Levels of lipoprotein (a) [Lp(a)], a complex between an LDL-like lipid moiety containing one copy of apoB, and apo(a), a plasminogen-derived carbohydrate-rich hydrophilic protein, are primarily genetically regulated. Although stable intra-individually, Lp(a) levels have a skewed distribution inter-individually and are strongly impacted by a size polymorphism of the LPA gene, resulting in a variable number of kringle IV (KIV) units, a key motif of apo(a). The variation in KIV units is a strong predictor of plasma Lp(a) levels resulting in stable plasma levels across the lifespan. Studies have demonstrated pronounced differences across ethnicities with regard to Lp(a) levels and some of this difference, but not all of it, can be explained by genetic variations across ethnic groups. Increasing evidence suggests that age, sex, and hormonal impact may have a modest modulatory influence on Lp(a) levels. Among clinical conditions, Lp(a) levels are reported to be affected by kidney and liver diseases.

Heritability of LPA allele, apo(a) isoform sizes, and isoform-associated lipoprotein(a) [Lp(a)] levels was studied in 82 Caucasian and African-American families with two parents and two children (age: 6-74 years). We determined: 1) Lp(a) levels; 2) LPA allele sizes; 3) apo(a) isoform sizes; and 4) isoform-specific apo(a) levels (ISLs), the amount of Lp(a) carried by an individual apo(a) isoform. Trait heritability was estimated by mid-parent-offspring analysis. The ethnicity-adjusted heritability estimate for Lp(a) level was 0.95. Heritability for ISLs corresponding to the smaller LPA allele in a given allele-pair was higher than that corresponding to the larger LPA allele (0.91 vs. 0.59, P = 0.017). Although not statistically different, heritability for both apo(a) isoforms (0.90 vs. 0.70) and LPA alleles (0.98 vs. 0.82) was higher for the smaller versus larger sizes. Heritability was generally lower in African-Americans versus Caucasians with a 4-fold difference for the larger LPA allele (0.25 vs. 0.94, P = 0.001). In Caucasians, an overall higher heritability pattern was noted for the older (≥47 years) versus younger (<47 years) families. In conclusion, Lp(a) level and traits associated with the smaller LPA alleles were strongly determined by genetics, although with a varying ethnic influence. Ethnic differences in heritability of the larger LPA allele warrant further investigations.

Objectives

Lipoprotein(a), Lp(a), represents an apolipoprotein (apo) B-carrying lipoprotein, yet the relationship between Lp(a) and apoB levels has not been fully explored.

Methods

We addressed the relationship between Lp(a) and apoB-containing lipoprotein levels in 336 Caucasians and 224 African-Americans. Our approach takes unique molecular properties of Lp(a) as well as contribution of Lp(a) to the levels of these lipoproteins into account.

Results

Levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apoB and apoB/apoA-1 did not differ across ethnicity. African-Americans had higher levels of Lp(a) and high-density lipoprotein cholesterol and lower triglyceride levels compared to Caucasians. Lp(a) levels were correlated with levels of TC (p < 0.005), LDL-C (p < 0.001), apoB (p < 0.05) or apoB/apoA-1 (p < 0.05) in both ethnic groups. These associations remained significant only in African-Americans after adjustments for the contribution of Lp(a)-cholesterol or Lp(a)-apoB. Furthermore, taking Lp(a)-apoB into account, allele-specific apo(a) levels were significantly associated with apoB levels and the apoB/apoA-1 ratio in African-Americans. The latter associations in African-Americans remained significant for allele-specific apo(a) levels for smaller apo(a) sizes (<26 K4 repeats), after controlling for the effects of age, sex, and BMI.

Conclusions

Although TC, LDL-C, and apoB levels were comparable between African-Americans and Caucasians, the associations of these parameters with Lp(a) and allele specific apo(a) levels differed between these two ethnic groups. In African-Americans, apoB and apoB/apoA-1 remained consistently and positively associated with both Lp(a) and allele-specific apo(a) levels after adjustments for the contribution of Lp(a)-apoB. The findings suggest an interethnic difference with a closer relationship between Lp(a) and apoB among African-Americans.

