Study links gout blood marker to higher risk of PAH in Europeans
Study in people of European ancestry supports genetic association
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Elevated blood levels of uric acid, a substance often associated with gout, are associated with a higher risk of pulmonary arterial hypertension (PAH) in people of European ancestry, a study suggested.
“Our study supports a positive genetic association between [blood uric acid] and PAH risk,” the researchers wrote. “Further research is needed to elucidate the underlying biological mechanisms and confirm these findings in diverse populations.”
The study, “Genetically predicted serum uric acid and pulmonary arterial hypertension: Mendelian randomization with an exploratory NHANES risk-burden analysis,” was published in Science Progress.
PAH is a rare condition in which the blood vessels in the lungs progressively narrow, leading to increased resistance to blood flow, elevated blood pressure, and strain on the right side of the heart. While newer, targeted pulmonary hypertension therapies have improved survival for some patients, treatment costs remain high, and many patients do not receive timely care. Finding biomarkers that can identify and predict outcomes in the early stages of PAH “appears to be urgent,” the researchers wrote.
Uric acid is a metabolic breakdown product long associated with gout (a type of inflammatory arthritis) and kidney stones. Over the past decade, elevated uric acid in the bloodstream has also been linked to a range of cardiovascular and metabolic conditions, including high blood pressure, heart failure, and diabetes.
Establishing a connection
Some observational studies have suggested a link between uric acid and PAH, but these findings haven’t established whether uric acid causes PAH or is merely coincidental.
To address this gap, researchers used Mendelian randomization (MR), a method that leverages genetic variants to estimate the causal effect of an exposure (in this case, uric acid) on an outcome (PAH).
The team collected publicly available data on 389,404 participants from a European ancestry uric acid genome-wide association study (GWAS), a large-scale analysis that identifies genetic variants associated with specific traits. PAH outcome data were obtained from a GWAS of 2,085 PAH patients and 9,659 healthy controls, also of European ancestry.
According to the analysis, a genetically predicted higher level of uric acid in the bloodstream was significantly associated with a 31% greater risk of PAH.
The scientists used a second uric acid GWAS involving 343,836 participants of European and East Asian ancestry. The researchers said they used this dataset as exploratory, secondary evidence because its ancestry composition did not fully match that of the PAH GWAS. It showed that higher uric acid levels were significantly associated with a 52% higher risk of PAH.
The authors emphasized that this result was not pooled with the European results and “should not be interpreted as formal replication or as a combined causal estimate” because of the ancestry mismatch.
The study also assessed data from the U.S. National Health and Nutrition Examination Survey (NHANES). Because NHANES doesn’t include a confirmed PAH diagnosis, the team created an exploratory “PAH-related risk-factor burden” profile using related factors such as systemic hypertension, diabetes, age, obesity, and sex.
Among the 15,835 NHANES participants with complete data, 2,668 were classified as having a higher PAH-related risk-factor burden and 13,167 as having a lower burden.
Participants in the higher-burden group had significantly higher uric acid levels than those in the lower-burden group. After adjusting for sex, age, and body mass index (BMI, a measure of body fat content based on weight and height), high uric acid was linked to a 71% higher PAH risk.
The team noted that because this risk-factor burden profile was not a validated PAH diagnosis, “these findings were interpreted only as descriptive and exploratory.”
The researchers discussed several biological pathways that could plausibly explain why elevated uric acid might contribute to PAH. These include damage to the cells lining blood vessels, impaired signaling of nitric oxide, which helps keep blood vessels relaxed and open, inflammation, and oxidative stress, or damage caused by unstable molecules called reactive oxygen species.
“Our study supports a positive genetic association between higher [uric acid] and increased PAH risk based on MR analysis,” the researchers concluded. “Further studies are needed to confirm these findings in populations of different ancestry and to elucidate the underlying biological mechanisms.”
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