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BACKGROUND: Limited evidence exists to support any specific medication over others to prevent dementia in older patients with type 2 diabetes (T2D). We investigated whether treatment with sodium-glucose cotransporter 2 (SGLT-2) inhibitors is associated with a lower risk of incident dementia and all-cause mortality, relative to dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RA). METHODS: In this retrospective, active-comparator cohort study, we used data from the TriNetX electronic health records network. Our primary cohort comprised patients with T2D aged ≥50 years, registered between January 2012 and December 2022. Patients with a history of dementia were excluded. We used Kaplan-Meier survival analysis to estimate the incidence of dementia and all-cause mortality in our cohort after they had used glucose-lowering drugs for at least 12 months. Propensity score matching was performed to balance the SGLT-2 inhibitor, DPP-4 inhibitor and GLP-1 RA cohorts. Subgroup analyses for sex and age were also conducted. RESULTS: Our first cohort comprised 193 948 patients treated with metformin and SGLT-2 inhibitors and an equal number of patients treated with metformin and DPP-4 inhibitors. In this cohort, the risk of dementia and all-cause mortality was lower in patients treated with SGLT-2 inhibitors than in those treated with DPP-4 inhibitors (hazard ratio [HR]: 0.62, 95% confidence interval [CI]: 0.59-0.65, for dementia; HR: 0.54, 95% CI: 0.52-0.56, for all-cause mortality). Our second cohort comprised 165 566 patients treated with metformin and SGLT-2 inhibitors and an equal number of patients treated with metformin and GLP-1 RAs. In this cohort, the risk of dementia and all-cause mortality was lower in those treated with SGLT-2 inhibitors than in those treated with GLP-1 RAs (HR: 0.92, 95% CI: 0.87-0.98, for dementia; HR: 0.88, 95% CI: 0.85-0.91, for all-cause mortality). CONCLUSIONS: The use of SGLT-2 inhibitor was associated with a lower risk of incident dementia and all-cause mortality in older adults with T2D compared to DPP-4 inhibitor and GLP-1 RA.
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BACKGROUND: Ankylosing spondylitis (AS) is an autoimmune disease affecting mainly spine and sacroiliac joints and adjacent soft tissues. Genome-wide association studies (GWASs) are used to evaluate genetic associations and to predict genetic risk factors that determine the biological basis of disease susceptibility. We aimed to explore the race-specific SNP susceptibility of AS in Taiwanese individuals and to investigate the association between HLA-B27 and AS susceptibility SNPs in Taiwan. METHODS: Genotyping data were collected from a medical center participating in the Taiwan Precision Medicine Initiative (TPMI) in the northern district of Taiwan. We designed a case-control study to identify AS susceptibility SNPs through GWAS. We searched the genome browser to find the corresponding susceptibility genes and used the GTEx database to confirm the regulation of gene expression. A polygenic risk score approach was also applied to evaluate the genetic variants in the prediction of developing AS. RESULTS: The results showed that the SNPs located on the sixth chromosome were related to higher susceptibility in the AS group. There was no overlap between our results and the susceptibility SNPs found in other races. The 12 tag SNPs located in the MHC region that were found through the linkage disequilibrium method had higher gene expression. Furthermore, Taiwanese people with HLA-B27 positivity had a higher proportion of minor alleles. This might be the reason that the AS prevalence is higher in Taiwan than in other countries. We developed AS polygenic risk score models with six different methods in which those with the top 10% polygenic risk had a fivefold increased risk of developing AS compared to the remaining group with low risk. CONCLUSION: A total of 147 SNPs in the Taiwanese population were found to be statistically significantly associated with AS on the sixth pair of chromosomes and did not overlap with previously published sites in the GWAS Catalog. Whether those genes mapped by AS-associated SNPs are involved in AS and what the pathogenic mechanism of the mapped genes is remain to be further studied.
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Estudio de Asociación del Genoma Completo , Espondilitis Anquilosante , Humanos , Antígeno HLA-B27/genética , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Espondilitis Anquilosante/genética , Espondilitis Anquilosante/patologíaRESUMEN
Rheumatoid arthritis (RA) is characterized by a deficiency in regulatory T cells (Treg), which play a crucial role in immune regulation. While conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) are widely used, there remains a challenge as efficacy varies among patients. In this genome-wide association study (GWAS) involving 410 RA patients, rs9373441 emerged as the most significantly linked single-nucleotide polymorphism (SNP) to csDMARDs response. This non-coding variant functions as a cis-acting regulatory element within the UTRN gene, which is associated with cortical erosion and osteoporosis. Particularly, individuals with the TT allele at rs9373441 exhibited a more favorable response, characterized by a significant increase in FOXP3 + Treg and Type 1 regulatory T cells (Tr1) (p = 0.04, 0.02) and a decrease in Effector T helper cells (Effector Th) (p = 0.03). The GATA3-GCM2-PTH and GATA3-FOXO1-FOXP3 pathways were implicated. RNA-sequencing (RNA-seq) analysis revealed increased expression levels of UTRN, PTH2R, FOXO1, and FOXO3 in good and moderate responders (p = 0.01, 0.03, 0.0005, and 0.02). Notably, the change in FOXP3 + Treg and Tr1 was positively correlated with UTRN expression (both p = 0.03). These findings underscore the critical link between rs9373441 and the response to csDMARDs, empowering clinicians to tailor treatments for enhanced outcomes in patients with RA.
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Antirreumáticos , Artritis Reumatoide , Humanos , Antirreumáticos/metabolismo , Antirreumáticos/uso terapéutico , Linfocitos T Reguladores , Estudio de Asociación del Genoma Completo , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/genética , Resultado del Tratamiento , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismoRESUMEN
Two isomeric C3-symmetric ligands, 1,3,5-tris(3-pyridylethynyl)benzene (L1) and 1,3,5-tris(4-pyridylethynyl)benzene (L2), were used to react with CuI to give a series of coordination frameworks containing various CuI clusters, {[(Cu2I2)2(L1)2]·C6H5CH3}n (1), {[(Cu2I2)1.5(L1)2]·1.5C6H6·CH3CN}n (2), [(Cu2I2)0.5(L1)]n (3), {[(Cu2I2)0.5(L2)]·C6H6}n (4), and {[(Cu2I2)(L2)]·C6H6}n (5), which have been isolated and structurally characterized by X-ray diffraction studies. Although 1 is simultaneously composed of a rhombohedral Cu2I2 cluster and a step-cubane Cu4I4 cluster and 2 contains two types of rhombohedral Cu2I2 clusters in the frameworks, both give similar 3-D supramolecular architectures interpenetrated by 2-D layer frameworks. 3 forms a 1-D double-zigzag framework, and significantly the interlocking of the 1-D frameworks into the 28-membered rings of the adjacent chains generates a novel 1-D (1-D â 1-D) polyrotaxane framework. However, as the structural and isomeric analogue, 4 only forms a 1-D double-zigzag framework leading to a 2-D supramolecular structure by ππ interactions and C-HN hydrogen bonding. 5, composed of polymeric (Cu2I2)n cluster chains, forms a 3-D coordination framework and interpenetrates to give a 2-fold interpenetrated framework. It is noted that these coordination frameworks show various structural motifs depending on the reaction conditions and ligands' backbones. In addition, the low-energy emissions at 538-615 nm for 1-5 either at room temperature or at 77 K have been observed, which are most likely to originate from an iodo-to-copper charge-transfer transition, possibly modified by Cu(i)Cu(i) interactions.