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PubMed1998

Rat liver phosphoribosylpyrophosphate synthetase is activated by free Mg2+ in a manner that overcomes its inhibition by nucleotides.

Phosphoribosylpyrophosphate synthetase is activated by Pi and free Mg2+ as an essential activator and inhibited by nucleotides, especially ADP and GDP. The rat liver enzyme is a complex aggregate of two highly homologous catalytic subunits (PRS I and PRS II) and two associated proteins (PAP39 and PAP41). PRS I is more sensitive to inhibition by ADP and GDP than is PRS II. The native liver enzyme showed a weaker sensitivity to inhibition by nucleotides than expected from its composition. To further understand the regulation of the liver enzyme, kinetic studies of each subunit component and the liver enzyme regarding Mg2+ activation and inhibition by ADP and GDP were carried out. Assay conditions were designed to keep free Mg2+ at constant concentrations. (1) GDP, as MgGDP, did not affect the apparent Km values of PRS I for MgATP and ribose-5-phosphate but did dramatically increase the apparent Ka value for free Mg2+. (2) In contrast, ADP, as MgADP, increased the Km value for MgATP of PRS I as well as the Ka value for free Mg2+. (3) High concentrations of free Mg2+ almost completely nullified the inhibitory effect of MgGDP and partly that of MgADP on PRS I. (4) At low free Mg2+ concentrations within the physiological range, inhibition by the nucleotides is of physiological significance and conversely, variation in free Mg2+ concentrations critically affects the enzyme activity in the presence of inhibitory nucleotides. (5) The response of PRS II and the native liver enzyme is similar to that of PRS I, while the effects of MgGDP and MgADP were smaller than that on PRS I. (6) We propose that MgGDP binds to a regulatory site of PRS I and PRS II and MgADP to the substrate MgATP site and also the regulatory site. The allosteric interaction of the regulatory site and the Mg2+ binding site is also considered.

Adenosine Triphosphate↗

PubMed2025

Polygenic risk of coronary artery disease for long-term survivors of breast cancer.

BACKGROUND: Cardiovascular disease is a leading cause of death for long-term breast cancer survivors. We evaluated whether a polygenic risk score for coronary artery disease (CAD-PRS) was associated with the risk of incident CAD for survivors of unilateral or contralateral breast cancer. METHODS: The study included 1307 women with breast cancer first diagnosed at younger than 55 years of age who participated in the Women's Environmental Cancer and Radiation Epidemiology Follow-up Study. The CAD-PRS was based on a PRS developed and validated in a separate population. We modeled the association between incident CAD and the CAD-PRS, adjusting for age, CAD risk factors, first (and second) breast cancer treatment, study recruitment phase, and genetic population stratification. We also explored whether the risk of CAD depended on interactions between the CAD-PRS and cardiotoxic cancer treatment. RESULTS: There were 66 incident CAD diagnoses reported at a median of 16 years after breast cancer diagnosis. Participants with CAD-PRS at or above the median had a 2.48-times increased risk of CAD (95% confidence interval [CI] = 1.44 to 4.29) relative to participants with CAD-PRS below the median. Anthracycline-based chemotherapy was associated with increased CAD risk (hazard ratio [HR] = 2.04, 95% CI = 1.04 to 3.98), and the association was not modified by the CAD-PRS. The association between incident CAD and left-sided radiation therapy (RT) was increased for those with CAD-PRS at or above the median (HR = 2.90, 95% CI = 1.26 to 6.68) but not for those with CAD-PRS below the median (HR = 0.96, 95% CI = 0.32 to 2.88). There was evidence of super-additive interaction between the CAD-PRS and left-sided RT (relative excess risk due to interaction = 2.06, 95% CI = 0.05 to 4.06). CONCLUSION: A genome-wide CAD-PRS was associated with nonfatal CAD risk for long-term breast cancer survivors, providing potential utility for personalized cardiovascular care, particularly after RT.

Humans↗

PubMed1997

Response to clamping of the inferior vena cava as a factor for predicting postreperfusion syndrome during liver transplantation.

