The message, so odd before, is now standard. Some cholesterol is good, and low levels of high-density lipoprotein (HDL) have repeatedly been implicated in cardiovascular disease. When the ABC1 transporter was found to be associated in the HDL deficiency of patients with Tangier disease,
In 2004, Alan Tall's group at Columbia University identified the function of the ABCG1 transporter and clarified the role of large HDL particles in...
Good News, Bad News
Tall's study seemed to clarify the role of so-called CETP inhibitors, such as Pfizer's torcetrapib, which act downstream of ABCG1 to keep cholesterol from returning to the more dangerous low-density (LDL) form. Drug companies had already been considering one major problem: The drug caused enlarged HDL particles, the kind that scientists feared would be nonprotective because they wouldn't interact with ABCA1. Tall's study alleviated that concern, showing that the large HDL particles could protect people from cardiovascular disease, as the epidemiology suggested, by interacting with ABCG1 instead of ABCA1.
"Discovering ABCG1 not only explained the epidemiology, but it provided the basis of how this new class of drugs might prevent cardiovascular disease," says Philip Barter, director of the Heart Research Institute in Sydney.
Barter, who first identified CETP in 1978, says his drug development work was emboldened by Tall's discoveries. He had been working with Pfizer on torcetrapib, which had entered a Phase III trial of 15,000 people. But the high expectations for the drug were dashed early this past December. The trial and the development program were terminated when preliminary results indicated increased deaths and heart problems in subjects taking the drug.
Data derived from the Science Watch/Hot Papers database and the Web of Science (Thomson ISI) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age.
N. Wang et al., "ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins," Proc Nat Acad Sci, 101:9774-9, 2004. (Cited in 133 papers) J. Cohen et al., "Multiple rare alleles contribute to low plasma levels of HDL cholesterol," Science, 305:869-72 2004. (Cited in 116 papers)
Back to Sequencing
Hobbs' 2004 study may provide a way to define other targets. To identify rare variants that affect HDL levels, Hobbs' lab scrutinized three genes involved in HDL production. Her lab studied a sample group of 128 Dallas County residents, chosen from a population-based study, who had either the top 5% HDL levels in the study or the lowest 5% Hobbs identified specific alleles that contribute to low HDL levels in plasma. She also did a similar study using a Canadian population.
There have been many of these kinds of studies, says Joel Hirschhorn, geneticist at Children's Hospital Boston. "The difficult part is that if you look hard enough you can always find individual mutations." This study used good controls by sequencing people with high HDL levels and low HDL levels, says Hirschhorn, and considered the variants found in only one group but not the other.
While common variants have been shown to be involved in some diseases, less is known about rare variants. "Probably the reason why it's not known if rare variants have an impact, is because it's been so much harder to look for them," says Hirschhorn. Hobbs and her lab have demonstrated the effectiveness of their approach over the past few years. Using a similar strategy, they have identified sequence variants contributing to cholesterol absorption
Not only are rare alleles difficult to find, but it also costs a lot of money to hunt for them. Using Hobbs' approach as a guide, others are searching for them too. "They were the first people to do it so well and on a large scale," says Hirschhorn. And their work "sets the standard for how to do these studies."
Richard Gibbs, director of the Baylor Sequencing Center, calls her work "a demonstration of the power of this kind of data." His center has launched the "Human Channelopathy Project" to screen all 250 ion-channel genes in patients with varying degrees of epilepsy. "Anybody working on polymorphic loci or thinking about genetic variability would agree that rare variants could play some role. Hobbs' paper really kicked this idea into a new orbit" says Gibbs. He adds, "It's the new wave of genetic sequencing."
References
1. S. Rust et al., "Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1," Nat Genet, 22:352-5, 1999. 2. N. Wang et al., "ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins," Proc Nat Acad Sci, 101:9774-9, 2004. (Cited in 133 papers) 3. J. Cohen et al., "Multiple rare alleles contribute to low plasma levels of HDL cholesterol," Science, 305:869-72, 2004. (Cited in 116 papers) 4. J. Cohen et al., "Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels," Proc Nat Acad Sci, 103:1810-5, 2006. 5. J. Cohen et al., "Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9," Nat Genet, 37:161-5, 2005.Interested in reading more?
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