The genetics of blood cholesterol

“Genes, not diet, may increase your chances of getting heart disease,” says The Independent. The newspaper reports that a study has made an important breakthrough that helps to explain why some people are born with a high risk of heart disease while others seem to be able to eat fatty food with very little or no increased risk.

The study behind this news has produced some new insights into the body’s fat metabolism by identifying 95 mutations that affect cholesterol levels, including 59 that were previously unknown. The researchers say that, taken together, these 95 variations in our DNA account for between a quarter and a third of the genetic factors that govern lipid levels.

The more that is known about cholesterol regulation, the better positioned we are for developing new drugs to treat high cholesterol, or tests to identify those who may be at greater risk of developing heart disease. This comprehensive genetic study constitutes an important first step down the long road leading to these goals.

Where did the story come from?

The study was carried out by international researchers from 117 institutions. The seven authors who conducted the main data analysis came from the United States and Iceland. The study received funding from multiple external sources and was published in the peer-reviewed journal Nature.

The newspapers covered this complex study fairly, but differed in their interpretation of its importance. Some (The Guardian ) concentrated on the possibility of it generating new tests, while others (Daily Mail and The Daily Telegraph ) emphasised new treatments it might lead to. Some newspapers discussed both possibilities (The Independent ).

What kind of research was this?

In addition to environmental factors such as diet, a person’s genetics can influence the levels of cholesterol and fat in their blood. This study used several different approaches to identify genetic variations that can affect a person’s “lipid traits”, the distribution of cholesterol and fat levels in the blood. The approaches included a statistical pooling (meta-analysis) of data from 46 past genome-wide association studies, additional association studies and some animal research.

The lipids of interest were:

• total cholesterol (TC)
• low-density lipoprotein cholesterol (LDL-C, sometimes referred to as “bad” cholesterol)
• high-density lipoprotein cholesterol (HDL-C, sometimes referred to as good cholesterol)
• triglycerides (TG, another type of lipid)

Levels of these lipids in the blood, particularly the level of LDL-C, are known to be related to the risk of heart disease and stroke, and therefore drugs that can influence these levels may be able to reduce the risk of these outcomes.

Previous studies of this type have each involved up to 20,000 individuals of European ancestry and have in total identified over 30 genetic loci (specific areas within the genetic code) that together explain some of the variation in blood lipid concentrations seen between individuals. The researchers wanted to pursue three areas of enquiry:

• Are the loci identified in Europeans important in non-European groups?
• Are these loci of clinical relevance?
• Do these loci correspond with genes with “biological relevance” to (i.e. directly involved in) lipid regulation and metabolism?

What did the research involve?

The study designs featured a number of investigations, including:

• A meta-analysis of genome-wide association studies lipids in over 100,000 individuals of European ancestry from 46 previous studies carried out in Europe, Australia and the US.
• An additional association study that evaluated whether the significant variants identified in the meta-analysis of Europeans individuals also existed in other ethnic groups: it examined the genes of approximately 15,000 East Asians, 9,000 South Asians and 8,000 African Americans, as well as a control group of 7,000 additional Europeans.
• Another association study looking for the presence of these variants in 24,607 European individuals with coronary artery disease (CAD) and 66,197 without CAD to compare the links and associations previously found.
• Evaluation of the genetic variants in patients with extreme blood plasma lipid concentrations.
• Analysis of what is known about genes at or near to the loci identified.
• Genetic manipulation of some of these genes in mouse models.

In their meta-analysis the researchers tested the possible associations between levels of four lipid traits (TC, LDL-C, HDL-C, and TG levels) and a total of 2.6 million SNPs (single letter variations in the genetic code).

What were the basic results?

The researchers explain that in their meta-analysis of genome-wide association studies they identified 95 genetic loci that showed significant associations with at least one of the four lipid traits tested (TC, LDL-C, HDL-C or TG levels).

The links included 36 loci previously reported to be associated with lipid levels and 59 loci for which an association was being reported for the first time.  When they looked at links for each of the blood lipids in turn, they found among the 59 new loci:

• 39 demonstrated statistically significant associations with TC levels
• 22 with LDL-C levels
• 31 with HDL-C levels
• 16 with TG levels

These loci were estimated to account for 25 to 30% of the genetic variance seen in each trait.

The majority, but not all, of these loci also showed association with lipid levels in the non-European populations tested.

Only 14 of the variants showed an association with coronary artery disease. Most of the variants that did were linked to LDL-C levels, but a few were linked to HDL-C and TG levels. In the analysis of people with extreme blood plasma lipid concentrations, individuals with more lipid-increasing variants were more likely to fall in the high plasma lipid group than the low plasma lipid group.

Some of the genetic loci identified as being linked to plasma lipid levels lay near to genes that are known to cause inherited lipid disorders. Other loci lay near to genes targeted by drug treatments for high plasma lipids, or genes known to be involved in dealing with lipids in the body.

One of the genetic variants lay in a region of chromosome 1 that contains only one known gene, called GALNT2. The researchers looked at the role of this gene by genetically engineering mice to over-produce the GALNT2 protein produced by this gene in their liver (the liver plays a key role in regulating lipid levels in the body). They found that this over-production of GALNT2 caused the levels of HDL-C in the mice’s blood to reduce by 24% compared to normal control mice. They also carried out other experiments in mice to look at the role of some of the other genes, called PPP1R3B and TTC39B, which are found near to the loci identified. Both of these genes were also shown to play a role in the regulation of lipid levels in the blood.

How did the researchers interpret the results?

The researchers conclude that at least 95 loci across the human genome harbour common variants associated with plasma lipid traits in Europeans and in multiple non-European populations.

They also say that some of these loci are associated not only with lipid levels but also with risk of heart disease, and that the three lipid-related genes might directly act through an effect on lipid metabolism. This finding was also confirmed in mice.

Conclusion

This large study with multiple parts helps scientists to understand more fully why many people from different ethnic backgrounds have abnormal levels of cholesterol and other blood lipids that might lead to heart disease.

This study precisely identifies areas on the chromosomes that may contain important genes in lipid metabolism, and is the sort of advance that researchers will be able to use in the next stage of research. This will involve using further investigations of these regions of DNA and the genes they contain to help identify new targets for the development of new drugs.

While this was a thorough, multidimensional study, there are several other important tests that need to be performed before these exciting findings could possibly lead to the development of new drugs or clinical tests.