Genes, Air Pollution Combine to Raise Lupus Risk

Exposure to high levels of common air pollutants significantly increased risk for new-onset systemic lupus erythematosus (SLE), and dramatically more so for people with known genetic risk markers, U.K. Biobank data indicated.

Analysis of some 460,000 people in the British healthcare database showed increases of 18%-27% in the likelihood of developing SLE for each step in quartiles for estimated exposure to particulate matter and nitrogen oxides, according to Jian Yang, PhD, of China Three Gorges University in Yichang, China, and colleagues.

Moreover, for those classified as having high genetic risk and who experienced high levels of four major pollutants — PM_2.5 and PM₁₀ (particulate matter 2.5 μm or less and 10 μm or less, respectively), nitrogen dioxide (NO₂₎, and any nitrogen oxide species (NO_x) — increases in SLE risk ranged from 316% to 461% relative to those with low genetic risk and pollution exposure, the researchers reported in Arthritis & Rheumatology.

These massive increases were driven largely by genetic risk. People rated high for this factor still faced quadrupled lupus risk even with low exposure to particulates and nitrogen oxides. In contrast, risk increases of about 30%-90% were estimated for people with low genetic risk and high pollution exposures, and these either fell short of statistical significance or were borderline.

Confidence intervals in general were quite broad, insofar as out of those 460,000 people, just 399 developed SLE during a median of 11.8 years of follow-up.

In consequence, Yang and colleagues were suitably cautious in their interpretations of the data. “Additional cohort studies are needed to elucidate the relationship between specific air pollutants and the development of SLE,” they wrote.

“In addition, the underlying biologic mechanisms linking air pollution exposure to SLE pathogenesis need to be further explored. Given that a meaningful correlation analysis result does not imply a causal association, more studies are needed in the future to confirm the causal link between air pollution and incident SLE.”

But the investigators still felt that their data deserved to be taken seriously. “Our current study provided crucial insights into the environmental factors contributing to autoimmune diseases,” they offered. “Findings can inform the development of stricter air quality regulations to mitigate exposure to harmful pollutants, thereby reducing the risk of SLE.”

Their findings add to a large body of research implicating environmental factors, including air pollution, in SLE. But Yang and colleagues noted that much of this work relied on short-term exposure data and outcomes such as disease activity and hospitalizations, rather than new-onset lupus. Studies of the latter have been conducted, but only in Taiwan. “It is essential to evaluate this association in Europe, where the air pollution level is significantly lower,” the current authors stated.

Yang’s group drew on the U.K. Biobank, a prospective project that collects health records for some 500,000 individuals in Britain, enrolled from 2006 to 2010, and also administers periodic questionnaires and physical exams. Tissue samples are collected to allow for genetic analysis.

One-year average exposures for the four pollutants were estimated for 2010 based on monitoring data from several years around that time, and this was the basis for the researchers’ statistical analysis. Biobank participants living in areas without regular monitoring were excluded. Levels of each pollutant were stratified into quartiles. The medians for each were as follows:

• PM_2.5: 9.93 μg/m³
• PM₁₀: 19.16 μg/m³
• NO₂: 28.11 μg/m³
• NO_x: 42.26 μg/m³

Polygenic risk scores were calculated for the included participants, and these were divided into tertiles that defined low, medium, and high risks for SLE based on earlier genome-wide association studies.

Statistical results were adjusted for a host of potential covariates including age, sex, race/ethnicity, employment, income, smoking and drinking status, and body mass index.

Mean participant age at baseline was about 57 (a potentially major limitation, insofar as SLE onset typically occurs in young adulthood), just over half were women, and over 90% were white.

Yang and colleagues also analyzed pollution exposure as a continuous variable, which indicated that the association with SLE risk was nonlinear for two of the four pollutants. Both PM_2.5 and NO_x showed a plateau effect, with a marked correlation with SLE risk at low to medium exposure levels, but without further increase as exposures continued to rise. Linear associations were seen for PM₁₀ and NO₂, on the other hand.

Limitations to the study, in addition to the small number of incident SLE cases and largely middle-age sample, included participants’ voluntary enrollment in the Biobank (meaning they might be more health-conscious than others), and the potential for individuals’ pollutant exposure to be more variable than was captured in the annual estimates. Also, many possible confounders, such as exposures to other pollutants like ground-level ozone or silica dust, were not accounted for.

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