2007 Gender Matters, Human Lupus Biology
While females are much more likely than males to get lupus—nine women for every one male is affected—illness that does develop in males tends to be particularly severe.
Dr. Tsao has LRI funding to pursue her novel hypothesis on potential genetic defects that may underpin male lupus.
Based in part on several reported cases in which males with lupus carried an extra copy of the X chromosome, Dr. Tsao hypothesizes that X chromosome genetic defects are critical in male lupus.
In 2010, Dr. Tsao published findings of research with human cells in the Proceedings of the National Academy of Sciences (PNAS) showing that humans—males in particular—with a variant form of the immune receptor gene "Toll Like Receptor 7 (TLR7)" are at increased risk of developing lupus. This breakthrough finding offers renewed hope for developing more targeted treatments.
Dr. Tsao's discovery that the lupus link to TLR7 is stronger in males supports the idea that there are different genetic pathways to lupus between males and females. Only 10 percent of people with lupus are male, but the disease tends to be particularly severe in this population.
In her novel study, Dr. Tsao and colleagues noted that men with an extra X (female) chromosome have a higher risk for lupus, and predicted that genes located on the X chromosome would be critical in male lupus. So they narrowed their search among the approximately 2,000 genes on the X chromosome to genes already implicated in lupus.
After genotyping DNA of blood samples from over 4,000 people with lupus from East Asia, the team discovered a variant form of the TLR7 gene associated with lupus. The link was stronger in men of Chinese and Japanese ethnicity—89% of men with lupus had the risk allele, compared with only 77% of healthy male subjects.
"Now that we know the sex-specific genetic contributions to lupus, we can proceed to find more targeted therapies than currently exist," said Dr. Tsao
Sex-specific association of X-linked Toll-like receptor 7 (TLR7) with male systemic lupus erythematosus. Shen N, Fu Q, Deng Y, Qian X, Zhao J, Kaufman KM, Wu YL, Yu CY, Tang Y, Chen JY, Yang W, Wong M, Kawasaki A, Tsuchiya N, Sumida T, Kawaguchi Y, Howe HS, Mok MY, Bang SY, Liu FL, Chang DM, Takasaki Y, Hashimoto H, Harley JB, Guthridge JM, Grossman JM, Cantor RM, Song YW, Bae SC, Chen S, Hahn BH, Lau YL, Tsao BP. Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15838-43. doi: 10.1073/pnas.1001337107. Epub 2010 Aug 23.