Dosage adjustment of common medications may be needed if you carry a variant of the Neanderthal gene

The Pharmacogenomics Journal (2022). DOI: 10.1038/s41397-022-00284-6″ width=”800″ height=”530″/>

Phylogeny of sequences covering the genomic region encoding CYP2C8*3 and CYP2C9*2. The tree contains five haplotypes from five current Yoruban individuals (a Nigerian population with minimal Neanderthal gene flow), one haplotype from an individual of European ancestry carrying CYP2C8*3 and CYP2C9*2, and four Neanderthal sequences and their sister group of Denisovans. The sequence with CYP2C8*3 and CYP2C9*2 alleles is most similar to the corresponding sequence of a Neanderthal from Chagyrskaya Cave in Siberia [11]. Numbers indicate bootstrap support (1000 repeats). Scale bar shows mutations per site. The haplotypes span the chr10 genomic region: 96,537,863–96,851,277 (hg19). Credit: The Pharmacogenomics Review (2022). DOI: 10.1038/s41397-022-00284-6

For a drug to be effective and not harmful, it must be given at the right dose. Certain enzymes in the body eliminate drugs and the activity of these enzymes varies from individual to individual. Researchers from the Max Planck Institute for Evolutionary Anthropology in Germany and the Karolinska Institute in Sweden have studied two enzyme variants that are less efficient at eliminating drugs and show that these enzyme variants are inherited from Neanderthals.

Precision medicine aims to personalize health care, with treatments adapted to each patient. The hope is that patients will be prescribed drugs in the right dosage, which are right for them, based on genetic and other factors. It is well known that genetic variants in the genes encoding enzymes of the cytochrome P450 family affect the efficiency of these enzymes.

In this study, published in The Pharmacogenomics Review, a team of researchers has discovered that two of the most important genetic variants influencing the ability to eliminate drugs are inherited from Neanderthals. These variants are worn by 20% of current Europeans.

The study, led by Hugo Zeberg, a researcher in the Department of Neuroscience and the Max Planck Institute for Evolutionary Anthropology, Karolinska Institutet, and Svante Pääbo, director of the Max Planck Institute for Evolutionary Anthropology, identified a segment of DNA inherited from Neanderthals, carrying two cytochrome P450 enzymes. These enzymes eliminate many common drugs such as warfarin, a blood thinner, phenytoin, an antiepileptic, statins, cholesterol-lowering drugs, and common painkillers, such as ibuprofen. Neanderthal variants of enzymes are generally less effective at removing drugs.

“This is a case where the mixture with Neanderthals has a direct clinical impact. Otherwise, therapeutic doses can be toxic for carriers of the Neanderthal gene variant”, explains Hugo Zeberg.

Neanderthals were a group of archaic humans who populated Europe and Asia before the arrival of modern humans. When modern humans and Neanderthals met 60,000 years ago, they intermingled. As a result, people with roots outside of Africa carry 1-2% of their Neanderthal genome.

Modern humans have developed more effective protection against oxidative stress

More information:
Sigrid Haeggström et al, The clinically relevant CYP2C8*3 and CYP2C9*2 haplotype is inherited from Neanderthals, The Pharmacogenomics Review (2022). DOI: 10.1038/s41397-022-00284-6

Provided by Karolinska Institutet

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