Polymorphism of Apolipoprotein(a): Lp(a) Concentration and Isoform Sizes in a Healthy Population

This foundational 1987 study characterized the polymorphism of apolipoprotein(a) — the distinctive protein that defines Lp(a) lipoprotein — in a healthy population, examining the relationship between apo(a) isoform size (assessed by SDS-agarose gel electrophoresis) and circulating Lp(a) concentration.

Apo(a) exists in multiple isoform sizes, varying by the number of kringle IV type 2 (KIV-2) repeating domains in the protein’s structure. Utermann et al. demonstrated that isoform size and plasma Lp(a) concentration are strongly inversely correlated: individuals with smaller apo(a) isoforms (fewer KIV-2 repeats) have higher plasma Lp(a) concentrations. Isoform inheritance was codominant, and plasma Lp(a) concentration was largely determined by isoform size at the LPA locus.

This inverse relationship between apo(a) isoform size and Lp(a) concentration is now understood as the genetic basis for Lp(a)‘s highly heritable, largely genetically determined plasma concentrations — approximately 80–90% of Lp(a) variation is genetic rather than environmental. Individuals who inherit two small-isoform alleles have the highest Lp(a) concentrations and the highest cardiovascular risk.

This early characterization explains why Lp(a) measurement does not meaningfully change with diet, exercise, or lifestyle modification — it is primarily genetically fixed. This biological reality has direct clinical implications: Lp(a) is best measured once as a lifetime genetic risk factor, not repeatedly as a modifiable lifestyle marker.

We rate the evidence moderate for its era. A foundational study establishing the genetic basis for Lp(a) concentration variation through apo(a) isoform size polymorphism — historically decisive for understanding Lp(a) as primarily a genetically determined cardiovascular risk factor.