Higher levels of certain fat molecules in the body may increase ALS risk
New genetic study highlights fat metabolism as 'pathway in ALS susceptibility'
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- A new genetic study links higher levels of specific fat molecules to increased ALS risk.
- Fat metabolism in the body was identified as a relevant pathway in ALS susceptibility.
- The scientists say further research is needed to understand the biological mechanisms underlying this risk.
Abnormal levels of certain fatty molecules in the body — which are broken down by metabolism to support daily functions —may increase the risk of amyotrophic lateral sclerosis (ALS), according to a new study.
The research, which was based on genetic data to reduce the influence of external factors, “provides genetic evidence supporting potential associations between specific lipids [types of fat molecules] and ALS risk,” the researchers wrote.
While the findings do “not directly establish biological mechanisms or therapeutic targets,” they do “highlight lipid [fat] metabolism as a relevant pathway in ALS susceptibility,” the team noted.
The study, “Unraveling the role of lipid metabolism in ALS risk: a Mendelian randomization analysis using GWAS data,” was published in the Orphanet Journal of Rare Diseases.
ALS is a neurological disorder in which motor neurons, the nerve cells that control movement, become gradually damaged and die. The causes of ALS remain obscure, and risk factors for the disease are only partially understood.
Turning to genetics to understand ALS risk
Fat molecules, more formally known as lipids, play vital roles in the health of nerve cells. In addition to acting as a source of energy, lipids are crucial for maintaining the cellular membrane and allowing nerves to efficiently send electrical signals.
There’s some research suggesting that abnormalities in lipid metabolism — that is, how the body processes different fats — may contribute to ALS. However, studying the role of lipids in ALS is complex because there are many different factors that can affect both lipid levels and ALS risk. More specifically, genetic differences, environmental exposures, and lifestyle habits all may play a role.
This complexity means that traditional observational studies are at high risk of confounding, a statistical phenomenon in which results are heavily influenced by external variables.
Another issue with studying lipids in ALS is the problem of reverse causation, meaning it’s often impossible to tease out cause-and-effect relationships. For example, if a study finds that ALS patients have elevated levels of a certain fatty molecule, it’s possible that the fat molecule helps drive ALS. But it’s equally plausible that nerve damage in ALS triggers an increase in that fat molecule.
Now, to get around these limitations, a team of scientists in China employed a type of genetic analysis known as Mendelian randomization (MR). In simple terms, MR uses naturally occurring genetic variants as a proxy for different traits — in this case, ALS risk and lipid levels.
Here, the researchers then looked to see whether genetic variants associated with higher or lower levels of certain lipids are also associated with a higher risk of ALS, thus implying a cause-and-effect relationship between those lipid levels and disease risk.
“Because genetic variants are randomly allocated at conception and remain stable throughout life, MR can reduce confounding and reverse causation compared with conventional observational studies,” the scientists wrote.
Work IDs fat species for further investigation
According to the team, “this study applied two-sample MR to investigate the potential association between genetically predicted lipid traits and ALS risk, with the aim of identifying lipid species that may warrant further mechanistic investigation.”
Their MR analysis specifically used a database involving 7,174 Finnish participants. The goal was to pinpoint which specific genetic variants naturally cause higher or lower levels of 179 distinct lipid molecules in the blood.
Then, the researchers used a large international database to compare 29,612 people with ALS against 122,656 healthy individuals, who served as controls. The team sought to determine which genetic variants are linked to developing ALS.
The results showed that genetically predicted higher levels of several lipid molecules — diacylglycerol, phosphatidylcholine, phosphatidylethanolamine, and triacylglycerols — were also associated with a higher ALS risk.
“These findings suggest that lipid metabolism may be involved in ALS susceptibility and identify candidate lipid species for future mechanistic investigation,” the researchers wrote.
The scientists noted that, although MR can help solve some problems associated with traditional observational studies, this type of genetic analysis has its own limitations.
In particular, MR analyses rely heavily on previous studies that identified genetic risk markers — and for both ALS and lipid levels, those studies mostly involved people of European descent. As such, it’s unclear whether these results may apply to other ethnic groups, the team noted.
The researchers also stressed that additional studies are needed to better understand the potential biological effects of these different types of lipids in ALS.
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