Postreperfusion syndrome (PRS) is an important cause of hemodynamic deterioration during orthotopic liver transplantation (OLT). We retrospectively studied 94 patients who had undergone OLT in an effort to establish whether the hemodynamic response to clamping of the inferior vena cava (IVC) could be used to predict hemodynamic behavior on reperfusion of the grafted liver. PRS was defined as a decrease in the mean arterial pressure of more than 30% below the baseline value for more than 1 min during the first 5 min after reperfusion of the graft. The patients were divided into two groups: those who developed PRS (PRS group) and those who did not (non-PRS group). We analyzed hemodynamic response before (dissection stage) and after (anhepatic stage) clamping of the IVC. Based on multivariate analysis methods (logistic regression), the percentage of change in the vascular resistance index from before clamping to after clamping of the IVC was an indicator of the risk of developing PRS, with an adjusted odds ratio of 1.04 for each unit of change (ENTER method, P = 0.01). In the non-PRS group, clamping of the IVC was followed by a 47.1% decrease in the cardiac index, compared with a 27.9% decrease in the PRS group (P < 0.05). The systemic vascular resistance index (SVRI) increased by 49% in the PRS group, as opposed to 85.7% in the non-PRS group (P < 0.05). PRS occurred in only 17.5% of patients in whom the SVRI increased by more than 50%. We conclude that the integrity of the vasoconstrictive response (increase in the peripheral vascular resistance greater than 50%) as measured immediately after clamping of the IVC correlates with occurrence of PRS.

Adult↗

PubMed2006

Effects of acute and chronic restraint stress on visceral sensitivity and neuroendocrine hormones in rats.

OBJECTIVE: To investigate the effects of acute and chronic partial restraint stress (PRS) on visceral sensitivity to colorectal distention and the neuroendocrine response in rats. METHODS: Male Sprague-Dawley rats were used in this study. The abdominal withdrawal reflex score was assessed before stress, immediately after acute or chronic PRS, and 7 days after the first stress. The plasma levels of corticosterone (CORT) and adrenocorticotropic hormone (ACTH) were detected by radioimmunoassay at different time points. RESULTS: The abdominal withdrawal reflex scores of the rats with acute or chronic PRS were significantly higher immediately after stress than those before and 7 days after the stress (P < 0.05). The levels of CORT (25.35 +/- 6.03 ng/mL) and ACTH (312.47 +/- 50.76 pg/mL) in rats with acute PRS showed a significant elevation immediately after stress compared to rats without PRS (7.24 +/- 2.97 ng/mL, 97.00 +/- 23.33 pg/mL, P < 0.05). However, these hormones returned to the baseline value 7 days after acute PRS. The levels of CORT (20.84 +/- 2.19 ng/mL) and ACTH (200.41 +/- 78.10 pg/mL) in rats with chronic PRS were significantly higher after stress than in rats without PRS (P < 0.05), and these hormones remained elevated 7 days after chronic PRS. CONCLUSIONS: Both acute and chronic PRS induce reversible visceral hypersensitivity. Acute PRS transiently elevates the plasma levels of CORT and ACTH, whereas chronic PRS has a longer term effect.

Abdomen↗

PubMed2025

Robust pleiotropy-decomposed polygenic scores identify distinct contributions to elevated coronary artery disease polygenic risk.

BACKGROUND: Polygenic risk score (PRS) have proved to offer robust risk prediction for coronary artery disease (CAD). However, the global CAD PRS summarizes the joint effects of all the markers in the genome, masking potential genetic heterogeneity that may be important for disease interpretation and targeted interventions. METHODS: Using summary-level data, we identified 43 significant CAD-related traits based on genetic correlations, and further classified them into eight pleiotropy clusters based on their biological functions. We then partitioned the genome into 2,353 near-independent regions. Variants in each region were assigned to the trait most genetically similar to CAD, and then were labeled with the corresponding pleiotropy cluster. We grouped variants without labels into a ninth, non-specific cluster. The Pleiotropy Decomposed (PD) PRSs for each of the nine clusters were calculated using variants assigned to each cluster for 407,903 samples of European ancestry from the UK Biobank (UKBB). RESULTS: We decomposed the CAD PRS into nine PD-PRSs and further stratified individuals with high CAD-PRS into nine subgroups. Each PD-PRS accounted for a higher proportion of the global CAD-PRS within its corresponding subgroup than in the remaining subjects with high CAD-PRS (e.g., 25.2% (0.07) vs. 10.06% (0.07) for lipids-PD-PRS). Additionally, these subgroups showed distinct clinical features. For example, in the lipids-related subgroup, lipoprotein(a) and LDL-cholesterol levels were 67.5% and 18.3% higher, respectively, compared to the remaining high-risk individuals. Furthermore, significant interactions were observed between blood pressure and BP PD-PRS, and between current smoking and respiratory system PD-PRS. CONCLUSION: Our findings suggest that PD-PRSs may reveal substantial genetic and phenotypic heterogeneity among individuals with high CAD-PRS. The unique PD-PRS compositions of each individual can highlight the relative importance of different pleiotropic regions.

