Preprint: Short telomeres remained linked to lung scarring after eight DNA variants were excluded

Preprint: Short telomeres remained linked to lung scarring after eight DNA variants were excluded

On 15 October, Sten Hanke posted a preprint on medRxiv reporting that short telomeres remained associated with idiopathic pulmonary fibrosis, a disease involving scarring of lung tissue, in a genetic analysis. The author tested whether this association persisted after excluding DNA variants near genes involved in telomere maintenance or known to be implicated in fibrosis.

Telomeres are regions at the ends of chromosomes. Short telomere length has long been associated with idiopathic pulmonary fibrosis. An earlier study used Mendelian randomization, a genetic method that relates inherited variants to disease frequency, based on just seven variants. Six were near genes involved in telomere maintenance, so the result could reflect both telomere length in blood and the activity of these genes in the lungs.

Hanke started with 81 variants and excluded eight near genes involved in telomere maintenance or fibrosis. In the European group of 5 159 clinically confirmed cases and 27 459 controls, 72 variants remained. In the author's model, a difference in telomere length of one standard deviation, a statistical measure of variability, corresponded to roughly fourfold lower odds of diagnosis (odds ratio 0,26; 95% CI 0,17–0,40).

This analysis separates two possible explanations for the result. The TERT gene encodes a component of telomerase, the enzyme that maintains telomeres. A variant in this gene had a greater effect on risk than would be expected from telomere length in blood. The author interprets this as a possible independent effect of telomerase in lung cells. Within the author's model, the association that persisted across the remaining variants separates the contribution of telomere length from that of known genes involved in telomere maintenance or fibrosis.

The same study examined associations between six genetic measures of aging and six diseases. After correction for multiple comparisons, only one pair retained a robust association: telomere length and the broad category of interstitial lung disease. Four epigenetic clocks, which estimate age from chemical marks on DNA, and an age measure based on blood proteins yielded no comparable result. Across these comparisons, telomere length was the only measure for which the author found a robust association with the risk of fibrotic lung disease.