About a decade ago, scores of people were faced with a frightening diagnosis: They had genetic mutations that increased their risk of developing hypertrophic cardiomyopathy, a thickening of the heart muscles that can lead to sudden death. The good news, says American doctor Alexander Bick, is that it was a lie. The test, based on genetic data from white patients, was wrong. In these blacks, the mutations were harmless. Bick's team takes a big step this Monday to correct these errors, suddenly releasing nearly 250,000 complete genomes, the vast majority of which come from groups traditionally ignored in these types of studies. “It is a unique opportunity to understand how genes influence human health,” he says.
The initiative is part of the All of Us scientific project, a program of the National Institutes of Health in Bethesda (USA) with the ultimate goal of reading the genomes of more than a million Americans. Almost half of the 250,000 genomes read so far come from “underrepresented racial and ethnic minorities.” A quarter also come from volunteers who live below the poverty line. And one in four people are people over 65 years of age. Analysis of this unpublished material has already revealed the existence of 275 million unknown genetic variants. “Each of them offers potential new clues to understanding and curing some of the world's most serious diseases,” says Bick of Vanderbilt University in Nashville.
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The doctor gives an example from his laboratory. His team used the immense diversity of the project to find a mutation that protects against chronic kidney disease linked to the APOL1 gene, a phenomenon more commonly seen in people of African descent. “The combination of disease-causing and protective mutations is very unusual and occurs in fewer than one in 200 African Americans. “To solve these complicated puzzles, it is very important to have very large data sets, not just diverse ones,” argues Bick .
The National Institutes of Health began recruiting volunteers in 2018 to increase the diversity of other similar projects such as the UK Biobank. “We know that DNA is one of the many factors that influence health. There are also many social factors, such as poverty. “In the past, many participants in research studies were middle class, so it was difficult to study how these social factors interact with genetic factors,” explains the American researcher. Their findings will be published this Monday in the journal Nature, the flagship of the world's best science.
Doctor Eliseo Pérez-Stable directs the National Institute on Minority Health and Health Disparities, a Bethesda-based organization that aims to “improve the health of minority and disadvantaged populations.” Pérez-Stable himself was born in Cuba and emigrated to the United States with his family at the age of 8 after the Cuban Revolution. The doctor highlights the historical lack of diversity in genomic research, confirming that more than 90% of studies have been conducted on populations with European ancestry.
Medications that don't work
Pérez-Stable recalls the case of clopidogrel, an antiplatelet drug used to prevent blood clots in patients who have suffered a heart attack or stroke, or who suffer from poor circulation in the arms and legs. “Clopidogrel doesn't work if a person has a genetic change that affects how the drug is processed.” And it turns out that the majority of people of Hawaiian or Pacific ancestry don't process it, so it doesn't work as advertised in those populations works,” warns the Cuban-American doctor. Three years ago, a court ordered pharmaceutical companies Bristol Myers Squibb and Sanofi to pay nearly 800 million euros to the state of Hawaii to market clopidogrel in the archipelago, “knowing that it was not effective in many patients,” it said there is a statement from the public prosecutor's office.
The director emphasizes that science has made great discoveries by including different populations in genetic analyses. In 2014, Pérez-Stable herself participated in a study that identified a specific mutation (6q25) that reduces the risk of breast cancer by 60% and is found only in Latin American women of indigenous ancestry.
The doctor remembers another case. The latest drugs to lower bad cholesterol – the so-called PCSK9 inhibitors – were discovered thanks to an African-American family with very low levels of this substance in their blood. A team of researchers led by American doctor Helen Hobbs developed drugs to replicate the effect seen in the family.
If you think of DNA as a string of chemical letters with instructions for how a person functions, epigenetic changes would be like accent marks that change the message and can cause diseases like cancer. Pérez-Stable emphasizes that living conditions such as poverty can cause epigenetic changes. “There are only a few studies that have the potential to capture this phenomenon, and this project is one of them,” he says happily.
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