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The Journal of Clinical Endocrinology and Metabolism logoLink to The Journal of Clinical Endocrinology and Metabolism
. 2008 Feb 5;93(4):1482–1488. doi: 10.1210/jc.2007-2416

High Levels of Inflammatory Biomarkers Are Associated with Increased Allele-Specific Apolipoprotein(a) Levels in African-Americans

Erdembileg Anuurad 1, Jill Rubin 1, Alan Chiem 1, Russell P Tracy 1, Thomas A Pearson 1, Lars Berglund 1
PMCID: PMC2291489  PMID: 18252779

Abstract

Background: A role of inflammation for cardiovascular disease (CVD) is established. Lipoprotein(a) [Lp(a)] is an independent CVD risk factor where plasma levels are determined by the apolipoprotein(a) [apo(a)] gene, which contains inflammatory response elements.

Design: We investigated the effect of inflammation on allele-specific apo(a) levels in African-Americans and Caucasians. We determined Lp(a) levels, apo(a) sizes, allele-specific apo(a) levels, fibrinogen and C-reactive protein (CRP) levels in 167 African-Americans and 259 Caucasians.

Results: Lp(a) levels were increased among African-Americans with higher vs. lower levels of CRP [<3 vs. ≥3 mg/liter (143 vs. 108 nmol/liter), P = 0.009] or fibrinogen (<340 vs. ≥340 mg/liter, P = 0.002). We next analyzed allele-specific apo(a) levels for different apo(a) sizes. No differences in allele-specific apo(a) levels across CRP or fibrinogen groups were seen among African-Americans or Caucasians for small apo(a) sizes (<22 kringle 4 repeats). Allele-specific apo(a) levels for medium apo(a) sizes (22–30 kringle 4 repeats) were significantly higher among African-Americans, with high levels of CRP or fibrinogen compared with those with low levels (88 vs. 67 nmol/liter, P = 0.014, and 91 vs. 59 nmol/liter, P < 0.0001, respectively). No difference was found for Caucasians.

Conclusions: Increased levels of CRP or fibrinogen are associated with higher allele-specific medium-sized apo(a) levels in African-Americans but not in Caucasians. These findings indicate that proinflammatory conditions result in a selective increase in medium-sized apo(a) levels in African-Americans and suggest that inflammation-associated events may contribute to the interethnic difference in Lp(a) levels between African-Americans and Caucasians.

Increased C-reactive protein or fibrinogen is associated with higher allele-specific medium-sized apolipoprotein (a) levels in African-Americans than Caucasians, possibly explaining the ethnic differences in lipoprotein (a) levels between these two groups.

The role of inflammation in the pathogenesis of cardiovascular disease (CVD) is well recognized. Inflammation contributes to all phases of atherosclerosis, from fatty streak initiation, growth, and complication of the atherosclerotic plaque to CVD events (1). Thus, virtually every step in atherosclerosis is believed to involve cytokines, bioactive molecules, and proinflammatory cells. The inflammatory response is mediated by acute-phase reactants such as C-reactive protein (CRP) and fibrinogen, and considerable attention has recently been paid to the association of such factors with coronary artery disease (CAD) (2,3,4,5). Notably, many prospective studies have demonstrated positive associations between the risk for CAD and plasma levels of CRP (6,7) or fibrinogen (8,9). In view of these results, a recent statement from the Centers of Disease Control and Prevention and the American Heart Association concluded that it is reasonable to measure CRP as an adjunct to established cardiovascular risk factors (10).

