Is lipoprotein(a) (Lp(a)) linked to a specific gene?

Lipoprotein(a) is Linked to the LPA Gene on Chromosome 6

Lipoprotein(a) [Lp(a)] is primarily determined by the LPA gene located on chromosome 6q26-q27, which is among the most polymorphic genes in humans and accounts for up to 90% of the variation in Lp(a) plasma concentrations. 1, 2

Genetic Basis of Lipoprotein(a)

The LPA gene encodes apolipoprotein(a) [apo(a)], which is the distinctive glycoprotein component of Lp(a). This gene has several key characteristics:

• Located on chromosome 6q26-q27 1
• Highly polymorphic with significant size heterogeneity 1
• Contains a variable number of kringle IV type 2 (KIV2) repeats, giving rise to >40 apo(a) isoforms 1
• The number of KIV2 repeats inversely correlates with plasma Lp(a) levels - larger isoforms result in lower Lp(a) levels and vice versa 1

Genetic Contribution to Lp(a) Levels

The genetic control of Lp(a) levels is remarkably strong:

• Up to 90-98% of the variation in Lp(a) concentrations is explained by the LPA gene 2, 3
• Approximately 43% of this variation is specifically attributed to size polymorphisms within the apo(a) gene 3
• Plasma Lp(a) levels can vary over a 1000-fold range between individuals (from <0.1 mg/dL to >300 mg/dL) 2

Secondary Genetic Influences

While the LPA gene is the primary determinant, other genetic factors have minor influences on Lp(a) levels:

• The APOE locus has some influence on Lp(a) concentrations 1
• PCSK9 R46L loss of function mutations affect Lp(a) levels 1
• The promoter region of the apo(a) gene contains a variable number of pentanucleotide repeats (TTTTA) and a +93 C/T polymorphism in the untranslated region 1

Clinical Significance of LPA Genetics

The genetic variants in the LPA gene have significant clinical implications:

• High Lp(a) levels (>30-50 mg/dL) affect 20-30% of the global population 1, 2
• Specific LPA variants (rs10455872 and rs3798220) are strongly associated with increased risk of coronary heart disease 1
• Carriers of genetic variants associated with high Lp(a) concentrations have markedly increased risk for cardiovascular events 4
• The LPA gene locus has been identified as a strong susceptibility locus for coronary artery disease in genome-wide association studies 1

Mendelian Randomization Studies

The strong genetic determination of Lp(a) has made it an ideal candidate for Mendelian randomization studies:

• This approach was first applied to Lp(a) to establish its causal role in cardiovascular disease 4
• These studies have confirmed causal associations between Lp(a) and cardiovascular disease, aortic valve stenosis, and an inverse association with type-2 diabetes 4

The pronounced genetic control of Lp(a) by the LPA gene makes it one of the most important genetically determined risk factors for cardiovascular disease, with implications for targeted therapies currently in development.