Turks have genetically low levels of HDL—about 20–25% lower than those seen in the U.S. and western Europe. More than half of Turkish men and one quarter of Turkish women have HDL levels <35 mg/dl. As a result, many Turks have high TC/HDL ratios and an increased risk of CHD. Perhaps the most striking finding of the Turkish Heart Study has been the dramatic decrease in HDL levels in Turks at puberty.

To test the new management criteria, the Gladstone team applied both the current NCEP guidelines and the guidelines incorporating the TC/HDL ratio to the Turkish Heart Study database of nearly 10,000 adults. In Turkey, the major risk factor for CHD is low HDL, not elevated LDL. The differences in the numbers of patients identified for treatment were striking. The NCEP guidelines recommended that 18.2% of adults receive drug therapy; the low HDL guidelines recommended therapy for 36.4%. These findings have significant public health implications, both in Turkey and in the United States.

This difference is of enormous importance because the number of CHD patients with HDL levels below 40 mg/dl is very large in all countries. Low HDL is also common in the general U.S. population, affecting about 33% of men and 20% of women. About half the variability of HDL levels derives from genetic factors. Acquired factors, such as physical inactivity, smoking, elevated triglycerides, type 2 diabetes, and in particular overweight and obesity, presumably account for the remaining variability.

Looking for the Genetic Causes of Low HDL

In pursuing the cause of the low HDL levels in Turks, Drs. Mahley and Bersot examined lipids in Turkish school children. They found clear evidence that puberty dramatically affects lipoprotein levels in Turks. In Turkish infants and prepubescent children, HDL levels are virtually identical to those in western European and American children at those ages. During about a 3-year period when children are going through puberty, the HDL levels of Turkish adolescents plummet by more than 40%. Since this dramatic decrease occurs during puberty, one might quickly conclude that it involves the sex hormones. However, many other factors could also be involved, including leptin, adiponectin, or other hormones that could affect HDL either directly or indirectly.

What happens in Turks to reduce their HDL levels? Drs. Mahley and Bersot and their colleagues have identified several factors associated with low HDL, including significantly elevated levels of hepatic lipase. Since hepatic lipase production is regulated by androgens, the Gladstone scientists believe that high levels of these male hormones might explain the high levels of hepatic lipase activity in Turkish men and women. This hypothesis remains to be proven.

Currently, the Gladstone investigators are examining the DNA from very large Turkish families to identify genes associated with lipid problems. In collaboration with the pharmaceutical company GlaxoSmithKline, a six-nation consortium is studying problems related to the metabolic syndrome, which combines low HDL levels, high triglyceride levels, hypertension, obesity, and diabetes. Turkish families are ideal for this sort of study because of their large size. In one family, for example, 171 members over four generations have been analyzed, and 45% have the metabolic syndrome. A goal of this study is to identify new drug targets that will raise HDL levels.

As it continues to evolve, the Turkish Heart Study surely demonstrates the wisdom in the words of the great Turkish statesman Atatürk that “Mankind is a single body.” By examining a specific population, the Gladstone scientists were able to extrapolate, from their findings in Turkey, general health guidelines for Americans and others around the world.