Humans↗

PubMed2001

Diagnosis and treatment of the Pierre Robin sequence: results of a retrospective clinical study and review of the literature.

UNLABELLED: We performed a retrospective study of all children with Pierre Robin sequence (PRS), admitted to our hospital from 1981-1998 in order to evaluate diagnosis, treatment and prognosis. Patients were divided into two categories: isolated PRS (group 1) and PRS plus, i.e. PRS as part of a more complex syndrome (group 2). A total of 74 patients with PRS were found, 29 (39%) males and 45 (61%) females of whom 47 (63.5%) could be categorised as isolated PRS and 27 (36.8%) as PRS plus. The most frequent diagnoses in patients with PRS plus were Stickler syndrome and the velocardiofacial syndrome. Ophthalmological and fluorescent in situ hybridisation of chromosome 22 investigations should therefore be performed in all patients, as soon as the diagnosis of PRS is established. Some form of airway treatment was necessary in the majority of patients (52 of 74), most could be treated conservatively with prone/lateral positioning and close observation. Endotracheal intubation was necessary in one child from group 1 versus five from group 2. Tracheostomy was performed in three children from group 1 and two from group 2. Feeding problems occurred in about 25% of all PRS patients and stunted growth was seen especially in boys with isolated PRS before the age of 10 months. CONCLUSION: In our series, 33% of patients with Pierre Robin sequence plus had Stickler and velocardiofacial syndromes. Conservative airway management was a sufficient treatment for respiratory problems in the majority of patients. Feeding and growth need special attention in patients with Pierre Robin sequence.

Child↗

PubMed2001

Analysis of postrevascularization syndrome after orthotopic liver transplantation: the experience of an Australian liver transplantation center.

BACKGROUND/PURPOSE: We investigated the causes and examined patient outcomes following the postrevascularization syndrome (PRS) during orthotopic liver transplantation (OLTx). METHODS: PRS was defined as a fall in the mean arterial pressure at 5 min after revascularization to less than 70% of the baseline and lasting for 5 min. Data from 100 adult patients who underwent OLTx between January 1998 and September 2000 were analyzed. Analyzed data included donor and recipient demographic data, recipient operative and postoperative courses, and recipient outcome. RESULTS: Twenty-nine patients (29%) exhibited PRS during OLTx (PRS group). There was a higher incidence of older donors (>50 years) in the PRS group (48% vs 23%; P < 0.05). Postrevascularization hyperkalemia and metabolic acidosis were observed in both the PRS and non-PRS groups. Transaminase and lactate levels after revascularization were significantly higher in the PRS group ( P < 0.05). Alkaline phosphatase and gamma-glutamyl transpeptidase levels on day 7 tended to be higher in the PRS group; although the difference was not significant (p > or = 0.05). Serum creatinine was significantly elevated on day 7 in the PRS group ( P < 0.01). CONCLUSIONS: Our results indicate that PRS following OLTx tended to be more common in liver allografts from older donors and was associated with posttransplantation liver and renal dysfunction.

Adolescent↗

PubMed1987

A functional test for protein S activity in plasma.

The physiological role of coagulation cofactor Protein S (PrS) for activated Protein C (APC) has recently been appreciated by the description of patients with PrS-deficiency, suffering from thromboembolism. The present study introduces a one-stage clotting assay for the assessment of PrS functional activity in plasma samples. The assay procedure is based on a factor Xa-initiated clotting test utilizing a mixture of AL(OH)3-adsorbed substrate plasma and patient's plasma supplemented with purified prothrombin (0.15 microM) and APC (0.05 microM), with phospholipids and CaCl2. Owing to the varying concentration of PrS in the sample plasma, clotting times were prolonged up to 25 seconds in the presence of APC, whereas no prolongation occurred in its absence. The test procedure proved to be specific for PrS, since preincubation with monospecific antibodies against PrS abolished the prolongation of clotting time, while reconstitution of adsorbed plasma with purified PrS restored its cofactor activity completely. The functional assay showed an inter-assay and intra-assay variation in the normal range of 11.7% and 10.1%, respectively (n = 20). PrS activity in a group of unselected patients (n = 34), revealing no abnormalities in global coagulation tests, amounted to 95.8 +/- 16.5% (mean +/- S.D.) with a range from 67% to 136% when analyzed in comparison to a plasma pool constituted from healthy volunteers. Patients (n = 32) undergoing oral anticoagulant therapy presented 21.1 +/- 10.8% residual PrS-activity accompanied by a concomitant decrease in PrS-antigen levels to 69.9 +/- 21.2%. The assay described is sensitive, it can be performed on routine basis and allows the detection of patients with PrS-deficiency.

