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PubMed2026

Polygenic risk scores and lifestyle factors predicting new onset of type 2 diabetes in the Japanese general population.

PURPOSE: This study investigated the association of polygenic risk scores (PRS) and lifestyle factors with type 2 diabetes mellitus development in Japanese populations and evaluated whether PRS can improve diabetes risk prediction beyond traditional risk factors. METHODS: We conducted a cross-sectional and a longitudinal study using the Shika resident cohort (n = 895) and the Toshiba worker cohort (n = 7019), respectively. Participants were categorized into low, intermediate, and high genetic risk groups using PRS constructed with genome-wide association study data from East Asian populations. We defined diabetes based on hemoglobin A1c, fasting blood glucose, self-reported diagnosis, or medication use. The associations of PRS and lifestyle factors with diabetes development were analyzed using multivariate logistic regression and Cox proportional hazards models. RESULTS: Higher PRS were associated with increased diabetes risk in both cohorts (resident cohort: odds ratio 4.51, 95% CI 2.53-8.04; worker cohort: hazard ratio 1.50, 95% CI 1.23-1.83 for high vs low PRS), which remained consistent across age, body mass index, and comorbidities. Regular exercise, absence of hypertension, and absence of dyslipidemia were associated with lower diabetes risk, particularly in the high PRS group. The addition of PRS to conventional prediction models improved the discrimination of diabetes risk. MAIN CONCLUSION: PRS are associated with diabetes risk in Japanese general populations, independent of traditional risk factors. Nonetheless, healthy lifestyle habits may reduce diabetes risk even among genetically susceptible individuals, which support the utility of PRS for personalized diabetes risk assessment and prevention strategies.

Adult↗

PubMed1997

Progesterone blockade of a luteinizing hormone surge blocks luteinizing hormone-releasing hormone Fos activation and activation of its preoptic area afferents.

Progesterone is capable of facilitating or blocking the luteinizing hormone (LH) surge, depending on the timing of its administration. However, the precise targets of progesterone's actions are unknown. Since recent studies described the presence of a periventricular preoptic area (pePOA) neuron population afferent to LH-releasing hormone (LHRH) neurons that is co-activated to express c-Fos with LHRH neurons at the time of the LH surge, the present study was designed to determine if the pePOA neurons contain progesterone receptors (PRs) and whether progesterone inhibition is manifested by a failure of LHRH and pePOA neurons to become activated at the time of an LH surge. For progesterone facilitation, a group of immature rats each received a silastic capsule (1.57 mm i.d., 3.18 mm o.d., 1.5 cm long) containing estradiol-17beta (E2) in peanut oil (150 microg/ml) at 09.00 h on postnatal day 28 followed 24 h later by a progesterone implant (crystalline, 1.57 mm i.d., 3.18 mm o.d., 1.5 cm long). For progesterone inhibition, a second group of rats received the estrogen capsule and a progesterone capsule (3.35 mm i.d., 4.65 mm o.d., 3.0 cm long) together at 09.00 h on day 28, and 24 h later received only a blank capsule. On the afternoon of postnatal day 29, all animals were anesthetized and perfused for localization of c-Fos and LHRH, PRs alone, or c-Fos and PRs. The present studies determined that following a progesterone-inhibition paradigm, along with blockade of the LH surge, both activation of LHRH and pePOA neurons was low or absent. Staining of PRs in progesterone-facilitated and progesterone-inhibited rats indicated that the pePOA neurons contained PRs in similar patterns. Double labeling of c-Fos and PRs in progesterone-facilitated rats indicated that nearly all the c-Fos-positive neurons of the pePOA (80 +/- 4.2%) co-expressed PRs; in progesterone-inhibited rats, only 32 +/- 12% of few c-Fos-positive neurons also contained PRs. In no instance were LHRH neurons found to contain PRs. Taken together, these data suggest that both progesterone facilitation and inhibition likely involve direct actions of progesterone on the pePOA neurons, and are consistent with a role for the pePOA neurons in transducing steroid effects on LHRH neurons.

Animals↗

PubMed1996

Overexpression of the normal phosphoribosylpyrophosphate synthetase 1 isoform underlies catalytic superactivity of human phosphoribosylpyrophosphate synthetase.