Diabetes mellitus is associated with increased risk for atherosclerotic cardiovascular disease (CVD). Recent prospective studies in healthy individuals suggest that the postprandial triglyceride (TG) level is a better independent predictor for assessing future CVD events than fasting TG levels. In contrast, results have been more controversial among diabetic patients, as some studies report a positive association between postprandial TG and CVD. This raises the issue of to what extent postprandial TG levels may be of predictive value in the diabetic population. One possibility impacting on the predictive power of postprandial TG in identifying CVD risk may be the presence of other risk factors, including alterations in lipid and lipoprotein metabolism, which could make it more difficult to identify the impact of postprandial lipemia on cardiovascular risk. The findings provide a challenge to develop a better approach to assess the impact of postprandial lipemia on CVD risk under diabetic conditions.

Objective

Age and inflammation are risk factors for cardiovascular disease but the impact of inflammation on cardiovascular risk across the lifespan is not understood. We investigated whether an inflammatory burden is modulated by age in healthy subjects.

Methods

Caucasian and African-American families were recruited from the general population (age range: 6-74 years, n = 267). Systemic inflammation was assessed by C-reactive protein (CRP), serum amyloid A (SAA), fibrinogen, haptoglobin and α-acid glycoprotein, and vascular inflammation was assessed by pentraxin-3 (PTX-3), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM). To collectively assess systemic or vascular factors across the age spectrum, a composite z-score for each marker category was calculated.

Results

There was a contrasting pattern in systemic versus vascular inflammatory burden over age with an increase in systemic but a decrease in vascular markers in both ethnic groups. The results remained unchanged after adjustments for the covariates and covariance. When looking at individual markers to examine which markers are most contributing factors to the composite scores, CRP and SAA were significantly and positively associated with age, while PTX-3 and sVCAM were significantly and negatively associated with age in both ethnic groups.

Conclusions

The composite z-score for systemic inflammation increased with age, while the composite z-score for vascular inflammation declined with age, irrespective of ethnicity. The findings illustrate a regulatory relationship between age and inflammation, and suggest that a perceived elevation of vascular markers among the very young may be an indication of physiological changes rather than reflecting a disease process.

The hypothesis was tested that plasma levels of adiponectin would be associated with coronary artery disease (CAD) across African-American and Caucasian ethnicity and gender. Adiponectin levels, cardiovascular risk factors, and extent of CAD were measured in 453 subjects (173 African-American and 280 Caucasian men and women). The distribution of adiponectin levels differed significantly between African-Americans and Caucasians (P<0.0001). Among African-Americans, the adiponectin distribution was skewed toward lower levels. For women, adiponectin levels were higher among Caucasians compared with African-Americans (P<0.001), whereas no interethnic difference was observed for men. Irrespective of ethnic group, subjects with CAD had lower levels of adiponectin than did subjects without CAD. Adiponectin was negatively and significantly associated with waist-hip ratio, body mass index, diastolic blood pressure, insulin level, and homeostasis model assessment-insulin resistance in both ethnic groups. Among lipid parameters, total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels were negatively correlated with adiponectin, whereas the high-density lipoprotein cholesterol level correlated positively for both African-Americans and Caucasians. In a multiple regression model, controlling for gender, ethnicity, and other CAD risk factors, adiponectin levels were negatively associated with CAD (P<0.05). The results indicate that, across gender and ethnicity, low adiponectin levels may be an independent risk factor for CAD.

Context

Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces lipoprotein(a) [Lp(a)] levels, but the association of PCSK9 with Lp(a) level and its major determinant, apolipoprotein(a) [apo(a)] size, is not fully understood.

Objective

To assess the relationship between PCSK9, Lp(a) level, apo(a) size, age, and ethnicity/race.

Design

Cross-sectional.

Setting

General population.

Participants

Healthy African Americans and Caucasians (n = 267); age range: 6 to 74 years.

Interventions

None.

Main outcome measures

PCSK9 levels, apo(a) isoform and LPA allele sizes, and isoform-specific Lp(a) levels.

Results

Plasma PCSK9 levels were significantly higher in African Americans vs Caucasians, in females vs males, and in adults vs children. PCSK9 levels were not associated with total plasma Lp(a) levels either in all participants or in ethnicity-specific analyses. However, PCSK9 levels were significantly positively associated with isoform-specific Lp(a) levels carried by the larger apo(a) size in all participants (r = 0.139, P = 0.0361). In ethnicity/race analyses, a significant association was seen for African Americans (r = 0.268, P = 0.0199), but not for Caucasians. In contrast, there were no significant associations of PCSK9 with isoform-specific Lp(a) levels for the smaller apo(a) sizes in all participants nor in ethnic-specific analyses. Furthermore, heritability (h²) analyses revealed a significant heritability for PCSK9 level in both ethnic groups, with a higher estimate in Caucasians than in African Americans (47% vs 22%, respectively).