Adult↗

PubMed1999

Positive rolandic sharp waves in preterm infants with periventricular leukomalacia: their relation to background electroencephalographic abnormalities.

The aim of this study was to clarify the significance of positive rolandic sharp waves (PRS) in preterm infants with periventricular leukomalacia (PVL) and their relation to background electroencephalographic (EEG) abnormalities. We retrospectively evaluated EEG findings of 93 preterm infants; 31 infants in the PVL group and 62 in the control group. PVL was diagnosed on the basis of ultrasonographic findings. We evaluated the EEG within 3 weeks of life in this study. PRS were defined as sharp transients of positive polarity appearing in the rolandic regions with an amplitude of more than 100 microV, sharply differentiated from the background activities. The number of PRS per minute was calculated over each record. PRS were defined as present when their frequency was beyond 0.1 per minute. PRS were observed in 14 (45%) and disorganized patterns in 27 (87%) of 31 infants in the PVL group, but both were not recognized in any infants in the control group. PRS were always associated with disorganized patterns. In the first EEG, PRS were absent in 8 of 11 infants with more than two recordings, although at least one of acute or chronic stage EEG abnormalities were already present. PRS were observed in 9 of 10 infants with severe diplegia, in 5 of 11 infants with moderate diplegia and none in 10 infants with mild diplegia. The average age of the first appearance of PRS was 7.6 days. The average age of the first appearance of periventricular echodensity and cyst was 4.2 days and 21.1 days, respectively. In conclusion, PRS are related to severe deep white matter injury and could be an early marker of severe PVL. PRS appeared in combination with disorganized patterns and were considered to be incorporated into chronic-stage EEG abnormalities. Detailed evaluation of background EEG activities can be helpful in detecting PVL with a high sensitivity from the early neonatal period.

Electroencephalography↗

PubMed2026

Comparison of Performance of Publicly Available Polygenic Risk Scores to Predict Clinically Actionable Coronary Artery Calcium Scores: The BioHEART-CT Cohort.

AIM: Coronary artery disease (CAD) remains the leading cause of morbidity and mortality globally. Polygenic Risk Scores (PRS) have been trained against major adverse cardiovascular outcomes (MACE) in large cohorts. Few studies have examined the effectiveness of these CAD MACE PRS tools in detecting individuals with subclinical coronary calcification. An association would provide an opportunity for clinical translation and targeting of CT imaging to new patients at risk for subclinical disease. METHODS: An analysis of 53 publicly available CAD PRS tools was completed in participants of the BioHEART-CT Discovery 1000 cohort presenting for clinically referred CT coronary angiography (CCTA). Associations between PRS and two binary CACS outcomes reflecting clinically significant coronary calcification were assessed: a) Absolute CACS (CACS ≥100 Agatston units [AU]; and b) Percentile CACS (CACS ≥75th age-/sex-adjusted percentile). Models were adjusted for genetic principal components, modifiable cardiovascular risk factors, and age/sex (in Absolute CACS). A subgroup analysis was performed using Framingham Risk Score (FRS) at baseline. RESULTS: Among 803 BioHEART-CT Discovery 1000 participants, 487 (60.6%) had any detectable coronary calcium. Most PRS tools demonstrated significant association with CACS outcomes, particularly evident when PRS was modelled as a continuous predictor. For Percentile CACS, 94.3% of PRS tools were significantly associated after full adjustment (median OR per PRS SD 1.41 (IQR 1.23-1.60). Quintile-based analysis revealed that individuals in the Top Quintile PRS had up to 7.99-fold increased odds of Percentile CACS ≥75th compared to those in the Bottom Quintile. Analysis by FRS group revealed positive performance, especially in individuals of Low FRS wherein incorporating a PRS increased pre-test probability from 14% to 26%. CONCLUSION: Whilst most CAD PRS tools have been developed against clinical events, we show their ability to predict clinically relevant coronary calcification. Utility appears strongest in individuals traditionally considered lower risk, presenting an opportunity for clinical translation for improved diagnosis in the primary prevention setting, with the potential to triage individuals into a CACS screening pathway.

coronary artery disease↗

PubMed2003

Postrelapse survival in osteosarcoma of the extremities: prognostic factors for long-term survival.