To define the enzymatic and genetic basis of X-linked phosphoribosylpyrophosphate synthetase (PRS) catalytic superactivity, we measured concentrations of X-linked PRS1 and PRS2 isoforms in cultured fibroblasts and lymphoblasts by immunoblotting after separation by polyacrylamide-urea isoelectric focusing. PRS1 comprised >80% of measurable PRS isoforms in all fibroblast strains, but PRS1 concentrations in cells from six affected males exceeded those in normal cells by 2-6-fold. PRS absolute specific activities (activity per mg of PRS isoforms) were comparable in all fibroblast strains and in purified recombinant normal PRS1, confirming selectively increased levels of PRS1 isoform as the enzymatic basis of PRS catalytic superactivity. Cloning, sequencing, and expression of normal subject- and patient-derived PRS cDNAs predicted normal translated region sequences for both PRS isoforms and revealed no differences in catalytic properties of recombinant PRS1. Normal and patient PRPS1 transcribed but untranslated DNA sequences were also identical. Northern blot analysis showed selective increase in relative concentrations of PRS1 transcripts in patient fibroblasts. In PRS catalytic superactivity, overexpression of the normal PRS1 isoform thus appears to result from an altered pretranslational mechanism of PRPS1 expression. In lymphoblasts, however, expression of this alteration is attenuated, explaining the absence of phenotypic expression of PRS catalytic superactivity in these cells.

Base Sequence↗

PubMed2025

Genetic Susceptibility to the Environment Moderates the Impact of Childhood Experiences on Psychotic, Depressive, and Anxiety Dimensions.

BACKGROUND AND HYPOTHESIS: Gene-by-environment (GxE) studies in psychosis have exclusively focused on negative exposures. However, evidence supports the resilience-enhancing effect of positive factors on psychosis outcome. The Differential Susceptibility (DS) model proposes that common genetic variants may confer not only disproportionate responsiveness to negative environments, but also greater sensitivity to positive, resilience-enhancing conditions. This study is the first to apply the DS model to the expression of subclinical psychosis, employing polygenic risk scores of environmental sensitivity (PRS-ES). PRS-ES were hypothesized to moderate, in a DS manner, associations between childhood adversity and psychosis, affective, and anxiety dimensions in young adults. An exploratory goal examined whether PRS for psychotic-like experiences (PRS-PLE) also showed DS patterns. STUDY DESIGN: PRS, schizotypy, PLE, depression, anxiety, and childhood adversity ratings were obtained for 197 nonclinical young adults. LEGIT software for testing competitive-confirmatory GxE models was employed. STUDY RESULTS: Results largely supported DS: Individuals high on PRS-ES showed increased subclinical psychosis, depression, and anxiety if they had experienced elevated childhood adversity, and lower symptoms if exposed to low levels of adversity as compared with those with low PRS-ES. Similarly, PRS-PLE moderated the effect of adversity on PLE, positive schizotypy, and depression following the DS model, but only PRS-ES moderation on PLE survived statistical correction. CONCLUSIONS: Our results suggest that genetic DS to the environment is relevant to psychosis, depression, and anxiety. Current debates on reconceptualization of genetic "risk" and resilience may benefit from this insight that support optimistic views on preventative efforts for early detection and intervention.

Humans↗

PubMed2025

Stratifying Lung Adenocarcinoma Risk with Multi-ancestry Polygenic Risk Scores in East Asian Never-Smokers.

BACKGROUND: Lung adenocarcinoma (LUAD) in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve LUAD risk prediction. METHODS: PRSs were developed using genome-wide association study summary statistics from East Asian (8,002 cases; 20,782 controls) and European (2,058 cases; 5,575 controls) populations. Single-ancestry models included PRS-25, PRS-CT, and LDpred2; multi-ancestry models included LDpred2+PRS-EUR128, PRS-CSx, and CT-SLEB. Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium (FLCCA) and externally validated in the Nanjing Lung Cancer Cohort (NJLCC). We assessed predictive accuracy via AUC, with 10-year and (age 30-80) absolute risks estimates. RESULTS: The best multi-ancestry PRS, using East Asian and European data via CT-SLEB (clumping and thresholding, super learning, empirical Bayes), outperformed the best East Asian-only PRS (LDpred2; AUC=0.629, 95% CI:0.618,0.641), achieving an AUC of 0.640 (95% CI:0.629,0.653) and odds ratio of 1.71 (95% CI:1.61,1.82) per SD increase. NJLCC Validation confirmed robust performance (AUC =0.649, 95% CI: 0.623, 0.676). The top 20% PRS group had a 3.92-fold higher LUAD risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year LUAD risk at age 50 (0.42%) by age 41, nine years earlier. CONCLUSIONS: Multi-ancestry PRS approaches enhance LUAD risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

