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Subsets of SNPs define rare genotype classes that predict ischemic heart disease

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Abstract

Single nucleotide polymorphisms (SNPs) are hypothesized to explain the genetic predisposition to ischemic heart disease (IHD) in the general population. Lack of evidence for a role of such variation is fostering pessimism about the utility of genetic information in the practice of medicine. In this study we determined the utility of exonic and 5′ SNPs in apolipoprotein E (APOE) and lipoprotein lipase (LPL) when considered singly and in combination for predicting incidence of IHD in 8,456 individuals from the general population during 24 years of follow-up. In men, LPL D9N improved prediction of IHD (P = 0.03) beyond smoking, diabetes and hypertension. The group of men heterozygous and homozygous for the rare D9N variant had a hazard ratio (HR) of 1.69 (95% confidence interval = 1.10–2.58) relative to the most common genotype. Pairwise combinations of D9N with −219G > T in APOE and N291S and S447X in LPL significantly improved the prediction of IHD (P = 0.05 in women, P = 0.04 in men, P = 0.03 in men, respectively) beyond smoking, diabetes and hypertension, and identified subgroups of individuals (n = 6–94) with highly significant HRs of 1.92–4.35. These results were validated in a case-control study (n = 8,806). In conclusion, we present evidence that combinations of SNPs in APOE and LPL identify subgroups of individuals at substantially increased risk of IHD beyond that associated with smoking, diabetes and hypertension.

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Acknowledgments

We thank Kenneth G. Weiss for his persistent attention to the data analyses. Mette Refstrup, Pia T. Petersen and Hanne Dam are greatly thanked for their excellent technical assistance. This study was supported by Chief Physician Johan Boserup and Lise Boserup’s Fund, The Danish Heart Foundation, The Danish Medical Research Council, Ingeborg and Leo Dannin’s Grant, The Research Fund at Rigshospitalet, Copenhagen University Hospital, National Institute of Health HL039107 and National Institute of General Medical Science grant GM065509.

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Authors and Affiliations

  1. Department of Clinical Biochemistry KB3011, Section for Molecular Genetics , Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen Ø, Denmark

    Ruth Frikke-Schmidt & Anne Tybjærg-Hansen

  2. Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA

    Charles F. Sing

  3. Department of Clinical Biochemistry, Herlev University Hospital, Herlev, Denmark

    Børge G. Nordestgaard

  4. The Copenhagen City Heart Study, Bispebjerg University Hospital, Copenhagen, Denmark

    Børge G. Nordestgaard & Anne Tybjærg-Hansen

  5. Department of Cardiology, Hillerød Hospital, Hillerød, Denmark

    Rolf Steffensen

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  1. Ruth Frikke-Schmidt
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  2. Charles F. Sing
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  3. Børge G. Nordestgaard
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  4. Rolf Steffensen
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  5. Anne Tybjærg-Hansen
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Correspondence to Anne Tybjærg-Hansen.

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Frikke-Schmidt, R., Sing, C.F., Nordestgaard, B.G. et al. Subsets of SNPs define rare genotype classes that predict ischemic heart disease. Hum Genet 120, 865–877 (2007). https://doi.org/10.1007/s00439-006-0233-y

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