Lipoprotein(a) [Lp(a)] is an independent CVD risk factor where plasma levels are largely determined by apolipoprotein(a) [apo(a)] gene size (11,12,13). The size of the apo(a) gene is highly variable, resulting in a size variation of the apo(a) protein, as manifested in a variable number of kringle 4 (K4) repeats (11,14). There is an inverse relationship between apo(a) size and Lp(a) levels, because smaller apo(a) sizes in general are associated with higher plasma Lp(a) levels. However, even for a defined apo(a) size, there is considerable variability in Lp(a) levels (15,16,17,18). The use of size allele-specific apo(a) levels offers opportunity to more accurately assess the relationship between apo(a) size and Lp(a) levels. Allele-specific apo(a) levels are higher among African-Americans compared with Caucasians, and the most pronounced interethnic difference is seen for medium-sized apo(a) alleles (15,18,19). Although genetic polymorphisms in the apo(a) gene have been reported to be contributory, the differences in allele-specific apo(a) levels between African-Americans and Caucasians has not been fully explained (16,17,20). It is well known that the apo(a) gene contains response elements for inflammatory factors such as IL-6 (21,22). However, the role of Lp(a) as an acute-phase reactant is controversial, and the effect of inflammation on allele-specific apo(a) levels is unknown. The objectives of our study were to investigate the potential effect of inflammation measured by two acute-phase reactants (CRP and fibrinogen) on allele-specific apo(a) levels in African-Americans and Caucasians.

Subjects and Methods

Subjects

Subjects were recruited from a patient population scheduled for diagnostic coronary arteriography either at Harlem Hospital Center in New York City or at the Mary Imogene Bassett Hospital in Cooperstown, NY. The clinical characteristics of the study population and the study design including inclusion and exclusion criteria have been described previously, and notably, exclusion criteria included use of lipid lowering drugs (19,23,24). Briefly, a total of 648 patients, self-identified as Caucasian (n = 344), African-American (n = 232), or other (n = 72) were enrolled. The apo(a) allele sizes, circulating apo(a) isoforms, and allele-specific apo(a) levels were available on 426 subjects (167 African-Americans, 259 Caucasians). The study was approved by the Institutional Review Boards at Harlem Hospital, the Mary Imogene Bassett Hospital, Columbia University College of Physicians and Surgeons, and University of California, Davis, and informed consent was obtained from all subjects.

Clinical and biochemical assessment

Fasting blood samples were drawn approximately 2–4 h before the catheterization procedure, and plasma samples were stored at −80 C before analysis. High-sensitivity CRP levels were measured using an ELISA, standardized according to the World Health Organization First International Reference Standard (25,26). Fibrinogen was measured by the clot-rate method of Clauss (27). Plasma total cholesterol, triglyceride, and high-density lipoprotein (HDL) cholesterol were determined by standard enzymatic procedures. Low-density lipoprotein (LDL) cholesterol levels were calculated in subjects with triglyceride levels of less than 400 mg/dl using the formula of Friedewald et al. (28). All analyses were carried out shortly after completion of the study.

Measurement of plasma Lp(a) levels

Lp(a) levels were measured by using a method insensitive to size variation in apo(a) by a sandwich ELISA (Sigma Diagnostics, St. Louis, MO). In our hands, the interassay coefficient of variation was 8.4% at an apo(a) level of 19.9 nm and 9.0% at an apo(a) level of 67.1 nm (19).

Apo(a) allele and isoform size determination

To determine apo(a) allele sizes, we performed genotyping using pulsed-field electrophoresis of DNA from leukocytes embedded in agarose plugs, essentially as described previously (29,30). Apo(a) isoform sizes were analyzed by SDS-agarose gel electrophoresis of plasma samples, followed by immunoblotting. Briefly, the apo(a) bands were visualized with the ECL Amersham technique using a second, labeled antibody (Pierce, Rockford, IL) (19,31,32).

Determination of allele-specific apo(a) levels and dominance

The protein dominance was determined by optical analysis of the apo(a) protein bands on the Western blots, and the visual estimations were validated by computerized scanning. For each of the apo(a) protein bands, levels were apportioned according to the degree of intensity of the bands on the Western blot, using 10% increments (30). For example, an individual with plasma Lp(a) level of 100 nmol/liter, carrying apo(a) proteins with 25 K4 and 35 K4 repeats, with the smaller protein dominating by 80%, would have allele-specific apo(a) level of 80 nmol/liter for 25 K4 and allele-specific apo(a) level of 20 nmol/liter apportioned to the 35-K4 repeat protein.

