New Papers from Nature Genetics Yield a Bounty of Cholesterol SNPs

The online publication of three papers by Nature Genetics this week has roughly doubled the number of genetic locations associated with levels of cholesterol and triglycerides in the blood.

With the addition of so many new SNPs, researchers have a wealth of opportunities to better understand how the body regulates cholesterol and triglyceride levels, find new targets for drugs to control them, and identify people who are at increased risk of cardiovascular disease.

Two of the Nature Genetics papers combined data from a number of previous studies to increase their statistical power to detect SNPs associated with cholesterol and triglyceride levels. One looked at between 17,798 and 22,562 European subjects (depending on the specific measurement being examined) and found six genes or locations on five chromosomes that were significantly associated with total cholesterol, HDL, LDL, or triglycerides. The other studied 20,623 people from Europe and the United States, and identified 11 genetic regions that were not previously known to be associated with cholesterol or triglyceride levels.

The third paper found five genetic regions associated with cholesterol or triglycerides in a cohort of 4,763 people born in northern Finland in 1966.

A number of the new associations were located near places in the genome where rare mutations are already known to completely disable cholesterol-regulating genes, causing serious disruptions in cholesterol metabolism. The newly discovered SNPs apparently cause much subtler effects, however; in most cases, they appear to modulate the activity of the genes they affect.

The authors of one study (Kathiresan et al.) also provided evidence that seven of their new SNPs modulate the expression of genes in the liver, where cholesterol is produced.

In spite of their success in both discovering new genetic locations associated with cholesterol and triglyceride levels – the papers also replicated virtually all previously known associations as well – the value of all this information for personal genomics is somewhat limited. After all, blood levels of cholesterol and trigylcerides are themselves indicators of cardiovascular disease risk. Knowing a person’s genetic risk on top of their actual cholesterol levels provides only an “incremental” amount of additional information, Kathiresan et al. wrote.

Even so, Kathiresan et al. developed an “allelic dosage score” that consisted of a person’s number of elevated-risk genotypes out of 32 previously known and newly discovered SNPs. Study subjects with scores in the top tenth of the distribution were more than twice as likely to have LDL cholesterol about 160 mg/dl, HDL cholesterol below 40 mg/dl and trigylcerides above 200 mg/dl.

Researchers still have captured only a small fraction of the gene variation that explains why one person’s cholesterol level is higher or lower than the next person’s. The authors of the Finnish study, who found one cholesterol-increasing version of the AR gene that was present in less than 2% of subjects, suggest that much of that unknown risk may lie in similarly rare variants.