Low HDL Cholesterol and Coronary Heart Disease

In a study of factors for coronary heart disease risk conducted as part of the Turkish Heart Study, low HDL cholesterol (HDL-C) levels were identified as a highly prevalent condition in Turks. Lipid analysis of approximately 10,000 Turkish adult men and women revealed that the Turks had the lowest HDL-C levels of any previously characterized population (~10–15 mg/dl lower than those in western Europe and the United States).

We have established that the low HDL-C levels in Turks are primarily of genetic origin. A survey of the activities of candidate enzymes and transfer proteins that could possibly be the genetic cause of the low HDL-C revealed that the Turks uniquely have elevated hepatic lipase mass and activity (6). Turkish men and women have 25–30% higher levels of hepatic lipase than non-Turkish American controls (8).

More recently, we have been characterizing the HDL subclasses and attempting to define more precisely the factors associated with low HDL. Turks have low levels of HDL₂, LpAI, and preb-1 HDL and increased levels of LpAI/AII particles (potentially an atherogenic lipid profile) (9). The frequency distributions of HDL-C and LpAI levels were skewed toward bimodality in Turkish women but were unimodal in Turkish men. The apoE genotype affected HDL-C and LpAI levels in women only. In women, but not men, the e2 allele was strikingly more prevalent in those with the highest levels of HDL-C and LpAI than in those with the lowest levels. The higher prevalence of the e2 allele in these subgroups of women was not explained by plasma triglyceride levels, total cholesterol levels, age, or body mass index. The modulating effects of apoE isoforms on lipolytic hydrolysis of HDL by hepatic lipase (apoE2 preventing efficient hydrolysis) or on lipoprotein receptor binding (apoE2 interacting poorly with the LDL receptor) may account for differences in HDL-C levels in Turkish women (the e2 allele being associated with higher HDL levels). In Turkish men, who have substantially higher levels of hepatic lipase activity than women, the modulating effect of apoE may be overwhelmed. The gender-specific effect of the apoE genotype on HDL-C and LpAI levels in association with elevated levels of hepatic lipase provides new insights into the metabolism of HDL. These studies are conducted in collaboration with Dr. Thomas Bersot.

Our most recent studies are designed to determine if HDL-C levels are unusually low throughout life in Turks and to determine the effect of puberty on plasma lipids in Turks. The plasma lipids of cord blood of healthy newborns (n = 105) and 8–10-year-old school children (n = 225) have been analyzed in ethnic Turks. Lipid values in typical western European populations and in Turks are shown in Table 1. Typically, newborns have very low cholesterol and HDL-C levels that are virtually identical in males and females. Both total cholesterol and HDL-C levels rise with age, and there are no gender differences before puberty. The HDL-C levels of 8–9-year-old western European children were 50–60 mg/dl and were virtually identical for both males and females. Turkish newborns and prepubescent children have somewhat lower total cholesterol levels (~140 mg/dl), but have similar HDL-C levels (mean for the group ~50 mg/dl) (Table 1).

However, after puberty, HDL-C levels in western European males decrease to typical adult levels (~47 mg/dl) and in females decrease much less to typical adult levels (~55<–57 mg/dl) (Table 1). On the other hand, the HDL-C levels in Turkish boys drop from a mean of ~50 mg/dl to 37 mg/dl and then the levels remain at 36<–37 mg/dl during adulthood. The HDL-C levels in Turkish girls decrease to 43 mg/dl and remain at an average of 40–43 mg/dl in adulthood. The changes in HDL-C levels in Turks are illustrated in Figure 3.

The mechanism for the striking reduction in HDL-C levels after puberty in Turks remains to be determined. We hypothesize that androgen production plays a major role in modulating HDL-C levels at puberty. Consistent with this hypothesis is the observation from Dr. Gerd Assmann’s lab (University of Munster, Germany) suggesting that Turks have lower levels of sex hormone–binding globulin, which should result in increased levels of free bioactive testosterone in both males and females. Hepatic lipase production is regulated by androgens, and high levels of androgens are associated with increased levels and activity of hepatic lipase. Thus, high levels of free testosterone may explain the high levels of hepatic lipase activity and protein mass that are characteristic of Turkish males and females. This hypothesis remains to be proven. These studies are being conducted in association with colleagues at the American Hospital in Istanbul and at Kocaeli University and Hacettepe University in Turkey.

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