PURPOSE: To identify factors that influence postrelapse survival (PRS) in patients with nonmetastatic osteosarcoma of the extremity. PATIENTS AND METHODS: One hundred sixty-two patients with recurrent osteosarcoma of the extremity were retrospectively reviewed. The first-line treatment included surgery of the primary lesion and chemotherapy with methotrexate, doxorubicin, cisplatin, and ifosfamide. RESULTS: The projected 5-year PRS rate was 28%. Patients who had complete surgery of recurrence had a 5-year PRS of 39%, whereas for those who did not have complete surgery, PRS was 0% at 3 years (P <.0001). In the latter group, PRS was not influenced by site of recurrence and relapse-free interval (RFI), although it was influenced (P =.006) by the use of second-line chemotherapy (PRS, 53% at 12 months for patients who received chemotherapy v 12% for those who did not). In patients who had complete surgery, PRS was influenced by site of relapse (5-year PRS, lung 44%, other 19%; P <.06), RFI (5-year PRS at < or = 24 months, 20%; at > 24 months, 60%; P <.0001), and number of lung metastases (5-year PRS, two or fewer nodules, 59%; more than two nodules, 14%; P <.0001) but not by the use of a second-line chemotherapy treatment. CONCLUSION: RFI, site of metastases, and number of pulmonary nodules are the main prognostic factors for PRS in osteosarcoma. Complete surgery of recurrence is pivotal in the strategy of treatment. Patients with unresectable recurrence benefit from second-line chemotherapy, whereas our data do not support a generalized use of chemotherapy after complete surgery of first recurrence.

Adolescent↗

PubMed2026

Genetic Susceptibility to Incisional Hernia Evaluation of Hernia Polygenic Risk Scores.

OBJECTIVES: Incisional hernia (IH) affects 13-30% of people after abdominal surgery, resulting in substantial morbidity and costs. While clinical risk factors have been studied extensively, genomic risk for IH is incompletely understood. We aimed to evaluate the impact of polygenic risk scores (PRS) on IH risk prediction. METHODS: We created and evaluated three PRS for abdominal hernia, ventral hernia and latent hernia susceptibility for prediction of IH in an institutional biobank. The primary outcome was defined as the diagnosis or repair of an IH based on ICD-9/10-CM/PCS and CPT codes. Clinical covariates included age, sex, body mass index (BMI), smoking status, index procedure type, and perioperative surgical site infection. A phenome-wide association study (PheWAS) was performed to assess clinical associations with increased PRS. We then tested the ability of the PRS to improve prediction for IH by modeling clinical covariates with and without PRS in patients who underwent abdominal surgery. Model performance was assessed using 10 iterations of 5-fold cross-validation to estimate Brier scores and area under the receiver operating characteristic curve (AUROC), which were compared using cross-model Bayesian analysis of variance. RESULTS: In 55,809 subjects, assessed PRS was significantly associated with incisional, umbilical, and ventral hernia on PheWAS, with 1.19 greater odds of developing IH per 1-SD increase in PRS (95% CI: 1.13-1.25, P < 0.001). Of 9,909 subjects who underwent qualifying abdominal surgery, 706 developed IH. In this cohort, the latent hernia susceptibility PRS was associated with a 16% increased hazard of developing IH per 1-SD increase (HR 1.16; 95% CI: 1.07-1.26; P < 0.001). Compared to a predictive model using clinical covariates (Brier score = 0.047, 95% CI: 0.046-0.048; AUROC = 0.660, 95% CI: 0.653-0.666), addition of the PRS showed similar Brier score and AUROC estimates (Brier score = 0.047, 95% CI: 0.046-0.048; AUROC: 0.667, 95% CI: 0.661-0.673) at five years. Cross-model Bayesian analysis demonstrated >99% probability of practical equivalence when trying to detect a difference of ≥ 0.02. CONCLUSION: All three PRS for hernia were independently associated with IH, suggesting that genomic factors contribute significantly to IH development. However, none of the three PRS meaningfully improved clinical IH risk prediction in patients who underwent abdominal surgery. This suggests that clinical comorbidities and surgical techniques may be equally as important as genomic architecture.

