NEW YORK (Reuters Health) - Researchers have identified two nonsense mutations in proprotein convertase subtilisin kexin 9 (PCSK9) that are common in individuals of African descent and are associated with a 50% reduction in plasma low-density lipoprotein (LDL) cholesterol.
It has been shown previously that missense mutations in PCSK9, which are probably gain-of-function mutations, cause hypercholesterolemia with raised LDL-C levels, which probably results from of a reduction in LDL receptor (LDLR) number, according to studies conducted in mice. (See Reuters Health report April 30, 2004).
To see whether loss-of-function mutations in PCSK9 have the opposite (hypocholesterolemic) effect, Dr. Jonathan Cohen and colleagues from the University of Texas Southwestern Medical Center at Dallas sequenced the coding region of PCSK9 in 128 adults with low plasma LDL levels in the Dallas Heart Study. Fifty-two percent of the subjects were African American.
Two nonsense mutations in PCSK9 -- Y142X and C679X -- were common in African Americans, with a combined frequency of 2%, but rare in European Americans (< 0.1%), they report in the January 16th advance online issue of Nature Genetics.
They noted a similar frequency of these two PCSK9 mutations in an independent population-based cohort of 850 African Americans from Cook County, Illinois.
In the Dallas cohort, carriers of the nonsense mutations had sharply lower LDL-C and total cholesterol levels compared with noncarriers (p < 0.001). In contrast, mean plasma levels of triglycerides and HDL-C were similar in individuals with or without these specific mutations.
“The nonsense mutations in PCSK9 probably reduce plasma levels of LDL by increasing the number of LDLRs,” the investigators write. They emphasize, however, that more study is needed to clarify the mechanistic link between the nonsense mutations identified and the LDL reductions observed.
Dr. Cohen’s group also notes in their report that the two PCSK9 nonsense mutations identified are “the most common sequence variants yet described to have large effects on plasma cholesterol levels.”
Nature Genet 2005. doi:10.1038/ng1509.
MeSH Headings:Behavioral Sciences: Data Collection: Demography: Behavioral Disciplines and Activities: Environment and Public Health: Epidemiologic Methods: Health: Health Occupations: Health Services Administration: Information Science: Medicine: Investigative Techniques: Morbidity: Population Characteristics: Preventive Medicine: Public Health: Quality of Health Care: Social Sciences: Specialties, Medical: Vital Statistics: Epidemiologic Measurements: Prevalence: Health Care Quality, Access, and Evaluation: Health Care Evaluation Mechanisms: Codon, Nonsense: Analytical, Diagnostic and Therapeutic Techniques and Equipment: Anthropology, Education, Sociology and Social Phenomena: Biological Sciences: Health Care: Information Science: Psychiatry and PsychologyCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
