Lipoprotein (a), or Lp(a), is a specific type of cholesterol-carrying particle found in the blood. It is an independent risk factor for atherosclerotic cardiovascular diseases, including heart attacks and strokes. Unlike other cholesterol markers that can fluctuate with lifestyle choices, an individual’s Lp(a) levels are primarily determined by their genetic makeup. Understanding this genetic influence provides insight into inherited predispositions for cardiovascular concerns.
The Central Role of the LPA Gene
The LPA gene controls a person’s Lp(a) level. This gene provides the instructions for producing a protein called apolipoprotein(a), or apo(a). Apolipoprotein(a) then attaches to a low-density lipoprotein (LDL)-like particle, forming the complete Lp(a) particle. This unique structure distinguishes Lp(a) from standard LDL cholesterol.
The primary genetic factor influencing Lp(a) concentration is the size of the apolipoprotein(a) protein. This size is dictated by a variable number of repeating sections within the LPA gene, known as Kringle IV type 2 (KIV-2) repeats. The number of these KIV-2 repeats can vary widely among individuals, ranging from 2 to more than 40 copies per allele.
Fewer KIV-2 repeats result in a smaller apolipoprotein(a) protein, which is more efficiently produced, leading to higher concentrations of Lp(a) in the bloodstream. Conversely, a greater number of KIV-2 repeats leads to a larger, less efficiently produced protein and lower Lp(a) levels. This inverse relationship between KIV-2 repeat number and Lp(a) concentration accounts for an estimated 19% to 69% of the variation in Lp(a) levels among individuals.
Inheritance Patterns of High Lipoprotein (a)
The genetic trait for high Lp(a) is passed down through families following an autosomal codominant inheritance pattern. “Autosomal” signifies the gene is on a non-sex chromosome, meaning both males and females can inherit and pass on the trait equally. “Codominant” indicates an individual inherits one copy of the LPA gene from each parent, and both inherited copies contribute to the final Lp(a) level.
Due to this inheritance pattern, if one parent carries a gene variant associated with high Lp(a), each child has approximately a 50% chance of inheriting that variant. Elevated Lp(a) levels and early onset cardiovascular disease often run in families. Lp(a) levels are largely established early in life, typically fully expressed by the first or second year of life in children and reaching adult concentrations by around age five years.
Testing for Genetically High Lipoprotein (a)
Determining an individual’s Lp(a) status involves a blood test that measures the concentration of Lp(a) particles in the blood. This measurement provides a direct reflection of the underlying genetic influences on a person’s Lp(a) levels. Results are often reported in nanomoles per liter (nmol/L) or milligrams per deciliter (mg/dL), with normal values generally considered below 30 mg/dL or 75 nmol/L.
While direct genetic testing of the LPA gene is possible, it is primarily used in research settings to study specific gene variants. For routine clinical purposes, measuring blood Lp(a) concentration remains the standard method for assessing an individual’s risk. Healthcare providers may recommend Lp(a) testing for individuals with a personal history of premature cardiovascular disease, such as a heart attack or stroke before age 55 in men or 65 in women, or for those with a strong family history of such events not fully explained by other common risk factors.
The Limited Impact of Lifestyle on Lp(a) Levels
Lp(a) levels are strongly determined by genetics, with approximately 70% to 90% of an individual’s Lp(a) levels attributed to genetic factors. This differs considerably from other lipid markers, such as LDL cholesterol, which can be significantly influenced by lifestyle interventions. Diet, regular physical activity, and weight management, while effective at lowering LDL cholesterol, have minimal to no substantial impact on Lp(a) concentrations.
Some studies have explored mild associations, though Lp(a) levels are largely resistant to lifestyle changes. For instance, weight loss, intense physical exercise, and red wine consumption have shown some association with slightly lower plasma Lp(a) levels. Conversely, diets rich in trans-unsaturated fatty acids have been linked to increased Lp(a) levels. These observed effects are modest and do not dramatically alter the overall Lp(a) concentration, reinforcing that genetic predisposition remains the dominant factor.
Ethnic and Population Differences in Lp(a) Genetics
The prevalence of LPA gene variants leading to elevated Lp(a) levels varies significantly across different ethnic and geographic populations worldwide. This genetic diversity contributes to observable differences in average Lp(a) concentrations among various groups. For example, individuals of African descent, on average, tend to have significantly higher Lp(a) levels compared to those of European or East Asian descent.
This disparity is largely attributed to the higher frequency of LPA gene variants with fewer KIV-2 repeats in populations of African ancestry. These smaller apo(a) isoforms are associated with increased Lp(a) concentrations. This highlights that what might be considered a “normal” Lp(a) range can differ based on an individual’s ethnic background, underscoring the deep-seated genetic roots of this cardiovascular risk factor.