Development and validation of LCMM prediction algorithms to estimate recovery pattern of postoperative AKI in type A aortic dissection: a retrospective study.

Background: Postoperative acute kidney injury (PO-AKI) is a prevalent complication among patients with acute type A aortic dissection (aTAAD) for which unrecognized trajectories of renal function recovery, and their heterogeneity, may underpin poor success in identifying effective therapies. Methods: This was a retrospective, single-center cohort study in a regional Great Vessel Center including patients undergoing aortic dissection surgery. Estimated glomerular filtration rate (eGFR) recovery trajectories of PO-AKI were defined through the unsupervised latent class mixture modeling (LCMM), with an assessment of patient and procedural characteristics, complications, and early-term survival. Internal validation was performed by resampling. Results: A total of 1,295 aTAAD patients underwent surgery and 645 (49.8%) developed PO-AKI. Among the PO-AKI cohort, the LCMM identified two distinct eGFR trajectories: early recovery (ER-AKI, 51.8% of patients) and late or no recovery (LNR-AKI, 48.2% of patients). Binary logistic regression identified five critical determinants regarding poor renal recovery, including chronic kidney disease (CKD) history, renal hypoperfusion, circulation arrest time, intraoperative urine, and myoglobin. LNR-AKI was associated with increased mortality, continuous renal replacement therapies, mechanical ventilation, ICU stay, and hospital stay. The assessment of the predictive model was good, with an area under the curve (AUC) of 0.73 (95% CI: 0.69-0.76), sensitivity of 61.74%, and specificity of 75.15%. The internal validation derived a consistent average AUC of 0.73. The nomogram was constructed for clinicians' convenience. Conclusion: Our study explored the PO-AKI recovery patterns among surgical aTAAD patients and identified critical determinants that help to predict individuals at risk of poor recovery of renal function.

Cis-regulation of antisense non-coding RNA at the JAZF1 locus in type 2 diabetes.

BACKGROUND: Several genomic loci of type 2 diabetes (T2D) nominated in genome-wide association studies (GWAS) have been suggested to regulate metabolism in muscle. However, a large portion of the genetic risk and the underlying regulation remain unexplained. The present study aimed to localize the potentially functional regions or genes at juxtaposed with another zinc finger protein 1 (JAZF1) locus and interpret their possible biological mechanisms in the muscle of T2D. METHODS: Seven GWAS datasets including 21,897 T2D patients and 32,710 healthy controls of 772 SNPs within JAZF1 locus were meta-analysed using unconditional logistic regression. The Sherlock and GTEx protal online algorithms were implemented to show the significant colocalizations. Multiple omics data were integrated to predict the potential biological functions of JAZF1-AS1 in muscle. The cis regulation of JAZF1-AS1 was analysed using in vitro cloning in Human skeletal muscle cells (HSkMC). RESULTS: With a cross-population meta-analysis of seven GWAS, we identified a linkage disequilibrium (LD) block within intron 1 of JAZF1 that was significantly associated with T2D (false discovery rate < 0.05). The colocalization analysis showed a significant association between genetically determined expression of JAZF1 in skeletal muscle and T2D with a strong probability of colocalization (PP4 = 75.09%). This region also encodes the upstream regulatory region of the antisense non-coding RNA JAZF1-AS1. Expression-quantitative trait loci analysis detected a regulatory SNP within this LD block, rs864745, which is associated with the expression of JAZF1-AS1 and JAZF1. With in vitro cloning, we further reported the role of JAZF1-AS1 in cis-regulating JAZF1 by directly forming RNA double strands. Downregulation of JAZF1, caused by JAZF1-AS1 depletion, inhibited the glucose uptake and lipid oxidation in skeletal muscle. CONCLUSIONS: The present study proposes a strategy for identifying a novel T2D gene at the reported locus and generating a model in which polymorphisms at JAZF1 influence T2D risk through antisense-mediated gene regulation.

Case Report: Identification of a Novel Variant (m.8909T>C) of Human Mitochondrial ATP6 Gene and Its Functional Consequences on Yeast ATP Synthase.

With the advent of next generation sequencing, the list of mitochondrial DNA (mtDNA) mutations identified in patients rapidly and continuously expands. They are frequently found in a limited number of cases, sometimes a single individual (as with the case herein reported) and in heterogeneous genetic backgrounds (heteroplasmy), which makes it difficult to conclude about their pathogenicity and functional consequences. As an organism amenable to mitochondrial DNA manipulation, able to survive by fermentation to loss-of-function mtDNA mutations, and where heteroplasmy is unstable, Saccharomyces cerevisiae is an excellent model for investigating novel human mtDNA variants, in isolation and in a controlled genetic context. We herein report the identification of a novel variant in mitochondrial ATP6 gene, m.8909T>C. It was found in combination with the well-known pathogenic m.3243A>G mutation in mt-tRNALeu. We show that an equivalent of the m.8909T>C mutation compromises yeast adenosine tri-phosphate (ATP) synthase assembly/stability and reduces the rate of mitochondrial ATP synthesis by 20-30% compared to wild type yeast. Other previously reported ATP6 mutations with a well-established pathogenicity (like m.8993T>C and m.9176T>C) were shown to have similar effects on yeast ATP synthase. It can be inferred that alone the m.8909T>C variant has the potential to compromise human health.

