HDL Dysfunctionality (Paraoxonase) Is Worse in Nondiabetic, Postmenopausal African American Than in White Women

African American women (AAW) suffer two- to fourfold greater rates of cardiovascular disease (CVD) mortality and morbidity compared with those in white American women (WAW). The reasons for the higher CVD mortality in African Americans are uncertain. It is generally well established that HDL cholesterol (HDL-C) is antiatherogenic and cardioprotective. Indeed, several prospective studies have revealed that HDL-C is protective of coronary heart disease. Most of these studies were in white populations (1). However, these HDL-C and coronary heart disease relationships do not appear to apply to African Americans. Indeed, AAW have higher HDL-C than WAW. Thus, the higher CVD in AAW in the presence of higher HDL-C is paradoxical and suggests that HDL is possibly less cardioprotective in AAW. We have postulated that in AAW, HDL appears to be qualitatively dysfunctional or AAW are resistant to HDL's cardioprotective effects, i.e., HDL resistance. In this regard, previous studies have attributed the antiatherogenic properties of HDL to reverse cholesterol transport (2). However, recent evidence suggests that HDL is an antioxidant and inhibits the oxidation of LDL as well as possesses anti-inflammatory properties (3).

Paraoxonase (PON1) enzyme activity is associated with HDL functionality. Serum PON1 is coassociated with HDL and apolipoprotein (apo) A1 (apoA1) in the circulation. PON1 is reported to be responsible for the antioxidant and anti-inflammatory properties of HDL (4,5). Therefore, to explore the paradox of higher HDL-C and worse CVD mortality and morbidity in AAW and WAW, we examined 1) the HDL-associated PON1 enzyme activity and oxidized LDL (ox-LDL) and 2) the concomitant subclinical proinflammatory markers (high-sensitivity C-reactive protein [hsCRP] and interleukin-6 [IL-6]) in AAW and WAW. We studied PON1 and the CVD risk factors in 42 nondiabetic, postmenopausal AAW and WAW (mean age 57.2 ± 3.6 years, BMI 30.3 ± 6.3 kg/m², systolic blood pressure 120.7 ± 15.5 mmHg, and diastolic blood pressure 74.3 ± 7.4 mmHg). Fasting blood samples for PON1, lipids and lipoproteins, apoAl and apoB, and hsCRP and IL-6 were obtained. Standard oral glucose tolerance test with fasting and 2-h serum glucose, insulin, and C-peptide was performed. Insulin resistance was calculated by homeostasis model assessment of insulin resistance (HOMA-IR). ox-LDL was measured by enzyme-linked immunosorbent assay.

Our AAW were more obese (BMI 32.8 ± 6.5 vs. 27.8 ± 5.0 kg/m², P = 0.007) compared with WAW. There were no significant differences in fasting and 2-h glucose, insulin, C-peptide, HOMA-IR, and blood pressure. We found no significant differences in total cholesterol, HDL-C (58 ± 16.54 vs. 55.04 ± 16.97 mg/dL, P = 0.57), LDL-C (89.22 ± 25.75 vs. 85.23 ± 16.37 mg/dL, P = 0.552), apoB, and IL-6 in AAW and WAW. However, we found significantly lower serum triglyceride level (62.2 ± 23.4 vs. 88.3 ± 46.5 mg/dL, P = 0.02) and higher apoA1 (185.2 ± 29.7 vs. 159.7 ± 46 mg/dL, P = 0.03) in AAW compared with WAW. In contrast, we found significantly lower PON1 (0.97 ± 0.35 vs. 2.09 ± 0.29 ng/mL, P = 0.0001) and higher ox-LDL (8.2 ± 2.5 vs. 4.5 ± 1.6 units/L, P = 0.001) and a tendency toward higher hsCRP (3.96 ± 3.7 vs. 2.2 ± 2.5 mg/L, P = 0.07) in AAW than WAW.

Our pilot study demonstrates several HDL-related functional differences in nondiabetic postmenopausal AAW and WAW. Despite a more favorable lipid and lipoprotein profile in AAW, we found significantly lower PON1 and higher ox-LDL and hsCRP in AAW compared with WAW. We conclude that HDL may be dysfunctional, as measured by PON1, in AAW compared with WAW. We speculate that the excess proinflammatory peptides and enhanced LDL oxidation, perhaps associated with HDL-related dysfunction, could mediate the higher CVD mortality and morbidity in AAW compared with WAW. Further studies to elucidate the ethnic HDL functionality differences are warranted.