RESULTS: Except for two tuberous deciduous species and a species with upright stems, a majority of Sino-Vietnamese limestone Begonia (SVLB), including sect. Coelocentrum (19 species sampled) and five species of sect. Diploclinium, Leprosae, and Petermannia, are rhizomatous and grouped in a strongly supported and yet internally poorly resolved clade (Clade SVLB), suggesting a single evolutionary origin of the adaptation to limestone substrates by rhizomatous species, subsequent species radiation, and a strong tendency to retain their ancestral niche. Divergence-time estimates indicate a late Miocene diversification of Clade SVLB, coinciding with the onset of the East Asian monsoon and the period of extensive karstification in the area.
CONCLUSIONS: Based on our phylogenetic study, Begonia sect. Coelocentrum is recircumscribed and expanded to include other members of the Clade SVLB (sect. Diploclinium: B. cavaleriei, B. pulvinifera, and B. wangii; sect. Leprosae: B. cylindrica and B. leprosa; sect. Petermannia: B. sinofloribunda). Because species of Clade SVLB have strong niche conservatism to retain in their ancestral habitats in cave-like microhabitats and Begonia are generally poor dispersers prone to diversify allopatrically, we propose that extensive and continuous karstification of the Sino-Vietnamese limestone region facilitated by the onset of East Asian monsoon since the late Miocene has been the major driving force for species accumulation via geographic isolation in Clade SVLB. Morphologically species of Clade SVLB differ mainly in vegetative traits without apparent adaptive value, suggesting that limestone Begonia radiation is better characterized as non-adaptive, an underappreciated speciation mode crucial for rapid species accumulations in organisms of low vagility and strong niche conservatism.
OBJECTIVE: To discover DNA methylation markers for allopurinol-induced SCAR which may improve the prediction accuracy of genetic testing.
STUDY DESIGN: The study was designed as a retrospective case-control clinical study in multicenter hospitals across Taiwan, Mainland China, Malaysia and Canada. 125 cases of allopurinol-induced SCAR patients and 139 cases of allopurinol tolerant controls were enrolled in this study during 2005 to 2021.
RESULTS: The results of genome-wide DNA methylation assay of 62 patients revealed that ITGB2 showed strong discriminative ability of allopurinol-induced SCAR in both HLA-B*58:01 positive and negative patients with AUC value of 0.9364 (95% CI 0.8682-1.000). In validation study, significant hypermethylation of ITGB2 were further validated in allopurinol-induced SCAR patients compared to tolerant controls, especially in those without HLA-B*58:01(AUC value of 0.8814 (95% CI 0.7121-1.000)). Additionally, the methylation levels of 2 sites on ITGB2 were associated with SCAR phenotypes. Combination of HLA-B*58:01 genotyping and ITGB2 methylation status could improve the prediction accuracy of allopurinol-induced SCAR with the AUC value up to 0.9387 (95% CI 0.9089-0.9684), while the AUC value of HLA-B*58:01 genotyping alone was 0.8557 (95% CI 0.8030-0.9083).
CONCLUSIONS: Our study uncovers differentially methylated genes between allopurinol-induced SCAR patients and tolerant controls with positive or negative HLA-B*58:01 allele and provides the novel epigenetic marker that improves the prediction accuracy of genetic testing for prevention of allopurinol-induced SCAR.
METHODS: Data were analysed from patients in a multinational longitudinal cohort with known anti-dsDNA results from 2013 to 2021. Patients were categorized based on their anti-dsDNA results as persistently negative, fluctuating or persistently positive. Cox regression models were used to examine longitudinal associations of anti-dsDNA results with flare.
RESULTS: Data from 37 582 visits of 3484 patients were analysed. Of the patients 1029 (29.5%) had persistently positive anti-dsDNA and 1195 (34.3%) had fluctuating results. Anti-dsDNA expressed as a ratio to the normal cut-off was associated with the risk of subsequent flare, including in the persistently positive cohort (adjusted hazard ratio [HR] 1.56; 95% CI: 1.30, 1.87; P 3. Both increases and decreases in anti-dsDNA more than 2-fold compared with the previous visit were associated with increased risk of flare in the fluctuating cohort (adjusted HR 1.33; 95% CI: 1.08, 1.65; P = 0.008) and the persistently positive cohort (adjusted HR 1.36; 95% CI: 1.08, 1.71; P = 0.009).
CONCLUSION: Absolute value and change in anti-dsDNA titres predict flares, including in persistently anti-dsDNA positive patients. This indicates that repeat monitoring of dsDNA has value in routine testing.