Gene Essentiality Is a Quantitative Property Linked to Cellular Evolvability.

Gene essentiality is typically determined by assessing the viability of the corresponding mutant cells, but this definition fails to account for the ability of cells to adaptively evolve to genetic perturbations. Here, we performed a stringent screen to assess the degree to which Saccharomyces cerevisiae cells can survive the deletion of ~1,000 individual "essential" genes and found that ~9% of these genetic perturbations could in fact be overcome by adaptive evolution. Our analyses uncovered a genome-wide gradient of gene essentiality, with certain essential cellular functions being more "evolvable" than others. Ploidy changes were prevalent among the evolved mutant strains, and aneuploidy of a specific chromosome was adaptive for a class of evolvable nucleoporin mutants. These data justify a quantitative redefinition of gene essentiality that incorporates both viability and evolvability of the corresponding mutant cells and will enable selection of therapeutic targets associated with lower risk of emergence of drug resistance.

NLRP1, PTPN22 and PADI4 gene polymorphisms and rheumatoid arthritis in ACPA-positive Singaporean Chinese.

Studies have shown that the genetic risk factors for rheumatoid arthritis (RA) differ substantially between Asian and Caucasian populations. Even among Asian populations, the genetic contributions of NLRP1, PTPN22 and PADI4 have been controversial. Consequently, we sought to address these separate findings and determine whether any of these proposed risk variants are associated with RA susceptibility, onset, DAS activity and erosion in a Singaporean Chinese cohort. We genotyped five SNPs within NLRP1 (rs878329 and rs6502867), PTPN22 (rs2488457 and rs6665194), and PADI4 (rs2240340) in 500 anti-cyclic citrullinated peptide antibody-positive (ACPA) patients with RA and 500 healthy controls using TaqMan assays. The CC genotype of NLRP1 rs878329 and TT genotype of PADI4 rs2240340 were associated with RA susceptibility. The risk association of the T allele of PADI4 rs2240340 with RA was confirmed through a meta-analysis based on previous reports in Asian populations. The GG genotype of PTPN22 rs6665194 (-3508A>G) was associated with significantly reduced risk of RA. No significant association was found for NLRP1 rs6502867 T/C and PTPN22 rs2488457 G/C polymorphisms. None of the five SNPs was associated with RA's clinical features. This work supports the association of the T allele of PADI4 rs2240340 with RA in Asians. The roles of NLRP1 rs878329 G/C and PTPN22 rs6665194 A/G polymorphisms were demonstrated for the first time. We also propose rs6665194 to be a promising candidate for RA risk evaluation between ethnicities.

The impact of diabetes mellitus on treatment and outcomes of rheumatoid arthritis at 5-year follow-up: results from a multi-ethnic Asian cohort.

OBJECTIVES: We evaluated the impact of type 2 diabetes mellitus (T2DM) on RA treatment and outcomes in a longitudinal RA cohort. METHODS: We analysed data collected in the period 2001-2013 involving 583 RA patients, including demographics, diabetes diagnosis, clinical features, treatment, ACR functional class, HAQ, and quality-of-life measurement using the Short-Form 36. RESULTS: Seventy-seven (13.2%) of the RA patients had T2DM. DAS28 was not different in patients with T2DM at 5 years post-RA diagnosis. Fewer T2DM patients received MTX than those without T2DM (51% vs 80%, P < 0.001). Using univariate analysis, T2DM patients were more likely to experience poorer outcomes in terms of ACR functional status (P = 0.009), joint surgery (P = 0.007), knee arthroplasty (P < 0.001) and hospital admissions (P = 0.006). Multivariate regression analyses showed more knee arthroplasty (P = 0.047) in patients with T2DM. CONCLUSION: Fewer patients with T2DM received MTX compared with those without T2DM. Patients with RA and T2DM were at higher risk of knee arthroplasty than RA patients without T2DM.