Genome-wide meta-analysis associates GPSM1 with type 2 diabetes, a plausible gene involved in skeletal muscle function.

Genome-wide association studies (GWASs) have identified many genetic variations associated with type 2 diabetes mellitus (T2DM) in Asians, but understanding the functional genetic variants that influence traits is often a complex process. In this study, fine mapping and other analytical strategies were performed to investigate the effects of G protein signaling modulator 1 (GPSM1) on insulin resistance in skeletal muscle. A total of 128 single-nucleotide polymorphisms (SNPs) within GPSM1 were analysed in 21,897 T2DM cases and 32,710 healthy controls from seven GWASs. The SNP rs28539249 in intron 9 of GPSM1 showed a nominally significant association with T2DM in Asians (OR = 1.07, 95% CI = 1.04-1.10, P < 10-4). The GPSM1 mRNA was increased in skeletal muscle and correlated with T2DM traits across obese mice model. An eQTL for the cis-acting regulation of GPSM1 expression in human skeletal muscle was identified for rs28539249, and the increased GPSM1 expression related with T2DM traits within GEO datasets. Another independent Asian cohort showed that rs28539249 is associated with the skeletal muscle expression of CACFD1, GTF3C5, SARDH, and FAM163B genes, which are functionally enriched for endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) pathways. Moreover, rs28539249 locus was predicted to disrupt regulatory regions in human skeletal muscle with enriched epigenetic marks and binding affinity for CTCF. Supershift EMSA assays followed luciferase assays demonstrated the CTCF specifically binding to rs28539249-C allele leading to decreased transcriptional activity. Thus, the post-GWAS annotation confirmed the Asian-specific association of genetic variant in GPSM1 with T2DM, suggesting a role for the variant in the regulation in skeletal muscle.

Common variant rs11191548 near the CYP17A1 gene is associated with hypertension and the serum 25(OH) D levels in Han Chinese.

The CYP17A1 gene, which encodes17α-hydroxylase and 17,20-lyase, has been identified as a common hypertension susceptibility locus in a European population. However, the association between CYP17A1 polymorphisms and hypertension is unclear in the Chinese population as well as in the role of serum 25(OH) D levels. Six single nucleotide polymorphisms (SNPs) in CYP17A1 were genotyped in two stages in a Han Chinese population, and the serum 25(OH) D levels were measured. Analysis in stage 1 showed that the rs1004467 minor G-allele and rs11191548 minor C-allele in CYP17A1 were significantly associated with a decreased risk of hypertension and higher serum 25(OH) D levels (all P < 0.05). The larger sample in stage 2 also showed that a mutation in rs11191548 was significantly associated with a decreased risk of hypertension (adjusted OR = 0.707, 95% CI: 0.553-0.904, P = 0.006). The rs11191548 minor C-allele was associated with higher serum 25(OH) D levels in hypertensive subjects (ßadj ± SEM = 0.094 ± 0.949, P = 0.003) and controls (ßadj ± SEM = 0.128 ± 1.025, P < 0.001). In conclusion, the rs11191548 CYP17A1 gene mutation was associated with hypertension and the serum 25(OH) D levels in Han Chinese.

hTERT gene polymorphism correlates with the risk and the prognosis of thyroid cancer.

OBJECTIVES: The study explored the association between rs10069690C/T and rs2736100G/T of human telomerase reverse transcriptase (hTERT) gene, and the prognosis of thyroid cancer. METHODS: The study had 452 thyroid cancer patients recruited as case group who hospitalized in Jingzhou Central Hospital from January 2001 to June 2004 and 452 healthy people recruited as control group at the same area. The hTERT gene polymorphisms at rs10069690 C/T and rs2736100 G/T were tested by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The association between patients' life quality and hTERT gene polymorphisms six months after surgery was evaluated based on the Cancer patients' quality of life index rating scale. RESULTS: There were statistical differences in genotype and allele frequencies of rs10069690 C/T between the case group and control group (both P < 0.05). An association between rs10069690C/T polymorphism and an increased risk of thyroid cancer was shown by logistic regression analysis (CT vs. CC, OR = 1.333, 95%CI = 1.006-1.766, P = 0.045; TT vs. CC, OR = 1.910, 95%CI = 1.084-3.367, P = 0.023; CT + TT vs. CC, OR = 2.246, 95%CI = 1.078-1.840, P = 0.006; T vs. C, OR = 1.376, 95%CI = 1.104-1.715, P = 0.004). Genotype frequency of rs2736100G/T between the two groups had no statistical differences (P > 0.05). After stratification according to age, T stage, tumor size and tumor node metastasis (TNM) stage, the distribution frequencies of CC genotype and CT + TT genotype of rs10069690C/T showed significant difference (P < 0.05). The life quality of patients with CC genotype was better than that of patients with CT $+$ TT genotype. The results of Cox regression model multifactor analysis showed that age, T stage, tumor size and rs10069690C/T were independent risk factors of thyroid cancer prognosis. CONCLUSIONS: hTERT gene polymorphism at rs10069690C/T is associated with the risk and prognosis of thyroid cancer, but hTERT gene polymorphism at rs2736100G/T is not.