Statistics

Analyses of data were done with SPSS statistical analysis software (SPSS Inc., Chicago, IL). Results are expressed as means ± sd. Triglyceride and CRP levels were logarithmically transformed, and Lp(a) levels and allele-specific apo(a) levels were square root transformed to achieve normal distributions. Proportions were compared between groups using χ2 analysis and Fisher exact test where appropriate. Group means were compared using Student’s t test. The CRP and fibrinogen levels were dichotomized as high and low groups (CRP, <3 vs. ≥3 mg/liter; fibrinogen, <340 vs. ≥340 mg/dl) based on common practice from previous studies (3,10,33,34,35,36). The distribution of apo(a) alleles for each CRP and fibrinogen group was analyzed using the nonparametric Kolmogorov-Smirnov test. Unless otherwise noted, a nominal two-sided P value < 0.05 was used to assess significance.

Results

The characteristics of the study population are shown in Table 1. Compared with Caucasians, African-Americans were younger and had significantly higher levels of mean and median Lp(a). Also in agreement with previous studies based on the National Health and Nutrition Examination Survey, African-Americans had higher levels of CRP and fibrinogen compared with Caucasians (37,38,39). There was no difference in the levels of total and LDL cholesterol between the two ethnic groups, whereas African-Americans had significantly higher levels of HDL cholesterol and lower levels of triglycerides compared with Caucasians.

Table 1.

Characteristics of study population

Clinical characteristics African-Americans (n = 231) Caucasians (n = 336)
Men/women (n) 132/99 218/118
Diabetes (n) 68 (29.4%) 69 (20.5%)a
Hypertension (n) 167 (72.3%) 188 (55.9%)b
Postmenopausal (n) 66 (66.7%) 94 (79.7%)a
Age (yr) 68 (29.4%) 69 (20.5%)a
Lp(a) (nmol/liter) 107.5 (59.3–179.9) 24.3 (7.4–78.9)b
CRP (mg/liter) 4.0 (1.9–10.6) 2.9 (1.4–7.8)a
Fibrinogen (mg/dl) 384 ± 8 328 ± 5b
Total cholesterol (mg/dl) 196 ± 3 198 ± 2
LDL cholesterol (mg/dl) 125 ± 2 123 ± 2
HDL cholesterol (mg/dl) 49 ± 1 41 ± 1b
Triglyceride (mg/dl) 105 (79–143) 153 (113–221)b
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Data are means ± sem or for nonnormally distributed variables as median (interquartile range). Group means were compared using Student’s t test. Values for triglyceride and CRP were logarithmically transformed, and values for Lp(a) were square root transformed before analyses. 

a

P < 0.05. 

b

P < 0.001. 

We next analyzed the effect of increased levels of CRP (≥3 mg/liter) or fibrinogen (≥340 mg/dl) on plasma Lp(a) levels in each ethnic group. As mentioned above, cutoff levels of CRP and fibrinogen were chosen based on previous studies (3,10,33,34,35,36). As seen in Table 2, Lp(a) levels were increased among African-Americans with higher vs. lower CRP (143 vs. 108 nmol/liter, P = 0.009) or fibrinogen (146 vs. 105 nmol/liter, P = 0.002), whereas no differences were found in Lp(a) levels across CRP or fibrinogen groups for Caucasians. We hypothesized that the different pattern of Lp(a) levels in African-Americans across CRP and fibrinogen groups might be due to either 1) a different distribution of apo(a) alleles or 2) a difference in allele-specific apo(a) levels. To test the first possibility, we compared the distribution of apo(a) alleles for each CRP (<3 vs. ≥3 mg/liter) or fibrinogen (<340 vs. ≥340 mg/dl) group using the Kolmogorov-Smirnov test. However, there were no significant differences in cumulative frequency distribution curves of apo(a) alleles for either CRP or fibrinogen levels in both ethnic groups (Fig. 1).

Table 2.

