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Apolipoprotein A kringle 4 polymorphism and serum lipoprotein (a) concentrations in African blacks
1Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, PA 15261, USA.
Insights
Elevated lipoprotein (a) [Lp(a)] is a risk factor for cardiovascular disease. This study in Nigerians found an inverse relationship between APOA kringle 4 repeat size and Lp(a) levels, explaining 15% of variation.
Area of Science:
- Cardiovascular Genetics
- Epidemiology
- Biochemistry
Background:
- Elevated serum lipoprotein (a) [Lp(a)] is an independent risk factor for cardiovascular diseases, stroke, and restenosis.
- Serum Lp(a) levels exhibit significant genetic control and are notably higher in populations of African ancestry compared to European ancestry.
- The APOA gene's hypervariable length polymorphism, due to variable kringle 4 repeats, is inversely related to serum Lp(a) levels, though data in African populations are limited.
Purpose of the Study:
- To investigate the relationship between serum Lp(a) levels and APOA Kringle 4 size polymorphisms in an African population.
- To determine the extent to which APOA size polymorphism explains Lp(a) level variation in Nigerians.
Main Methods:
- Serum Lp(a) levels and APOA Kringle 4 size polymorphisms were analyzed in 781 unrelated Nigerians.
- SDS-agarose gel electrophoresis was used to detect APOA isoforms.
- Statistical analyses, including Spearman's correlation and random effects analysis of variance, were employed.
Main Results:
- Mean and median serum Lp(a) levels were 25.6 ± 0.6 mg/dl and 20.9 mg/dl, respectively.
- A significant inverse correlation was observed between APOA isoform size and Lp(a) levels (r = 0.46, p < 0.0001).
- APOA size polymorphism accounted for approximately 15% of the phenotypic variation in Lp(a) levels.
Conclusions:
- A significant inverse relationship exists between APOA kringle 4 size polymorphism and serum Lp(a) levels in Nigerians.
- While APOA size polymorphism is a contributing factor, other genetic variations likely explain the higher Lp(a) levels observed in African populations.
Abstract:
Several epidemiological studies have established that elevated serum lipoprotein (a) [Lp(a)] levels are independent risk factors for coronary heart disease, stroke, and restenosis of coronary lesions in white and Asian populations. Serum Lp(a) levels vary over a 1000-fold range among individuals and are under strict genetic control. Serum Lp(a) levels are significantly higher in populations with African ancestry than in populations of European ancestry. The APOA gene exhibits hypervariable length polymorphism resulting from a variable number of expressed kringle 4 repeats. An inverse relationship exists between the size of kringle 4 repeats and serum Lp(a) levels. However, most studies have been conducted in whites, and the data are scanty in African populations. To explore this relationship among Africans, we determined serum Lp(a) levels and APOA Kringle 4 size polymorphisms in 781 unrelated Africans (490 men, 291 women) from Benin City, Nigeria. Mean and median serum Lp(a) values were 25.6 +/- 0.6 mg/dl and 20.9 mg/dl, respectively. Although there was no difference in mean Lp(a) values between men and women, median Lp(a) values were higher in women than in men (p = 0.02). Using SDS-agarose gel electrophoresis, we detected 38 APOA isoforms, the highest number recorded to data. There were 10 consecutive medium-size alleles whose frequencies ranged between 4.2% and 10.9%, and together they accounted for 72.8% of the alleles observed in this population. Spearman's correlation coefficients showed an inverse relationship between the size of the APOA isoform and Lp(a) levels using either single-banded (r = 0.46; p < 0.0001) or double-banded (r = 0.42; p < 0.0001) phenotypes. Using random effects analysis of variance on the entire sample, the APOA size polymorphism explained about 15% of the phenotypic variation in Lp(a) levels. These data suggest that despite significant correlation between the APOA kringle 4 size polymorphism and Lp(a) levels, other sequence variations either in the APOA gene or closely linked genes may account for relatively higher Lp(a) levels found in Africans.