Shoushen Granule improves the atherosclerosis lesions in rats, and the mechanism may be related to regulating telomere length and telomerase activity.

34Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome with poor survival. The 35 current recommendations have proposed uniform surveillance strategies for all patients, neglecting 36 the obvious phenotypic varieties. In this study, we aim to confirm the phenotypic heterogeneity in 37 VHL disease and the underlying mechanism. A total of 151 parent-child pairs were enrolled for 38 genetic anticipation analysis, and 77 sibling pairs for birth order effect analysis. Four statistical 39 methods were used to compare the onset age of patients among different generations and different 40 birth orders. The results showed that the average onset age was 18.9 years earlier in children than 41 in their parents, which was statistically significant in all of the four statistical methods. 42Furthermore, the first-born siblings were affected 8.3 years later than the other ones among the 43 maternal patients. Telomere shortening was confirmed to be associated with genetic anticipation in 44 VHL families, while it failed to explain the birth order effect. Moreover, no significant difference 45 was observed for overall survival between parents and children (p=0.834) and between first-born 46 patients and the other siblings (p=0.390). This study provides definitive evidence and possible 47 mechanisms of intra-familial phenotypic heterogeneity in VHL families, which is helpful to the 48 update of surveillance guidelines. 49 50 4 / 22