Rare Cystic Fibrosis Mutations Dominate in Caribbean Patients

NEW YORK – Cystic fibrosis patients from Puerto Rico and the Dominican Republic carry different genetic variants in the CFTR gene than most CF patients, a new sequencing-based study has found, which could impair their ability to benefit from screening or treatment with new targeted therapies.

While most of the 80,000 people across the globe who have cystic fibrosis are white, the percentage of CF patients who are Latino has climbed from 5.6 percent to 8.7 percent in the last 15 years, and the course of the disease is more severe for them. Alterations to the CFTR gene, which encodes a chloride channel, cause cystic fibrosis, and about 2,000 such mutations have been identified.

Researchers led by the University of California, San Francisco's Esteban Burchard sought to more fully characterize CFTR gene alterations found among CF patients living in Puerto Rico and the Dominican Republic. As they reported yesterday in the journal Pediatric Pulmonology, they sequenced the genomes of patients from those locations and found that they rarely carried the most common CFTR mutations, which could have implications for disease screening and treatment.

"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," Burchard, a pulmonologist and professor of bioengineering and therapeutic sciences at UCSF, said in a statement.

Burchard and his colleagues sequenced the genomes of 21 Puerto Rican and 61 Dominican CF patients, representing most of the CF patients from those islands. Overall, the uncovered 30 CFTR variants: 16 CF-causing variants, four variants with differing clinical effects, six variants of uncertain significance, and four that were predicted to be deleterious.

No variants were detected, though, in 69 percent of Dominican and 10 percent of Puerto Rican patients, even though they exhibited clear symptoms of the condition.

The most common CTFR variant among the general CF patient population — p.Phe508del, which is present among nearly 90 percent of CF patients in the US — occurred only in 33 percent of Puerto Rican and 10 percent of Dominican patients, they reported.

At the same time, variants that are rare in the general CF patient population were more prominent in Puerto Rican and Dominican patients. For instance, the p.Ile507del alteration occurred in about 14 percent of Puerto Rican CF patients, as compared to 0.8 percent of the general CF population.

Similarly, the p.Arg344Trp alteration was also found in 14 percent of Puerto Rican CF patients and in 3 percent of Dominican CF patients, but is only found in 0.3 percent of the general CF population.

Not only did the distribution of CFTR variants differ between the Caribbean CF population and the general, predominantly Caucasian CF population, but it also differed between various Latino populations. The researchers noted that in the US, 37 percent of Latino CF patients have the p.Phe508del alteration and 11 percent have the p.Gly542x or p.Arg334Trp alterations. In the Southwest, 47 percent of Latino CF patients have the p.Phe508del alteration and 5 percent have the p.Gly542x alteration.

These differences in CFTR variant proportions between Caribbean and US Latino populations could be due to differences in their African ancestries, the researchers noted. This, they said, highlights the need for investigating population-specific CFTR variants.

Many of the variants the researchers uncovered in the Caribbean populations are not included on newborn screens, making such screens less effective for Latino populations, the researchers noted. Additionally, new CFTR modulator treatments that target the effects of certain CFTR variants are only approved for certain mutations that have been tested in trials, underscoring the need to recruit diverse patients to participant in clinical trials.

"If people with different mutations aren't being included in those trials, they're never going to benefit," co-first author Meghan McGarry of UCSF said in a statement. "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."

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