Plasma levels of Lp(a) in African-American and Caucasian subjects with low and high levels of CRP and fibrinogen

African-Americans (n = 231) Caucasians (n = 336)
Lp(a) CRP < 3 mg/liter 107.6 ± 8.7 64.0 ± 6.8
  CRP ≥ 3 mg/liter 143.3 ± 8.8a 54.3 ± 6.0
Lp(a) fibrinogen < 340 mg/dl 104.8 ± 8.6 56.8 ± 5.5
  Fibrinogen ≥ 340 mg/dl 145.6 ± 8.8b 63.9 ± 7.8
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Data are means ± sem. Group means were compared using Student’s t test. Values for Lp(a) were square root transformed before analyses. 

a

P < 0.005 compared with low CRP (<3 mg/liter) group. 

b

P < 0.005 compared with low fibrinogen (<340 mg/dl) group. 

Figure 1.

Figure 1

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Cumulative frequency distribution curves of apo(a) alleles in 167 African-American and 259 Caucasians across CRP (<3 vs. ≥3 mg/liter) and fibrinogen (<340 vs. ≥340 mg/dl) groups.

Because we did not observe any difference in the apo(a) allele distribution across either CRP and/or fibrinogen levels, we next analyzed allele-specific apo(a) levels for different apo(a) sizes. Further analysis for allele-specific apo(a) levels was done on 426 subjects (167 African-Americans, 259 Caucasians). First we dichotomized apo(a) sizes by using the median apo(a) size (26 K4 repeats), as in our previous studies (16,17). As seen in Fig. 2A, allele-specific apo(a) levels for apo(a) sizes less than 26 K4 were significantly higher among African-Americans with high levels of CRP (≥3 mg/liter) compared with those with low levels (125 vs. 84 nmol/liter, P = 0.034). Increased allele-specific apo(a) levels were also seen among African-Americans with high fibrinogen levels (≥340 mg/dl) carrying apo(a) sizes less than 26 K4 compared with those with lower fibrinogen levels (125 vs. 81 nmol/liter, P = 0.019) (Fig. 3A). For African-American subjects with larger apo(a) sizes (≥26 K4), there was no difference in allele-specific apo(a) levels between the two CRP or fibrinogen groups (data not shown). Notably, no difference was observed across CRP or fibrinogen groups for either apo(a) size range among Caucasians.

Figure 2.

Figure 2

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Allele-specific apo(a) levels (nanomoles per liter) for median <26 K4 (A), small <22 K4 (B), and medium 22–30 K4 (C) apo(a) sizes across low and high CRP level groups in African-Americans and Caucasians. Data are means ± se. *, P < 0.05; P values were calculated using Student’s t test analysis, and values for allele-specific apo(a) levels were square root transformed before analyses. The nontransformed values are shown in the graphs. The data are based on n = 37 with less than 26 K4, n = 10 with less than 22 K4, and n = 106 with 22–30 K4 repeats in African-Americans, and n = 90 with less than 26 K4, n = 59 with less than 22 K4, and n = 102 with 22–30 K4 repeats in Caucasians.

Figure 3.

Figure 3

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Allele-specific apo(a) levels (nanomoles per liter) for median <26 K4 (A), small <22 K4 (B), and medium 22–30 K4 (C) apo(a) sizes across low and high fibrinogen level groups in African-Americans and Caucasians. Data are means ± se. *, P < 0.05, P values were calculated using Student’s t test analysis, and values for allele-specific apo(a) levels were square root transformed before analyses. The nontransformed values are shown in the graphs. The data are based on n = 37 with less than 26 K4, n = 10 with less than 22 K4, and n = 106 with 22–30 K4 repeats in African-Americans, and n = 90 with less than 26 K4, n = 59 with less than 22 K4, and n = 102 with 22–30 K4 repeats in Caucasians.

