Genetic Markers Enhance Coronary Risk Prediction in Men : The MORGAM Prospective Cohorts
Background: More accurate coronary heart disease (CHD) prediction, specifically in middle-aged men, is needed to reduce the burden of disease more effectively. We hypothesised that a multilocus genetic risk score could refine CHD prediction beyond classic risk scores and obtain more precise risk est...
Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Format: | Others |
Language: | English |
Published: |
Umeå universitet, Medicin
2012
|
Online Access: | http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-61227 |
id |
ndltd-UPSALLA1-oai-DiVA.org-umu-61227 |
---|---|
record_format |
oai_dc |
spelling |
ndltd-UPSALLA1-oai-DiVA.org-umu-612272013-06-25T16:09:48ZGenetic Markers Enhance Coronary Risk Prediction in Men : The MORGAM Prospective CohortsengHughes, Maria F.Saarela, OlliStritzke, JanKee, FrankSilander, KaisaKlopp, NormanKontto, JukkaKarvanen, JuhaWillenborg, ChristinaSalomaa, VeikkoVirtamo, JarmoAmouyel, PhillippeArveiler, DominiqueFerrieres, JeanWiklund, Per-GunnarBaumert, JensThorand, BarbaraDiemert, PatrickTregouet, David-AlexandreHengstenberg, ChristianPeters, AnnetteEvans, AlunKoenig, WolfgangErdmann, JeanetteSamani, Nilesh J.Kuulasmaa, KariSchunkert, HeribertUmeå universitet, MedicinSAN FRANCISCO, USA : PUBLIC LIBRARY SCIENCE2012Background: More accurate coronary heart disease (CHD) prediction, specifically in middle-aged men, is needed to reduce the burden of disease more effectively. We hypothesised that a multilocus genetic risk score could refine CHD prediction beyond classic risk scores and obtain more precise risk estimates using a prospective cohort design. Methods: Using data from nine prospective European cohorts, including 26,221 men, we selected in a case-cohort setting 4,818 healthy men at baseline, and used Cox proportional hazards models to examine associations between CHD and risk scores based on genetic variants representing 13 genomic regions. Over follow-up (range: 5-18 years), 1,736 incident CHD events occurred. Genetic risk scores were validated in men with at least 10 years of follow-up (632 cases, 1361 non-cases). Genetic risk score 1 (GRS1) combined 11 SNPs and two haplotypes, with effect estimates from previous genome-wide association studies. GRS2 combined 11 SNPs plus 4 SNPs from the haplotypes with coefficients estimated from these prospective cohorts using 10-fold cross-validation. Scores were added to a model adjusted for classic risk factors comprising the Framingham risk score and 10-year risks were derived. Results: Both scores improved net reclassification (NRI) over the Framingham score (7.5%, p = 0.017 for GRS1, 6.5%, p = 0.044 for GRS2) but GRS2 also improved discrimination (c-index improvement 1.11%, p = 0.048). Subgroup analysis on men aged 50-59 (436 cases, 603 non-cases) improved net reclassification for GRS1 (13.8%) and GRS2 (12.5%). Net reclassification improvement remained significant for both scores when family history of CHD was added to the baseline model for this male subgroup improving prediction of early onset CHD events. Conclusions: Genetic risk scores add precision to risk estimates for CHD and improve prediction beyond classic risk factors, particularly for middle aged men. Article in journalinfo:eu-repo/semantics/articletexthttp://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-61227doi:10.1371/journal.pone.0040922ISI:000306806600029PLoS ONE, 1932-6203, 2012, 7:7, s. e40922-application/pdfinfo:eu-repo/semantics/openAccess |
collection |
NDLTD |
language |
English |
format |
Others
|
sources |
NDLTD |
description |
Background: More accurate coronary heart disease (CHD) prediction, specifically in middle-aged men, is needed to reduce the burden of disease more effectively. We hypothesised that a multilocus genetic risk score could refine CHD prediction beyond classic risk scores and obtain more precise risk estimates using a prospective cohort design. Methods: Using data from nine prospective European cohorts, including 26,221 men, we selected in a case-cohort setting 4,818 healthy men at baseline, and used Cox proportional hazards models to examine associations between CHD and risk scores based on genetic variants representing 13 genomic regions. Over follow-up (range: 5-18 years), 1,736 incident CHD events occurred. Genetic risk scores were validated in men with at least 10 years of follow-up (632 cases, 1361 non-cases). Genetic risk score 1 (GRS1) combined 11 SNPs and two haplotypes, with effect estimates from previous genome-wide association studies. GRS2 combined 11 SNPs plus 4 SNPs from the haplotypes with coefficients estimated from these prospective cohorts using 10-fold cross-validation. Scores were added to a model adjusted for classic risk factors comprising the Framingham risk score and 10-year risks were derived. Results: Both scores improved net reclassification (NRI) over the Framingham score (7.5%, p = 0.017 for GRS1, 6.5%, p = 0.044 for GRS2) but GRS2 also improved discrimination (c-index improvement 1.11%, p = 0.048). Subgroup analysis on men aged 50-59 (436 cases, 603 non-cases) improved net reclassification for GRS1 (13.8%) and GRS2 (12.5%). Net reclassification improvement remained significant for both scores when family history of CHD was added to the baseline model for this male subgroup improving prediction of early onset CHD events. Conclusions: Genetic risk scores add precision to risk estimates for CHD and improve prediction beyond classic risk factors, particularly for middle aged men. |
