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Pia R. Kamstrup, MD, PhD; Anne Tybjærg-Hansen, MD, DMSc; Rolf Steffensen, MD; Børge G. Nordestgaard, MD, DMSc

JAMA. 2009;301(22):2331-2339.

Context  High levels of lipoprotein(a) are associated with increased risk of myocardial infarction (MI).

Objective  To assess whether genetic data are consistent with this association being causal.

Design, Setting, and Participants  Three studies of white individuals from Copenhagen, Denmark, were used: the Copenhagen City Heart Study (CCHS), a prospective general population study with 16 years of follow-up (1991-2007, n = 8637, 599 MI events); the Copenhagen General Population Study (CGPS), a cross-sectional general population study (2003-2006, n = 29 388, 994 MI events); and the Copenhagen Ischemic Heart Disease Study (CIHDS), a case-control study (1991-2004, n = 2461, 1231 MI events).

Main Outcome Measures  Plasma lipoprotein(a) levels, lipoprotein(a) kringle IV type 2 (KIV-2) size polymorphism genotype, and MIs recorded from 1976 through July 2007 for all participants.

Results  In the CCHS, multivariable-adjusted hazard ratios (HRs) for MI for elevated lipoprotein(a) levels were 1.2 (95% confidence interval [CI], 0.9-1.6; events/10 000 person-years, 59) for levels between the 22nd and 66th percentile, 1.6 (95% CI, 1.1-2.2; events/10 000 person-years, 75) for the 67th to 89th percentile, 1.9 (95% CI, 1.2-3.0; events/10 000 person-years, 84) for the 90th to 95th percentile, and 2.6 (95% CI, 1.6-4.1; events/10 000 person-years, 108) for levels greater than the 95th percentile, respectively, vs levels less than the 22nd percentile (events/10 000 person-years, 55) (trend P < .001). Numbers of KIV-2 repeats (sum of repeats on both alleles) ranged from 6 to 99 and on analysis of variance explained 21% and 27% of all variation in plasma lipoprotein(a) levels in the CCHS and CGPS, respectively. Mean lipoprotein(a) levels were 56, 31, 20, and 15 mg/dL for the first, second, third, and fourth quartiles of KIV-2 repeats in the CCHS, respectively (trend P < .001); corresponding values in the CGPS were 60, 34, 22, and 19 mg/dL (trend P < .001). In the CCHS, multivariable-adjusted HRs for MI were 1.5 (95% CI, 1.2-1.9; events/10 000 person-years, 75), 1.3 (95% CI, 1.0-1.6; events/10 000 person-years, 66), and 1.1 (95% CI, 0.9-1.4; events/10 000 person-years, 57) for individuals in the first, second, and third quartiles, respectively, as compared with individuals in the fourth quartile of KIV-2 repeats (events/10 000 person-years, 51) (trend P < .001). Corresponding odds ratios were 1.3 (95% CI, 1.1-1.5), 1.1 (95% CI, 0.9-1.3), and 0.9 (95% CI, 0.8-1.1) in the CGPS (trend P = .005), and 1.4 (95% CI, 1.1-1.7), 1.2 (95% CI, 1.0-1.6), and 1.3 (95% CI, 1.0-1.6) in the CIHDS (trend P = .01). Genetically elevated lipoprotein(a) was associated with an HR of 1.22 (95% CI, 1.09-1.37) per doubling of lipoprotein(a) level on instrumental variable analysis, while the corresponding value for plasma lipoprotein(a) levels on Cox regression was 1.08 (95% CI, 1.03-1.12).

Conclusion  These data are consistent with a causal association between elevated lipoprotein(a) levels and increased risk of MI.

Author Affiliations: Department of Clinical Biochemistry (Drs Kamstrup and Nordestgaard) and Copenhagen General Population Study (Drs Kamstrup, Tybjærg-Hansen, and Nordestgaard), Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark (Dr Tybjærg-Hansen); Copenhagen City Heart Study, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen, Denmark (Drs Tybjærg-Hansen and Nordestgaard); Department of Internal Medicine, Nordsjællands Hospital–Hillerød, Hillerød, Denmark (Dr Steffensen); and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark (Drs Kamstrup, Tybjærg-Hansen, and Nordestgaard).

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