Because a cutoff of 22 K4 commonly has been used to define small-size apo(a), we repeated our analysis using this cutoff. We did not detect any significant differences in allele-specific apo(a) levels across CRP (<3 vs. ≥3 mg/liter) (Fig. 2B) or fibrinogen groups (<340 vs. ≥340 mg/dl) (Fig. 3B) among either African-Americans or Caucasians for small apo(a) sizes (<22 K4). These results suggested that an increase in CRP or fibrinogen was not associated with any change of allele-specific small-size apo(a) levels. However, because our finding was limited to African-Americans and because the major difference in allele-specific apo(a) levels between African-Americans and Caucasians have been found for the medium-sized apo(a) range, we extended our approach to include medium apo(a) sizes (22–30 K4). As seen in Fig. 2C, allele-specific apo(a) levels for medium apo(a) sizes were significantly higher among African-Americans with high levels of CRP compared with those with low levels (88 vs. 67 nmol/liter, P = 0.014). Similar results were observed for fibrinogen, where higher allele-specific medium-size apo(a) levels were found among subjects with higher compared with lower fibrinogen levels (91 vs. 59 nmol/liter, P < 0.0001) (Fig. 3C). In contrast, there were no significant differences in allele-specific apo(a) levels across CRP or fibrinogen groups among Caucasians with medium-sized apo(a) alleles.

Finally, we divided our study population into quartiles and repeated the analyses. In agreement with our findings, allele-specific apo(a) levels for the two middle quartiles, i.e. 23–25 K4 and 26–28 K4 repeats representing medium-sized apo(a), were higher among African-American subjects with high levels of CRP or fibrinogen (supplemental Fig. 1, published as supplemental data on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org). Notably, no difference was observed across CRP or fibrinogen groups for either quartile among Caucasians.

Discussion

The main novel finding in our study was that increased levels of inflammatory markers such as CRP or fibrinogen were associated with higher allele-specific apo(a) level for medium apo(a) sizes (22–30 K4 repeats) in African-Americans but not in Caucasians. No difference in allele-specific apo(a) levels was seen in African-Americans or Caucasians with higher vs. lower CRP or fibrinogen for small (<22 K4) apo(a) sizes. Our findings suggest that inflammation-associated events may selectively affect apo(a) levels representing specific apo(a) genotypes in African-Americans and provide a potential explanation for differences in Lp(a) levels between African-Americans and Caucasians.

Lp(a) levels vary across ethnicities with the most profound differences between populations of African descent, including African-Americans, and non-Africans, e.g. Caucasians (18,40,41,42,43). This difference is not due to differences in apo(a) size distribution between the two groups (44). Instead, African-Americans have higher allele-specific apo(a) levels compared with Caucasians (15,30). However, this difference varies across the apo(a) size spectrum, and the most pronounced interethnic difference is seen for medium-sized apo(a) alleles (19). This difference in allele-specific apo(a) levels has attracted much interest but is not fully understood. Recently, we demonstrated that African-American-Caucasian differences in allele-specific apo(a) levels were partially explained for large apo(a) sizes by apoE genotype (17) and for small apo(a) sizes by the other apo(a) allele size in a given genotype and an upstream pentanucleotide repeat polymorphism (16). Furthermore, three polymorphisms in the apo(a) gene are reported to contribute to the differences in Lp(a) levels between African-Americans and Caucasians in subjects with end-stage renal disease (20). However, allele-specific levels were not taken into account, and subjects with end-stage renal disease generally have increased allele-specific apo(a) levels (20,45).

In the present study, we found that the presence of inflammation as detected by increased levels of CRP and fibrinogen resulted in increased Lp(a) levels among African-Americans. Although inflammation is a complex phenomenon involving multiple cytokines and acute-phase reactants, CRP and fibrinogen have commonly been used as well established and robust markers of inflammation (6,7,8,9,10). The role of Lp(a) during the acute-phase proinflammatory condition has been controversial with conflicting results reported from different studies (46,47,48,49). Under extreme conditions, such as sepsis, Lp(a) levels decrease along with those of other lipids (46); however, under more moderate inflammatory conditions, both an increase or no change in Lp(a) levels have been reported (47,48,49). Recently, it was shown that a combination of high Lp(a) levels with a high level of either CRP or fibrinogen was associated with an increased risk for CAD (50). Furthermore, Tsimikas et al. (51) have shown that Lp(a) levels increased significantly during an extended post-myocardial infarction period. Taken together, these results suggest the possibility of an interaction between Lp(a) and inflammatory markers and, furthermore, that the presence of inflammation modulates risk factor properties of Lp(a).

