A genomewide linkage study of 1,933 families affected by premature coronary artery disease: The British Heart Foundation (BHF) Family Heart Study

BHF Family Heart Study Research Group

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1011-20
Number of pages10
JournalAmerican Journal of Human Genetics
Volume77
Issue number6
DOIs
Publication statusPublished - Dec 2005
Externally publishedYes

Fingerprint

Coronary Artery Disease
Chromosomes, Human, Pair 2
Myocardial Infarction
Siblings
Genome
Western World
Premature Mortality
Age of Onset
Microsatellite Repeats
Cause of Death

Keywords

  • Age of Onset
  • Chromosome Mapping
  • Chromosomes, Human, Pair 2
  • Coronary Artery Disease
  • Coronary Vessels
  • Diseases in Twins
  • Family Health
  • Genetic Linkage
  • Genetic Markers
  • Genome, Human
  • Humans
  • Lod Score
  • Microsatellite Repeats
  • Myocardial Infarction
  • Reproducibility of Results
  • Risk
  • Siblings
  • Twins, Monozygotic
  • United Kingdom
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

A genomewide linkage study of 1,933 families affected by premature coronary artery disease : The British Heart Foundation (BHF) Family Heart Study. / BHF Family Heart Study Research Group.

In: American Journal of Human Genetics, Vol. 77, No. 6, 12.2005, p. 1011-20.

Research output: Contribution to journalArticle

@article{f06aa69c71da46d38dfd627371a0ca91,
title = "A genomewide linkage study of 1,933 families affected by premature coronary artery disease: The British Heart Foundation (BHF) Family Heart Study",
abstract = "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.",
keywords = "Age of Onset, Chromosome Mapping, Chromosomes, Human, Pair 2, Coronary Artery Disease, Coronary Vessels, Diseases in Twins, Family Health, Genetic Linkage, Genetic Markers, Genome, Human, Humans, Lod Score, Microsatellite Repeats, Myocardial Infarction, Reproducibility of Results, Risk, Siblings, Twins, Monozygotic, United Kingdom, Journal Article, Research Support, Non-U.S. Gov't",
author = "{BHF Family Heart Study Research Group} and Samani, {Nilesh J} and Paul Burton and Massimo Mangino and Ball, {Stephen G} and Balmforth, {Anthony J} and Jenny Barrett and Timothy Bishop and Alistair Hall and Julian Stribling and {de Souza}, Pat and Ravi Singh and Jenny Ogleby and Cathy Ridge and Elaine Logtens and Laura Hopwood and Julie Faulkes and Christine Morrell and Lynne Barthorpe and Natalie Burtonwood and Micha Dorsch and Nigel Durham and Claire Forest and Natasha Kelly and Vera Hall and Richard Lawrance and Julia Oldham and Elizabeth Rennie and Adrian Smith and Samantha Thompson and Sue Adams and Jenny-Rebecca Clemitson and Claire Bodycote and Andrea Koekemoer and Stuart Raleigh and Azhar Maqbool and Nadira Yuldasheva and Stacey Ellis and Samantha Mason and Lynne Midgley and Natalie Pleasants and Richard Cuthbert and Tooze, {Peter F.} and Mark Platts and Joanne Fox and Rick Dixon and Nuala Sheehan and Katrina Scurrah and Sarah Pickett and Kevin Walters and Jeremie Nsengimana",
year = "2005",
month = "12",
doi = "10.1086/498653",
language = "English",
volume = "77",
pages = "1011--20",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Elsevier",
number = "6",

}

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

VL - 77

SP - 1011

EP - 1020

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 6

ER -