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Mutation in Inflammation-Related Gene Protects Against Nasal Polyps, Chronic Rhinosinusitis

NEW YORK (GenomeWeb) – A loss-of-function variant in a gene involved in inflammatory processes appears to protect against the development of nasal polyps and chronic rhinosinusitis, according to a new set of genome-wide association studies.

While nasal polyps are not malignant, they can cause nasal obstructions, runny nose, and postnasal drip. They are also a risk factor for chronic rhinosinusitis, or inflamed sinuses, which often occurs in combination with asthma.

Researchers from Amgen's Decode Genetics in Iceland conducted genome-wide association studies using almost 4,400 cases of nasal polyps, 5,600 chronic rhinosinusitis cases, and 700,000 controls. As they reported in Nature Genetics yesterday, they found a missense variant in the gene ALOX15 that affects the enzyme arachidonate 15-lipoxygenase and confers protection against both nasal polyps and chronic rhinosinusitis. 15-LO, the researchers added, could represent a possible drug target for nasal polyps and chronic rhinosinusitis.

"Our findings point to the potential of 15-LO inhibition as a target to exploit in an attempt to contain NP and CRS," Decode's Kari Stefansson and his colleagues wrote in their paper. "The absence of serious disease in homozygous carriers of the loss-of-function mutation in ALOX15 indicates that it may be safe."

The researchers conducted two GWAS of nasal polyps, one using 1,175 cases and 309,305 controls from Decode Genetics and one using 3,191 cases and 405,376 controls from the UK Biobank. A, meta-analysis of the data linked variants at 10 loci to nasal polyps.

They likewise performed two GWAS of chronic rhinosinusitis, using 3,188 cases and 353,939 controls from Iceland and 2,420 cases and 406,147 controls from the UK that they, again, combined in a meta-analysis. From this, the researchers identified signals at two loci that were linked to chronic rhinosinusitis and were also detected in the nasal polyp GWAS.

As asthma often co-occurs with nasal polyps — which the researchers noted can be difficult to treat — they also investigated whether these variants were more strongly tied to asthma, rather than just nasal polyps. When they stratified the nasal polyp population based on asthma status, they found that the 10 loci remained significant among the non-asthma nasal polyp cases, though they exerted a greater effect on cases with nasal polyps and asthma.

Nasal polyps are also often infiltrated with eosinophils, and the researchers examined in the Icelandic population whether there was a correlation between the loci they found and circulating eosinophils. Eight of the 10 loci were associated with eosinophil count, they reported.

One variant the researchers uncovered — a missense mutation in ALOX15 — was associated with a 68 percent reduction in nasal polyp risk and a 36 percent reduction in chronic rhinosinusitis risk. ALOX15 encodes 15-LO, an enzyme involved in inflammatory processes, specifically in the metabolism of polyunsaturated fatty acids like arachidonic acid, that is highly expressed in airway tissue. This missense mutation, p.Thr560Met, is associated with loss of 15-LO protein function and is linked among Icelanders to a decreased number of circulating eosinophils. 

This suggested to the researchers that the protective effect of this mutation is due to the inactivation of the 15-LO enzyme, which could lead to the reduced production of pro-inflammatory mediators.

As about 1 in 1,700 Europeans are homozygous for this missense mutation and don't appear to be at higher risk for other diseases, based on a phenome screen, the researchers said 15-LO inhibitors could be a viable treatment for nasal polyps and chronic rhinosinusitis.