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Apolipoprotein(a) kringle IV repeat number predicts risk for coronary heart disease
H G Kraft1, A Lingenhel, S Köchl
1Institute for Medical Biology and Human Genetics, University of Innsbruck, Austria.
Insights
High lipoprotein(a) [Lp(a)] levels are linked to coronary heart disease (CHD). Genetic variations in the apo(a) gene, specifically kringle IV repeat numbers, directly influence Lp(a) levels and CHD risk.
Area of Science:
- Cardiovascular Genetics
- Molecular Biology
- Epidemiology
Background:
- Elevated lipoprotein(a) [Lp(a)] is a suspected risk factor for coronary heart disease (CHD), though recent studies have debated its significance.
- Plasma Lp(a) levels are largely determined by the apo(a) gene locus, characterized by variable numbers of kringle IV type 2 repeats, with an inverse correlation between repeat number and Lp(a) concentration.
Purpose of the Study:
- To investigate the association between apo(a) gene variation, specifically kringle IV repeat number, and the risk of coronary heart disease (CHD).
Main Methods:
- Apo(a) genotypes were determined using pulsed-field gel electrophoresis/genomic blotting in 69 CHD patients and 69 matched controls.
- Genotypes were correlated with plasma Lp(a) concentration, apo(a) isoform, and CHD status.
Main Results:
- Apo(a) alleles with fewer than 22 kringle IV repeats, associated with high Lp(a), were significantly more prevalent in the CHD group (P < .001).
- Conversely, larger, non-expressed alleles were more common in control subjects.
- The odds ratio for CHD increased with decreasing kringle IV repeat number, ranging from 0.3 ( > 25 repeats) to 4.6 ( < 20 repeats).
Conclusions:
- This study provides direct genetic evidence linking variation in the apo(a) gene locus to coronary heart disease (CHD) risk.
- The number of kringle IV repeats in the apo(a) gene is a significant determinant of both Lp(a) levels and an individual's susceptibility to CHD.
Abstract:
A high plasma concentration of lipoprotein(a) [Lp(a)] has been suggested as a risk factor for coronary heart disease (CHD), but some recent prospective studies have questioned the significance of Lp(a). Lp(a) concentrations are determined to a large extent by the hypervariable apo(a) gene locus on chromosome 6q2.7, which contains a variable number of identical tandemly arranged transcribed kringle IV type 2 repeats. The number of these repeats correlates inversely with plasma Lp(a) concentration. We analyzed whether apo(a) gene variation (kringle IV repeat number) is associated with CHD. Apo(a) genotypes were determined by pulsed-field gel electrophoresis/genomic blotting in CHD patients who had undergone angiography (n = 69) and control subjects matched for age, sex, and ethnicity (n = 69) and were related to Lp(a) concentration, apo(a) isoform in plasma, and disease status. Apo(a) alleles with a low kringle IV copy number ( < 22) and high Lp(a) concentration were significantly more frequent in the CHD group (P < .001), whereas large nonexpressed alleles were more frequent in control subjects. The odds ratio for CHD increased continuously with a decreasing number of kringle IV repeats and ranged from 0.3 in individuals with > 25 kringle IV repeats on both alleles to 4.6 in those with < 20 repeats on at least one allele. This provides direct genetic evidence that variation at the apo(a) gene locus, which determines Lp(a) levels, is also a determinant of CHD risk.