Bayesian analysis↗

PubMed1999

Mastoid pneumatization and aging in children with Pierre-Robin syndrome and in the cleft palate population out of syndrome.

We examined the characteristics of mastoid pneumatization in the Pierre-Robin syndrome (PRS) and non-PRS cleft palate population in relation to age. There were 14 patients with PRS (median age, 5 years), 7 patients with bilateral cleft lip-palates (BCLP: median age, 6 years), 29 patients with unilateral cleft lip-palates (UCLP: median age, 6 years) and 15 patients with isolated cleft palates (ICP: median age, 7 years). All had secretory otitis and ventilation tubes inserted. Pneumatization was assessed by standard computerized planimetric methods. Temporal bone (Schüller view) X-rays were obtained. Areas of bone pneumatization were outlined and measured separately for each ear. The median pneumatized area of the mastoid (MBP) in PRS patients (6.73 cm2) was significantly lower than in non-PRS cleft patients (7.29 cm2). It was also lower than in UCLP (7.35 cm2; P = 0.01) and ICP (7.19 cm2; P = 0.02). MBP did not change significantly with age in PRS (Spearman rs = 0.11) and BCLP (Spearman rs = 0.11), but did increase significantly in the ICP group (Spearman rs = 0.23; P = 0.04). Cubic regression showed the best fit in the BCLP (r2 = 0.61; P = 0.01) and ICP (r2 = 0.10; P = 0.05). It was not significant for PRS (r2 = 0.132) or UCLP (r2 = 0.049). We concluded that pneumatization in all cases increases with age, but it is statistically significant only in ICP. PRS patients have a lower area of mastoid air-cell size than the non-PRS cleft palate population. The extent of mastoid pneumatization in PRS patients does not correlate with age because of the negative influence of the mandibular hypoplasia and glossoptosis present.

Adolescent↗

PubMed1993

Molecular characterization of phosphoribosylpyrophosphate synthetase from Leishmania donovani.

The phosphoribosylpyrophosphate synthetase (PRS) enzyme from parasitic protozoa plays a critical role in the acquisition of exogenous purine bases by providing the phosphoribosylpyrophosphate substrate for phosphoribosylation. To characterize a PRS enzyme from parasitic protozoa, the prs gene was isolated from a genomic library of Leishmania donovani DNA. A 1936-bp SalI fragment was sequenced that encompassed an open reading frame of 1113 nucleotides encoding a polypeptide of 371 amino acids and 40 787 Da. After gap alignment, the leishmanial PRS exhibited 40-42% amino acid identity with a variety of mammalian and prokaryotic PRSs. L. donovani PRS also contained an approx. 20-amino acid stretch that was highly homologous to the phosphoribosylpyrophosphate binding domains of mammalian phosphoribosyltransferase enzymes. Two prs-specific transcripts of 2.6 and 2.1 kb were detected by Northern analysis, and Southern blots of genomic DNA implied that the prs locus was not tandemly repeated in the L. donovani genome. PRS activity was detected in L. donovani extracts, and apparent Km values of approx. 30 microM and approx. 1 mM were calculated for ribose-5-phosphate and ATP, respectively. PRS was sensitive to inhibition by AMP and ADP but refractory to IMP, GMP, GTP, CTP, and UTP. The high apparent Km value of the parasite enzyme for ATP and its insensitivity to inhibition by many nucleotides suggested that kinetic differences between the L. donovani and human PRSs could provide an avenue for rational therapeutic manipulation of parasitic disease. The isolation of the L. donovani prs gene now provides an opportunity to genetically dissect the determinants responsible for the function and regulation of this indispensable enzyme of purine and pyrimidine metabolism in a genus of parasitic protozoa.

Amino Acid Sequence↗

PubMed2025

Rare variants and survival of patients with idiopathic pulmonary fibrosis: analysis of a multicentre, observational cohort study with independent validation.

