In Caribbeans cystic fibrosis (CF) is driven by very rare CFTR mutations

Last Updated on November 5, 2019 by Joseph Gut – thasso

November 03, 2019 – Cystic fibrosis (CF) is a lethal, inherited genetic disease affecting more than 70,000 people worldwide. It is usually diagnosed in childhood and causes abnormal buildup of thick mucus in the lungs and digestive tract that leads to trouble breathing, chronic infections, malnutrition, and liver disease. People with CF typically die young, though the development of prenatal and infant genetic screening for the disease and new pharmacogenomic therapies, i.e., drugs targeted to patients’ specific gene mutations, have increased patients’ average life expectancy to nearly 40.

Most CF cases are caused by one or more mutations in a gene called CFTR, which codes for a chloride channel protein that plays a key role in hydrating the body’s mucus membranes. Scientists have so far identified more than 2000 different mucus-thickening CFTR mutations in CF patients, some occurring in as many as 90 percent of patients and others much rarer.

However, there are significant disparities in who has benefited from the dramatic improvements in health outcomes for CF patients. For instance, patients of Latino descent, who now represent nearly nine percent of CF cases, experience more severe symptoms and die earlier than Caucasian CF patients. They are also, unfortunately, severely underrepresented in CF clinical trials, according to previous research and confirming a obvious bias towards patients of Caucasian descent in clinical research.

The latter is a serious problem in today’s precision and personalised medicine, in that many of the findings in the field primarily apply to patients and patients populations of Caucasian descent, because other ethnicities have been largely underrepresented in the according studies. A good example of this situation would be the case of Caribbean CF patients, where researchers / physicians have noted that as many as 25 percent of patients of Caribbean descent with symptoms of CF were testing negative for the disease in standard screens for the most common CF mutations. This means that these patients, if it hadn’t been for their clear clinical symptoms would have been called CF-free based on the current standard genetic test for CF.

But no, they are not at all CF-free. Quite to the contrary: It turned out that CF in Puerto Rico and the Dominican Republic is dominated by unusual gene mutations not often observed in previously studied CF populations, according to comprehensive genome sequencing in these patients. Remarkably, as rare mutations drive CF in Caribbeans, a majority of Dominican patients had none of the known functional mutations in the CF gene that are seen in 95 percent of CF cases. Thus, the researchers discovered that most common CFTR mutations in the general population were quite rare in Puerto Rico and the Dominican Republic. For example, the most common CF mutation in the world, called p.Phe508del, is present in nearly 90 percent of CF patients in the US, but occurred in only 33 percent of Puerto Rican patients and 10 percent of Dominican patients. Even mutations seen more commonly in Latinx CF patients in the mainland US were present at much lower rates in the Caribbean.

As a result of these findings, one has to expect that minority CF patients auch as Puerto Ricans and Dominicans are less likely to be diagnosed by genetic panels that screen for better-studied CF mutations, and most cannot yet benefit from the new generation of targeted CF drugs, which the US Food and Drug Administration (FDA) only approves for patients with specific mutations that have been tested in formal clinical trials and which have led to three types of so-called CFTR modulator treatments have been developed to target the distinct biology of a handful of common CTFR mutations such as i) help cells produce more CFTR proteins, ii) fix misfolded CFTR proteins so they can reach the cell surface, and iii)  boost the protein’s ability to hydrate mucous membranes. For some patients these new therapies have turned a disease that used to be a death sentence into a liveable condition and in some cases almost a cure.

These data illustrate one of the big challenges of personalized medicine: it only works if you are including diverse groups in your studies; otherwise it just reinforces existing racial and ethnic health inequalities.

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