Conclusions

Among African Americans, but not Caucasians, PCSK9 levels were associated with isoform-specific Lp(a) levels carried on larger, but not smaller, apo(a) sizes. The findings illustrate a diverging relationship of PCSK9 with isoform-specific Lp(a) levels across ethnicity.

Background

Levels of lipoprotein(a), Lp(a), a genetically regulated independent cardiovascular risk factor present in humans and Old World monkeys, are impacted by the apolipoprotein(a), apo(a), gene. Allele-specific apo(a) levels, taking both the apo(a) genotypic and phenotypic characteristics into account, are useful markers to determine atherosclerotic cardiovascular risk.

Methods

We determined (i) the genetic variability of apo(a), (ii) Lp(a) levels, and (iii) allele-specific apo(a) levels in rhesus monkeys (n = 95).

Results

Lp(a) levels differed substantially between animals (range: 4-247 nmol/l) with a skewed distribution toward lower levels. Lp(a) and allele-specific apo(a) levels were inversely related to the number of apo(a) Kringle 4 (K4) repeats. The median apo(a) size was 23 K4 repeats, and the prevalence of a small size apo(a) (≤22 K4) was 43%.

Conclusions

Distribution of Lp(a) and allele-specific apo(a) levels in rhesus monkeys reflected the corresponding human patterns, but with a high prevalence of smaller apo(a) sizes.

NIH offers multiple mentored career development award mechanisms. By building on the UC Davis Clinical and Translational Science Center (CTSC) from its initial NIH funding in 2006, we created an institution-wide K scholar resource. We investigated subsequent NIH funding for K scholars and to what extent CTSC research resources were used. Using NIH RePORTER, we created a database of UC Davis investigators who obtained K01, K08, K23, K25, or K99, as well as institutional KL2 or K12 awards and tracked CTSC research resource use and subsequent funding success. Overall, 94 scholars completed K training between 2007 and 2020, of which 70 participated in one of four institutional, NIH-funded K programs. An additional 103 scholars completed a mentored clinical research training program. Of 94 K awardees, 61 (65%) later achieved NIH funding, with the majority receiving a subsequent individual K award. A higher proportion (73%) of funded scholars used CTSC resources compared to unfunded (48%). Biostatistics and Biomedical Informatics were most commonly used and 55% of scholars used one or more CTSC resource. We conclude that institutional commitment to create a K scholar platform and use of CTSC research resources is associated with high NIH funding rates for early career investigators.

Background Lp(a) (lipoprotein(a)) is the major lipoprotein carrier of oxidized phospholipids (OxPL) and this function mediates Lp(a) atherogenicity. However, the relationship between OxPL, Lp(a), and genetic and biological characteristics remains poorly understood. We assessed the relationship between Lp(a)-bound OxPL, apolipoprotein(a) (apo(a)) size, age, and family structure in 2 racial groups. Methods and Results Healthy Black and White families were recruited from the general population (age: 6-74 years, n=267). OxPL and Lp(a) levels were assayed enzymatically; apo(a) isoform, LPA allele sizes, and allele-specific Lp(a) levels were determined. Lp(a)-OxPL levels did not differ significantly by racial and age groups. Lp(a)-OxPL levels were associated with total plasma Lp(a) in all participants and in race-specific analyses. Further, OxPL levels were significantly associated with allele-specific Lp(a) levels carried by the smaller apo(a) size in all participants (β=0.33, P=0.0003) as well as separately for Black (β=0.50, P=0.0032) and White (β=0.26, P=0.0181) participants. A significant association of OxPL with allele-specific Lp(a) levels for larger apo(a) sizes was seen only in Black participants (β=0.53, P=0.0076). In this group, Lp(a)-OxPL levels were also heritable (h²=0.29, P=0.0235), resulting in a significant interracial difference in heritability between Black and White people (P=0.0352). Conclusions Lp(a)-OxPL levels were associated with allele-specific Lp(a) level carried on smaller apo(a) sizes and among Black participants also for larger apo(a) sizes. The heritability estimates for Lp(a)-bound OxPL differed by race.