BACKGROUND: Rare pathogenic variants in telomere-related genes are associated with poorer clinical outcomes in idiopathic pulmonary fibrosis (IPF). We aimed to assess whether rare qualifying variants in monogenic adult-onset pulmonary fibrosis genes are associated with IPF survival. Using polygenic risk scores (PRS), we also evaluated the influence of common IPF risk variants in patients carrying the qualifying variants. METHODS: We identified qualifying variants in telomere and non-telomere genes using whole-genome sequences from individuals clinically diagnosed with IPF and enrolled in the Pulmonary Fibrosis Foundation Patient Registry (PFFPR), a large multicentre, observational cohort study (March 29, 2016 to June 15, 2018, n=888). We also derived a PRS for IPF (PRS-IPF) from known common sentinel IPF variants. The primary outcome was the association between qualifying variants and survival. The secondary outcome was the association between qualifying variants and PRS-IPF. We used logistic regression models adjusted for sex, age at diagnosis, and principal components of genetic heterogeneity to examine the mutual relationship of qualifying variants and PRS-IPF. The association between qualifying variants and PRS-IPF with survival was tested using Cox proportional hazard models adjusted for baseline confounders. Validation of the results was sought in data from an independent multicentre, prospective, observational cohort study of IPF in the UK (PROFILE, May 17, 2010 to Sept 5, 2017, n=472), and results were meta-analysed under a fixed-effects model. FINDINGS: We included 888 patients from PFFPR and 472 from PROFILE, totalling 1360 participants. In the PFFPR, carriers of qualifying variants in monogenic adult-onset pulmonary fibrosis genes were associated with lower PRS-IPF (odds ratio 1·79 [95% CI 1·15-2·81]; p=0·010) and shorter survival (hazard ratio 1·53 [1·12-2·10]; p=7·33 × 10-3). Individuals with the lowest PRS-IPF also had worse survival (1·61 [1·25-2·07]; p=1·87 × 10-4). These findings were validated in PROFILE and the meta-analysis of the results showed a consistent direction of effect across both cohorts. INTERPRETATION: We found non-additive effects between qualifying variants and common risk variants in IPF survival, suggesting distinct disease subtypes and raising the possibility of using PRS to guide sequencing prioritisation. Assessing the carrier status for qualifying variants and modelling PRS-IPF promises to further contribute to predicting disease progression among patients with IPF. FUNDING: Instituto de Salud Carlos III; Instituto Tecnológico y de Eenergías Renovables; Cabildo Insular de Tenerife; Fundación DISA; National Heart, Lung, and Blood Institute of the US National Institutes of Health; and UK Medical Research Council.

Humans↗

PubMed2025

A multi-ancestry polygenic risk score for Alzheimer disease is associated with cognitive decline, hippocampal atrophy and neuropathological hallmarks in diverse populations.

Alzheimer disease (AD) has a strong genetic basis, yet previously derived polygenic risk scores (PRS) are heavily weighted by the APOE locus and perform inconsistently across diverse ancestries. We developed an APOE-independent multi-ancestry AD PRS using genome-wide association study summary statistics from cohorts in the United States, Europe and East Asia that were applied to European ancestry (EA), African American (AA), Caribbean Hispanic (CH), and East Asian cohorts from the Alzheimer's Disease Genetics Consortium. PRS performance was evaluated in the multi-ancestry Alzheimer's Disease Sequencing Project (ADSP) dataset and validated in several additional multi-ancestry cohorts. The PRS was significantly associated with AD in the ADSP EA, AA, CH, and Native American Hispanic groups with adjusted odds ratios (ORs) between 1.14 and 1.52 per standard deviation of the PRS. PRS performance was validated in the replication cohorts (ORs 1.21-1.65). The PRS was also associated with poorer memory, executive function, and language performance; greater AD-related neuropathological burden (including CERAD, Braak stage, and Thal phase scores); reduced hippocampal volume; lower CSF Aβ42; and elevated total tau and phosphorylated tau (p-tau), with stronger p-tau associations observed in women. Longitudinal analyses revealed that individuals in the highest PRS decile exhibited the steepest cognitive decline, particularly among those who progressed to AD. Our findings demonstrate the utility of an ancestry-aware and APOE-independent PRS for advancing understanding of the genetic basis of AD across diverse populations. Associations observed with early biological and cognitive changes and potential sex-specific differences support the incorporation of a PRS in clinical trials and personalized intervention and prevention strategies.

Journal Article↗

PubMed1994

The use of the donor oocyte program to evaluate embryo implantation.

