Sex disparity in systemic sclerosis-associated pulmonary fibrosis.

Systemic sclerosis (SSc) is a fibrotic disease with high mortality and SSc-associated pulmonary fibrosis (SSc-PF) as the leading cause of death. SSc shows a significant sex disparity with a sex ratio of 1:3 men to women, yet SSc-PF is more severe in men. This study investigates gene expression differences between men and women with SSc-PF. Whole lung tissues from healthy donors and SSc-PF patients of both sexes were analyzed by RNA sequencing. Selected genes were validated by quantitative polymerase chain reaction (qPCR) and Western blotting analyses. Notably, in whole lung, genes related to extracellular matrix production, such as COL3A1, COL5A1, PDGFA, THBS1, and THBS2, were upregulated in females, while genes that are less-explicitly related to fibrosis, like GNB3, PCSK4, and PCSK7, were upregulated in males. Additionally, normal lung fibroblasts were treated with recombinant TGFβ to determine if there is a differential response in lung fibroblasts depending on sex. This study reveals differentially expressed genes that are unique to female and male SSc-PF patients and identifies potential sex-specific clinical targets.