Humans
KW - Lod Score
KW - Microsatellite Repeats
KW - Myocardial Infarction
KW - Reproducibility of Results
KW - Risk
KW - Siblings
KW - Twins, Monozygotic
KW - United Kingdom
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1086/498653
DO - 10.1086/498653
M3 - Article
C2 - 16380912
SN - 0002-9297
VL - 77
SP - 1011
EP - 1020
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -