A new study published by researchers at the Perelman School of Medicine at the University of Pennsylvania, the Broad Institute, and Massachusetts General Hospital, challenges the conventional concept that raising a person's HDL levels (good cholesterol) will always help lower their risk of a heart attack. In the study, published in May 17 edition of The Lancet, the research team analyzed previously identified DNA sequence variations (also known as single nucleotide polymorphisms, or SNPs) directly associated with elevated HDL levels in humans. After analyzing the genes of roughly 170,000 individuals, the team discovered that none of these established genetic variations actually reduced the risk of heart attack.

"The concept that genetic data can directly test the relationship between a biomarker like HDL to heart attack is an extremely potent one. Through our research, we have found that all roads that raise HDL do not always lead to the promise land of reduced risk of heart attack," said Benjamin F. Voight, PhD, assistant professor of Pharmacology at Penn and lead author of the new study. "These data have important implications for future development of therapies based on raising HDL levels."

The new study consisted of two stages. First, using a Mendelian randomization design — a powerful means of testing connections between genes, biomarkers, and disease — with data from six prospective cohort studies, they tested the association of heart attack with a single SNP known to substantially raise plasma HDL-C in the protein code of a gene called endothelial lipase (shown to be a major genetic determinant for concentration, structure, and metabolism of HDL). Second, combining the cohort data with additional large, case-control studies, the research team tested a set of recently discovered HDL-associated SNPs for correlation with heart attack risk.

They found that carriers of the protein-coding change in the endothelial lipase gene had increased HDL by about 10 percent, an elevation expected to decrease heart attack risk by 13 percent. However, the study found that these same carriers had a similar risk of heart attack compared to non-carriers. The team evaluated a panel of 14 additional sequence variants, also exclusively associated with higher HDL, and devised a score that ranked individuals from lowest to highest HDL. They found no association between genetic elevation of HDL as measured by the score and risk to heart attack.

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