European Heart Journal Advance Access originally published online on May 12, 2009
European Heart Journal 2009 30(14):1711-1719; doi:10.1093/eurheartj/ehp161
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Common lipid-altering gene variants are associated with therapeutic intervention thresholds of lipid levels in older people
1 Peninsula Medical School, RD&E Wonford Site, Barrack Road, Exeter EX2 5DW, UK
2 Laboratory of Clinical Epidemiology, Geriatrics Department, Italian National Research Council on Aging, Florence, Italy
3 Tuscany Regional Health Agency, I.O.T, Firenze, Italy
4 Department of Medical and Surgical Critical Care, University of Florence, Florence, Italy
5 Longitudinal Studies Section, Clinical Research Branch, Gerontology Research Center, National Institute on Aging, Baltimore, MD, USA
6 Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, Bethesda, MD, USA
7 Laboratory of Neurogenetics, National Institute of Ageing, Porter Neuroscience, Research Center Building 10, Room 1A-1000, 35 Convent Drive, MSC 3707, Bethesda, MD 20892-3707, USA
Received 13 August 2008; revised 1 March 2009; accepted 23 March 2009; online publish-ahead-of-print 12 May 2009.
* Corresponding author. Email: david.melzer{at}pms.ac.uk
Aims: There are a large number of common genetic variants that have been robustly associated with low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglyceride concentrations. The majority of these have been identified or confirmed in recent genome-wide association studies, but few studies have assessed the combined effect of known lipid variants. We hypothesized that these variants would influence both the need for interventions and myocardial infarction (MI) outcomes. We aimed to estimate combined effects of proven SNPs on LDL, HDL, and triglyceride concentrations and MI history in a representative older population.
Methods and results: In the InCHIANTI Study of Aging (age 
65 years), we calculated individual dyslipidaemia risk allele counts for increased LDL (range 4–14, n = 594), reduced HDL (5–16, n = 635), and increased triglycerides (7–16, n = 611). Lipid levels were compared with ATPIII National Cholesterol Education Panel (NCEP) intervention guidelines. Individual variants and the APOE haplotype explained <2.1% of the variance in their respective lipid concentrations, with the exception of the CETP SNP rs1800775 and HDL levels (4.76%). Combined risk allele counts outperformed the largest single-SNP effects for LDL (explaining 7.1% of variance) and triglycerides (4.8%), but not HDL (3.4%). Risk alleles were divided as near as possible into quartiles. The 31% of respondents with 10 or more LDL increasing alleles were more likely to have LDL levels above the intervention threshold (OR 3.00, 95% CI 1.67–5.39, P = 2.5 x 10–4), compared with the 21% with 7 or less risk alleles. Similarly, the 35% with 13 or more triglyceride risk alleles were more likely to exceed NCEP intervention thresholds (OR 2.98, 95% CI 1.43–6.22, P = 0.004) compared with the 24% with 10 or less alleles. The number of individuals reporting an MI event was small (n = 67), but an event was more common in the 36% of respondents who had the highest combined risk allele score for all three lipids (OR 3.68, 95% CI 1.21–11.2, P = 0.021) compared with the lowest risk 22%.
Conclusion: In a representative older population, the cumulative effects of proven LDL- and triglyceride-altering genetic variants increased the odds of crossing the lipid-level threshold for therapeutic intervention by approximately three-fold.
Key Words: Lipid • SNP • Genome-wide association • HDL • LDL • Triglyceride • Myocardial infarction
These authors contributed equally to this work.