Genetic Factors Explain a Major Fraction of the 50% Lower Lipoprotein(a) Concentrations in Finns

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Objective— Lp(a) (lipoprotein(a)) concentrations are widely genetically determined by the LPA isoforms and show 5-fold interpopulation differences. Two- to 3-fold differences have been reported even within Europe. Finns represent a distinctive population isolate within Europe and have been repeatedly reported to present lower Lp(a) concentrations than Central Europeans. The significance of this finding was unclear for a long time because of the difficult comparability of Lp(a) assays. Recently, a large standardized study in >50 000 individuals from 7 European populations confirmed this observation but could not provide insights into the causes. Approach and Results— We investigated Lp(a) concentrations, LPA isoforms, and genotypes of established genetic variants affecting Lp(a) concentrations (LPA variants, APOE isoforms, and PCSK9 R46L) in the Finnish YFS (Cardiovascular Risk in Young Finns Study) population (n=2281) and 3 Non-Finnish Central European populations (n=10 003). We observed ≈50% lower Lp(a) concentrations in Finns. The isoform distribution was shifted toward longer isoforms, and the percentage of low-molecular-weight isoform carriers was reduced. Most interestingly, however, Lp(a) was reduced in each single-isoform group. In contrast to the known inverse relationship between LPA isoforms and Lp(a) concentrations, especially very short isoforms presented unexpectedly low Lp(a) concentrations in Finns. The investigated genetic variants, as well as age, sex, and renal function, explained 71.8% of the observed population differences. Conclusions— The population differences in Lp(a) concentrations between Finnish and Central European populations originate not only from a different LPA isoform distribution but suggest the existence of novel functional variation in the small-isoform range.