title: Clinical Utility of a Coronary Heart Disease Risk Prediction Gene Score in UK Healthy Middle Aged Men and in the Pakistani Population.
abstract: BACKGROUND
  Numerous risk prediction algorithms based on conventional risk factors for Coronary Heart Disease (CHD) are available but provide only modest discrimination. The inclusion of genetic information may improve clinical utility.
  
  
  METHODS
  We tested the use of two gene scores (GS) in the prospective second Northwick Park Heart Study (NPHSII) of 2775 healthy UK men (284 cases), and Pakistani case-control studies from Islamabad/Rawalpindi (321 cases/228 controls) and Lahore (414 cases/219 controls). The 19-SNP GS included SNPs in loci identified by GWAS and candidate gene studies, while the 13-SNP GS only included SNPs in loci identified by the CARDIoGRAMplusC4D consortium.
  
  
  RESULTS
  In NPHSII, the mean of both gene scores was higher in those who went on to develop CHD over 13.5 years of follow-up (19-SNP p=0.01, 13-SNP p=7x10-3). In combination with the Framingham algorithm the GSs appeared to show improvement in discrimination (increase in area under the ROC curve, 19-SNP p=0.48, 13-SNP p=0.82) and risk classification (net reclassification improvement (NRI), 19-SNP p=0.28, 13-SNP p=0.42) compared to the Framingham algorithm alone, but these were not statistically significant. When considering only individuals who moved up a risk category with inclusion of the GS, the improvement in risk classification was statistically significant (19-SNP p=0.01, 13-SNP p=0.04). In the Pakistani samples, risk allele frequencies were significantly lower compared to NPHSII for 13/19 SNPs. In the Islamabad study, the mean gene score was higher in cases than controls only for the 13-SNP GS (2.24 v 2.34, p=0.04). There was no association with CHD and either score in the Lahore study.
  
  
  CONCLUSIONS
  The performance of both GSs showed potential clinical utility in European men but much less utility in subjects from Pakistan, suggesting that a different set of risk loci or SNPs may be required for risk prediction in the South Asian population.
authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Science, University College London, University Street, London, United Kingdom.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Beaney
authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Science, University College London, University Street, London, United Kingdom.
authors.forename: Jackie A
authors.initials: JA
authors.lastname: Cooper
authors.affiliation: Department of Microbiology and Molecular Genetics, New Campus, University of the Punjab, Lahore, Pakistan.
authors.forename: Saleem
authors.initials: S
authors.lastname: Ullah Shahid
authors.affiliation: Department of Microbiology, University of Haripur, Haripur, Pakistan.
authors.forename: Waqas
authors.initials: W
authors.lastname: Ahmed
authors.affiliation: COMSATS Institute of Information Technology, Park Road, Chak Shahzad, Islamabad, Pakistan.
authors.forename: Raheel
authors.initials: R
authors.lastname: Qamar
authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Science, University College London, University Street, London, United Kingdom; Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Fotios
authors.initials: F
authors.lastname: Drenos
authors.affiliation: Molecular Diagnostics Group, Randox Laboratories Ltd, Crumlin, United Kingdom.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Crockard
authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Science, University College London, University Street, London, United Kingdom.
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
mesh_terms: D044466:Asian People; D016022:Case-Control Studies; D003327:Coronary Disease / Q000175:diagnosis / Q000208:ethnology* / Q000235:genetics* / Q000473:pathology; D021901:DNA, Intergenic / Q000235:genetics; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D010154:Pakistan; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011446:Prospective Studies; D012372:ROC Curve; D012307:Risk Factors; D006113:United Kingdom; D044465:White People
chemical_list: D021901:DNA, Intergenic