High Levels of Lp(a) With a Small Apo(a) Isoform Are Associated With Coronary Artery Disease in African American and White Men

Abstract

Abstract-Elevated levels of lipoprotein(a) [Lp(a)] and the presence of small isoforms of apolipoprotein(a) [apo(a)] have been associated with coronary artery disease (CAD) in whites but not in African Americans. Because of marked race/ethnicity differences in the distribution of Lp(a) levels across apo(a) sizes, we tested the hypothesis that apo(a) isoform size determines the association between Lp(a) and CAD. We related Lp(a) levels, apo(a) isoforms, and the levels of Lp(a) associated with different apo(a) isoforms to the presence of CAD (Ն50% stenosis) in 576 white and African American men and women. Only in white men were Lp(a) levels significantly higher among patients with CAD than in those without CAD (28.4 versus 16.5 mg/dL, respectively; Pϭ0.004), and only in this group was the presence of small apo(a) isoforms (Ͻ22 kringle 4 repeats) associated with CAD (Pϭ0.043). Elevated Lp(a) levels (Ն30 mg/dL) were found in 26% of whites and 68% of African Americans, and of those, 80% of whites but only 26% of African Americans had a small apo(a) isoform. Elevated Lp(a) levels with small apo(a) isoforms were significantly associated with CAD (PϽ0.01) in African American and white men but not in women. This association remained significant after adjusting for age, diabetes mellitus, smoking, hypertension, HDL cholesterol, LDL cholesterol, and triglycerides. We conclude that elevated levels of Lp(a) with small apo(a) isoforms independently predict risk for CAD in African American and white men. Our study, by determining the predictive power of Lp(a) levels combined with apo(a) isoform size, provides an explanation for the apparent lack of association of either measure alone with CAD in African Americans. Furthermore, our results suggest that small apo(a) size confers atherogenicity to Lp(a) for cardiovascular disease. [1][2][3] In numerous, but not all, prospective studies, mainly in white populations, elevations of plasma Lp(a) levels, usually defined as Ն30 mg/dL, were significantly correlated with coronary artery disease (CAD). 4 -13 Curiously, although mean Lp(a) levels are twice as high in African Americans compared with whites, studies to date have failed to establish a significant association between elevated Lp(a) levels (Ն30 mg/dL) and CAD among African Americans. 1,14 -16 The lack of understanding of this racial difference has made it difficult to conclude with full confidence that Lp(a) is a risk factor for CAD..In addition to high Lp(a) levels, the presence of small apo(a) isoforms has been associated with CAD in whites. [17][18][19][20][21][22][23][24] In the majority of studies using high-resolution sizing techniques, small apo(a) size has been defined as Ͻ22 kringle 4 (K4) repeats. 17,18,24 The majority of whites with high Lp(a) levels possesses at least 1 small apo(a) isoform; however, the majority of African Americans with high Lp(a) levels has no small apo(a) isoform. 25 The high degree of correlation between elevated levels of Lp(a) and small apo(a) isoforms in whites makes it difficult to ascerta...

Factors contributing to variation in lipoprotein (a) in Melbourne Anglo-Celtic population

“…Wilkund et al, (1990) and Wang et al, (1990) have published data on Lp(a) level and infant and parent gene status, but the distribution of phenotypes has not yet been reported in the literature, although several studies have been carried out in other countries on white populations (Paultre et al, 2000(Paultre et al, , 2002Albers et al, 1974). The present study focuses on apo(a) phenotypes and Lp(a) concentration in a white Australian migrant population of Anglo-Celtic origin.…”

Lipoprotein(a)

“…[57][58][59][60][61][62][63][64][65][66][67][68][69][70] It has proven more difficult to detect an association between Lp(a) and cardiovascular disease among blacks; 71,72 however, using assessment of apo(a) size allele-specific Lp(a) levels as discussed, we found an association between cardiovascular disease and Lp(a) among black and white men with small apo(a) sizes. 38 Further, the possibility that Lp(a) levels could be increased secondary to cardiovascular disease has been raised, implying that an increased Lp(a) level could be a result of disease rather than a part of the causal pathway. Studies in model systems demonstrating a stimulation of apo(a) secretion from monkey hepatocytes by interleukin (IL)-6 have provided some support for this concept.…”

“…38,65,114 Furthermore, although Lp(a) levels have been reported to be increased in women with myocardial infarction, 115 a recent prospective study on cerebrovascular disease demonstrated an association between Lp(a) and stroke in men but not in women. 116 This does not necessarily conflict with an association between plasma Lp(a) levels and cardiovascular disease among women, although it could suggest that any risk carried by specific apo(a) sizes may be subject to modulation by gender-specific factors.…”

“…Thus, use of isoform-specific or allele-specific levels may be more informative in assessing Lp(a) as a risk factor. 38,112 This further implies that determination of predictors of allele-specific apo(a) levels would be of interest in relation to Lp(a) atherogenicity. Recently, we assessed the effect of apo(a) size together with 2 other genetic variants, the upstream C/T and pentanucleotide repeat polymorphisms, on allele-specific apo(a) levels in whites and blacks (Rubin et al, unpublished observations).…”

The Value of Lipoprotein(a) as a Risk Factor and Its Association With Major Risk Factors in High and Low-Risk Dyslipidemic Patients According to Framingham Risk Scoring

“…Lp(a)'nın risk faktörü olarak değerlendirilemeye-ceği sonucu çalışma kitimizin ateroskleroz açısından daha riskli olduğu bilinen küçük boyutlu apo(a)'nın oranını saptayamamasına bağlı olabilir. Allele veya izoforma özel kitlerin kullanımının Lp(a)'nın risk faktörü olarak değerlendirilmesinde özellikle erkeklerde daha tanımlayıcı olabileceği yapılan geniş ölçekli çalışmalarda zaten ortaya çıkmış bir gerçektir 35,36 . Üçüncüsü herhangi bir risk faktörünün Framingham toplumundaki mutlak riski, diğer tüm toplumlar için geçerli olmayabilir.…”