Pregnancy rates (PRs) are generally higher in most IVF programs when embryos derived from donor oocytes are transferred compared to the PRs of women undergoing IVF-ET. DeZiegler et al., using the transfer of frozen embryos (either patient or donor derived) in natural cycles, found a higher PR following donor oocyte derived ET and thus concluded that the lower PR in the non-donor cycles was not related to the controlled ovarian hyperstimulation (COH) regimen. Their data thus suggested the improved PR with donor embryos may be related to better quality oocytes used for recipients; however, a more receptive endometrium in the oocyte recipients could also explain the data. The studies presented herein further evaluated the latter hypothesis of improved endometrial environment for recipients by comparing PRs in donors vs recipients in a shared oocyte program. Also the study would determine if endometrial echo patterns (EP) and/or thickness (ET) help predict better PRs as they do in stimulated cycles. Finally studies would be performed to compare PRs in older vs younger oocyte recipients to see if there may be a uterine senescence in humans as in other animals and to see if age has an adverse effect on the endometrium as evidenced by sonographic studies. Study 1 compared the clinical PRs in donors vs recipients in a shared program from 1/1/92 to 12/31/92. PR for donors was 23.6% (17 pregnant in 72 transfers) compared to 34.6% for recipients (26/75). Mean age of the donors was 32 compared to 39.8 for recipients. If recipients > 40 were eliminated the PR for recipients was 44.1% (15/34). Study 2 evaluated PRs according to ET and EP in 58 transfers using donor oocytes (44 patients). There were only 2 clinical pregnancies of 22 transfers (9%/cycle) when ET was < 10 mm at the time of the donor's hCG injection compared to 14 pregnant of 36 transfers (38.7%) when ET was > or = 10 mm (p < 0.01). However, there were no differences in PR when the endometrium compared to myometrium was hypoechogenic, isoechogenic, or hyperechogenic. The respective PRs were 16.7% (1/6), 31% (9/39) and 26.1% (6/23). Study 3 evaluated PRs in donor oocyte recipients according to age (< 40 vs > or = 40 years). After evaluating PRs after the first 58 ETs to recipients of shared oocytes we found a much lower PR in women > or = 40 (2/23, 8.6%/cycle) vs 14/55 (25.4%) in those < 40.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed2025

Development and evaluation of patient-centred polygenic risk score reports for glaucoma screening.

BACKGROUND: Polygenic risk scores (PRS), which provide an individual probabilistic estimate of genetic susceptibility to develop a disease, have shown effective risk stratification for glaucoma onset. However, there is limited best practice evidence for reporting PRS and patient-friendly reports for communicating PRS effectively are lacking. Here we developed patient-centred PRS reports for glaucoma screening based on the literature, and evaluated them with participants using a qualitative research approach. METHODS: We first reviewed existing PRS reports and literature on probabilistic risk communication. This informed the development of a draft glaucoma screening PRS report for a hypothetical high risk individual from the general population. We designed three versions of the report to illustrate risk using a pictograph, a pie chart and a bell curve. We then conducted semi-structured interviews to assess preference of visual risk communication aids, understanding of risk, content, format and structure of the reports. Participants were invited from an existing study, which aims to evaluate the clinical validity of glaucoma PRS among individuals > 50 years from the general population. Numeracy and literacy levels were assessed. RESULTS: We interviewed 12 individuals. The cohort was highly educated (42% university education), all were European and 50% were female. Numeracy (mean 2.1 ± 0.9, range 0 to 3), graph literacy (mean 2.8 ± 0.8, range 0 to 4) and genetic literacy (mean 24.2 ± 6.2, range - 20 to + 46) showed a range of levels. We analysed the reports under three main themes: visual preferences, understanding risk and reports formatting. The visual component was deemed important to understanding risk, with the pictograph being the preferred visual risk representation, followed by the pie chart and the bell curve. Participants expressed preference for absolute risk in understanding risk, along with the written content explaining the results. The importance of follow-up recommendations and time to glaucoma onset were deemed important. Participants expressed varied opinions in the level of information and the colours used, which informed revisions of the report. CONCLUSIONS: Our study revealed preferences for reporting PRS information in the context of glaucoma screening, to support the development of clinical PRS reporting. Further research is needed to assess PRS communication in other groups representative of target populations and with other target audiences (e.g. referring clinicians), and its potential psychosocial impact in the wider community.

Humans↗