author |
Hughes, Maria F. Saarela, Olli Stritzke, Jan Kee, Frank Silander, Kaisa Klopp, Norman Kontto, Jukka Karvanen, Juha Willenborg, Christina Salomaa, Veikko Virtamo, Jarmo Amouyel, Phillippe Arveiler, Dominique Ferrieres, Jean Wiklund, Per-Gunnar Baumert, Jens Thorand, Barbara Diemert, Patrick Tregouet, David-Alexandre Hengstenberg, Christian Peters, Annette Evans, Alun Koenig, Wolfgang Erdmann, Jeanette Samani, Nilesh J. Kuulasmaa, Kari Schunkert, Heribert |
spellingShingle |
Hughes, Maria F. Saarela, Olli Stritzke, Jan Kee, Frank Silander, Kaisa Klopp, Norman Kontto, Jukka Karvanen, Juha Willenborg, Christina Salomaa, Veikko Virtamo, Jarmo Amouyel, Phillippe Arveiler, Dominique Ferrieres, Jean Wiklund, Per-Gunnar Baumert, Jens Thorand, Barbara Diemert, Patrick Tregouet, David-Alexandre Hengstenberg, Christian Peters, Annette Evans, Alun Koenig, Wolfgang Erdmann, Jeanette Samani, Nilesh J. Kuulasmaa, Kari Schunkert, Heribert Genetic Markers Enhance Coronary Risk Prediction in Men : The MORGAM Prospective Cohorts |
author_facet |
Hughes, Maria F. Saarela, Olli Stritzke, Jan Kee, Frank Silander, Kaisa Klopp, Norman Kontto, Jukka Karvanen, Juha Willenborg, Christina Salomaa, Veikko Virtamo, Jarmo Amouyel, Phillippe Arveiler, Dominique Ferrieres, Jean Wiklund, Per-Gunnar Baumert, Jens Thorand, Barbara Diemert, Patrick Tregouet, David-Alexandre Hengstenberg, Christian Peters, Annette Evans, Alun Koenig, Wolfgang Erdmann, Jeanette Samani, Nilesh J. Kuulasmaa, Kari Schunkert, Heribert |
author_sort |
Hughes, Maria F. |
title |
Genetic Markers Enhance Coronary Risk Prediction in Men : The MORGAM Prospective Cohorts |
title_short |
Genetic Markers Enhance Coronary Risk Prediction in Men : The MORGAM Prospective Cohorts |
title_full |
Genetic Markers Enhance Coronary Risk Prediction in Men : The MORGAM Prospective Cohorts |
title_fullStr |
Genetic Markers Enhance Coronary Risk Prediction in Men : The MORGAM Prospective Cohorts |
title_full_unstemmed |
Genetic Markers Enhance Coronary Risk Prediction in Men : The MORGAM Prospective Cohorts |
title_sort |
genetic markers enhance coronary risk prediction in men : the morgam prospective cohorts |
publisher |
Umeå universitet, Medicin |
publishDate |
2012 |
url |
http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-61227 |
work_keys_str_mv |
AT hughesmariaf geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT saarelaolli geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT stritzkejan geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT keefrank geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT silanderkaisa geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT kloppnorman geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT konttojukka geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT karvanenjuha geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT willenborgchristina geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT salomaaveikko geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT virtamojarmo geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT amouyelphillippe geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT arveilerdominique geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT ferrieresjean geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT wiklundpergunnar geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT baumertjens geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT thorandbarbara geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT diemertpatrick geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT tregouetdavidalexandre geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT hengstenbergchristian geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT petersannette geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT evansalun geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT koenigwolfgang geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT erdmannjeanette geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT samaninileshj geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT kuulasmaakari geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts AT schunkertheribert geneticmarkersenhancecoronaryriskpredictioninmenthemorgamprospectivecohorts |
_version_ |
1716589912088641536 |