Latinos in the Caribbean with cystic fibrosis (CF) carry rare CFTR gene mutations not often seen in Latin or other CF populations elsewhere, a study led by physician-scientists at the University of California, San Francisco (UCSF) found.
CF patients in Puerto Rico and the Dominican Republic have CFTR mutations that are present in less than 1% of the general CF population. No typical disease-causing mutations were detected in a majority of Dominican patients, despite the fact they had clear symptoms of CF.
Genetic tests and new therapies targeting CFTR mutations are unlikely to benefit these patients, who tend to be underrepresented in studies and clinical trials, the researchers added.
These findings are detailed in the study “Identification of CFTR variants in Latino patients with cystic fibrosis from the Dominican Republic and Puerto Rico,” published in the journal Pediatric Pulmonology.
CF is caused by one or more mutations in the CFTR gene. The disease manifests only if both CFTR gene copies are mutated, the one inherited from the mother and the one from the father.
Over 2,000 mutations have been described in the CFTR gene, some widespread, others rarer. In general, these mutations are well-characterized in Caucasian populations, but other ethnic groups have few or no genetic studies.
These differences may underly the disparities seen in health outcomes of different CF populations. For instance, Latino CF patients, who currently account for nearly 9% of CF cases, have more severe symptoms and die earlier than Caucasians. They are also poorly represented in clinical trials.
Recognizing this gap, researchers investigated CFTR mutations in patients from the Dominican Republic and Puerto Rico, whose genetics have never been described.
The study was conducted after José Rodríguez-Santana, MD, a study author and a CF expert at Centro de Neumología Pediátrica in San Juan, Puerto Rico, realized that as many as 25% of CF patients in this U.S. territory tested negative on standard genetic screens for CFTR mutations.
The team sequenced the entire genomes of 61 Dominican Republican patients, and 21 Puerto Rican patients — most of the CF patients on the two islands.
Researchers found that CFTR mutations common in the general population were indeed quite rare in Puerto Rico and the Dominican Republic. Most frequent mutations in Dominican patients were F508del and p.Ala559Thr, and for Puerto Rican patients were F508del, p.Arg1066Cys, p.Arg334Trp, and p.I507del.
Only 19 of the mutations identified in Dominicans had been previously identified, accounting for 25 out of 122 gene copies in the population (20%). In Puerto Rican patients, 16 CFTR mutations were known, accounting for 36 out of 42 gene copies (86%).
“The gene mutations we observed most frequently in Puerto Rican and Dominican CF patients are much rarer in the predominantly Caucasian CF population at large, and haven’t yet been included in standard genetic screens or investigated as therapeutic targets,” Esteban Burchard, MD, MPH, a pulmonologist and professor at UCSF, and one of the study’s authors, said in a university news release written by Nicholas Weiler.
The most common CF mutation in the world, found in nearly 90% of patients in the U.S. and called F508del, was present in only 33% of Puerto Rican patients, and 10% of Dominican patients.
Even more striking, no mutations disturbing the function of CFTR could be detected in 69% of Dominican patients and 10% of Puerto Rican patients.
“This was remarkable because outside of the Dominican Republic 95 percent of patients have one or more functional CFTR mutations,” said Meghan McGarry, MD, a pulmonologist and professor at UCSF, and a leading study author.
Researchers speculated that some of the mutations in Caribbean patients may be DNA alterations hidden in noncoding parts of the genome, which are normally not analyzed in genetic studies. The team is now trying to spot these DNA variants.
These findings also raise another issue, as CFTR modulator treatments, which have revolutionized CF care, target the most common CF-associated mutations, and thus mainly benefit “the Caucasian patients in whom CF genetics has been best studied,” Burchard said.
The researchers urge companies and scientists to launch more diverse trials that include not only Caucasians but other patient populations as well, in a bid to find therapies that fit all.
“If people with different mutations aren’t being included in those trials, they’re never going to benefit,” McGarry said. “This is one of the 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 inequality.”