The mechanism for an impact of inflammation on Lp(a) remains unknown. The apo(a) gene contains response elements for inflammatory factors, such as IL-6 (21,22). Ramharack et al. (21) have reported that Lp(a) and apo(a) mRNA levels in primary monkey hepatocyte culture are responsive to cytokines. Thus, in vivo Lp(a) levels can be positively (IL-6) or negatively (TGF-β1 and TNF-α) regulated by physiological levels of cytokines. However, any effect of inflammation on allele-specific apo(a) levels is unknown. Our finding that African-Americans had a different Lp(a) response to a proinflammatory stimulus compared with Caucasians, with a selective increase in Lp(a) levels carrying medium-sized apo(a), is to our knowledge the first report on inflammation and allele-specific apo(a) levels. This finding has several implications. First, it suggests that proinflammatory conditions may impact differently on Lp(a) levels in African-Americans and Caucasians. Second, the effect was limited to a range of apo(a) sizes, suggesting the possibility of an interaction between an inflammatory stimulus and genetic factors. Third, our findings provide a potential explanation for differences in Lp(a) levels between African-Americans and Caucasians and suggest that inflammation-associated events may contribute to this interethnic difference.

We acknowledge some of the limitations of this study. Subjects in our study were recruited from patients scheduled for coronary angiography and are likely more typical of a high-risk patient group than the healthy population at large. This may explain the relatively high levels of CRP and fibrinogen among our subjects. Furthermore, we did not measure other inflammatory biomarkers such as IL-6. However, none of the patients had a history of acute coronary symptoms or surgical intervention within 6 months, arguing against any secondary increase in inflammatory parameters due to an acute CAD. Furthermore, clinical and laboratory parameters were in agreement with differences generally observed between healthy African-American and Caucasian populations from other studies (37,38,39,52,53). Although the subjects in our study may not be fully representative of the healthy population, our findings still suggest that even within a high-risk population, proinflammatory conditions may differentially influence Lp(a) levels among African-Americans carrying medium-sized apo(a).

In conclusion, increased levels of CRP or fibrinogen are associated with higher allele-specific medium-sized apo(a) levels in African-Americans but not in Caucasians. Our results indicate that a proinflammatory stimulus may result in a selective increase in Lp(a) levels among African-Americans carrying medium-sized apo(a). These findings provide a potential explanation for differences in Lp(a) levels between African-Americans and Caucasians and suggest that inflammation-associated events may contribute to this interethnic difference. Further studies are needed to verify these results in other populations and explore whether such events may impact on the role of Lp(a) as risk factor.

Supplementary Material

[Supplemental Data]
jcem_jc.2007-2416_index.html (1.1KB, html)

Footnotes

The project was supported by Grants 49735 (to T.A.P.) and 62705 (to L.B.) from the National Heart, Lung, and Blood Institute. This work was supported in part by the University of California, Davis, Clinical and Translation Science Center (RR 024146), and E.A. is a recipient of an American Heart Association Postdoctoral Fellowship (0725125Y).

Disclosure Statement: E.A., J.R., A.C., and R.P.T. have nothing to disclose. T.A.P. reports having received consulting fees from Bayer, Cardex, Coca-Cola, Forbes Medi-Tech, and Merck and lecture fees from Abbott, Bayer, KOS Pharmaceuticals, Merck, and Merck/Schering Plough. L.B. reports having received consulting fees from Merck, Novartis, and Merck/Schering Plough; lecture fees from Merck, Astra-Zeneca, and Merck/Schering Plough; and equity interest in Pfizer.

First Published Online February 5, 2008

Abbreviations: Apo(a), Apolipoprotein(a); CAD, coronary artery disease; CRP, C-reactive protein; CVD, cardiovascular disease; HDL, high-density lipoprotein; K4, kringle 4; LDL, low-density lipoprotein; Lp(a), lipoprotein(a).

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