Some of us are part Neanderthals, and this may affect how a person metabolizes drugs

(ORDO NEWS) — Living on the blood-thinning drug warfarin involves carefully calculating each dose. Too little – and the drug may be ineffective. Too much – and there is a risk of uncontrolled bleeding.

According to a recent study, those of us who share genes with one of our closest relatives, the Neanderthal, may face a more difficult process of achieving balance.

Researchers’ discovery that the enzyme variants responsible for breaking down cholesterol-lowering drugs like warfarin, ibuprofen and cholesterol-lowering statins are so ancient in origin could help explain why we don’t all respond to the same drugs in the same way.

“This is one of the cases where mixing with Neanderthals has a direct impact in the clinic. Otherwise, therapeutic doses can be toxic for carriers of the Neanderthal gene variant,” says lead researcher of the study, evolutionary geneticist Hugo Seberg from the Swedish Karolinska Institute.

Advances in genetic sequencing have revealed the extent to which our direct ancestors – those who wandered to every corner of the globe for tens of thousands of years – paused to create families with previous groups of migrants along the way.

The legacy of the genes passed down from this mixing has yet to be fully appreciated, although year by year researchers are finding hints about how genes evolved in long-extinct populations may contribute to differences in our own biology.

In many cases, these differences can be quite trivial. But when it comes to how an ancestral form of an enzyme or protein channel affects our health, it can be important to know as much as possible about its evolution.

CYP2C9 is the gene that codes for cytochrome P450, a superfamily of enzymes in the liver that break down a wide variety of drugs that we commonly use to treat everything from inflammation to epilepsy.

It also comes in many forms, each of which is the result of one of 20 unique CYP2C9 encodings.

Of course, some of these structural variations are better at metabolizing drugs than others, which means that the version of CYP2C9 you inherit can determine how long your drug dose stays in the body.

In fact, one type, called CYP2C9*2, is 70 percent less active than the more common CYP2C9*1 gene variant, meaning that CYP2C9*2 carriers may metabolize some drugs more slowly.

It appears that CYP2C9*2 is quite common with other variants classified as CYP2C8*3, especially in the same families. This would not be so strange if not for the fact that they are separated by tens of thousands of DNA bases.

Knowing that other examples of commonly occurring gene variants located far apart on our chromosomes are rooted in Neanderthal genomes, Seberg and colleagues compared sequences taken from 146 families to see how they differ from similar code points in genetic bases. data representing other modern and ancestral populations.

They found that a stretch of DNA containing two variants of the cytochrome gene that codes for cytochrome P450 was close enough to the Neanderthal version that the two genes were almost certainly passed on when our family lines intermingled tens of thousands of years ago.

The researchers note that this finding may not have much of an impact on how we treat people on medications like warfarin or statins. Specialists are already closely monitoring how we process “fastidious” drugs, using frequent blood tests to make sure dosages are within reasonable limits.

Tracing the origin of variations in such important enzymes can give us a better understanding of the environment in which they evolved, adding context that will help us understand the diversity of health we see today.


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