East Asian never smokers↗

PubMed1991

Mandible, tongue, and airway in Pierre Robin sequence: a longitudinal cephalometric study.

The purpose of this retrospective longitudinal cephalometric study was to analyze size, growth, and relations of the mandible, tongue, and airway in the isolated, nonsyndromic Pierre Robin Sequence (PRS) infant. The objective was to understand better the early morphologic changes that occur in these structures. The data were obtained from lateral cephalometric radiographs taken in the first 2 years of life on 17 PRS infants, 26 isolated cleft palate (CP), and 26 normal control (N) infants. Mean values of each variable were compared using a univariate analysis of variance. A multivariate discriminant function analysis (DFA) was also used to characterize group differences. The three groups were distinct throughout the period of study. Differences were greater at the earliest age and the distinction was greater between the PRS and N infants with the CP infant in between, but having more similarity to the PRS infant. Initially, the PRS infant had a shorter tongue and mandibular length, narrower airway, smaller tongue area and the hyoid position was more posterior and inferior as compared to N. The tongue shape and position were specific to the PRS infants. This group distinction diminished with age and resulted from an increased mandibular growth rate in the PRS infant. These findings support the hypothesis of "partial mandibular catch-up growth" in the PRS infant. The increased growth rate in the PRS infant improved the airway dimension, which might be partly responsible for the natural resolution of the respiratory distress. This increased growth rate did not allow for the various structures to reach values equal to normal.

Adult↗

PubMed2026

Addition of CAD polygenic risk score to coronary artery calcium score enhances prediction of MACE.

BACKGROUND: Coronary heart disease (CHD) is prevalent in the United States, highlighting the need for accurate risk prediction to inform primary prevention strategies. While multivariate risk models like the Framingham Risk Score and ACC/AHA Pooled Cohort Equations are commonly utilized, novel risk markers, such as the coronary artery calcium score (CACS) and polygenic risk score (PRS), are increasingly gaining recognition. OBJECTIVES: This study aimed to compare the diagnostic utility of CACS and CAD PRS, both individually and in combination, for predicting major adverse cardiovascular events (MACE). METHODS: We conducted a retrospective analysis of a cohort comprising 1,380 predominantly Caucasian participants from the Sanford Health System. CAD PRS was constructed using genetic variants, while CACS was assessed via cardiac computed tomography (CT). Statistical analyses evaluated the relationship between each modality and MACE. RESULTS: Both CAD PRS and CACS were significantly associated with future MACE. Following the adjustment for covariates, the area under the curve (AUC) for both the CACS and PRS models was comparable, indicating similar predictive capabilities for MACE. However, the combination of CAD PRS with CACS significantly enhanced predictive accuracy, outperforming either modality alone. CONCLUSIONS: This study underscores the value of integrating CACS and CAD PRS in predicting MACE. The synergistic effect of CAD PRS combined with CACS markedly improves predictive power. Further research and prospective studies are necessary to validate these findings and assess their clinical implications. Investigating the interactions between PRS and CACS will be crucial for refining cardiovascular risk prediction and optimizing prevention strategies.

cardiac genetics↗

PubMed2026

Polygenic risk score and its role in cancer susceptibility.

BACKGROUND: Polygenic risk score (PRS) has the ability to stratify inherited susceptibility to cancer and, as a complement to monogenic testing, can identify individuals at increased genetic risk even when no pathogenic variant is detected in high- or moderate-penetrance genes. It reflects the combined additive effects of a large number of low-penetrance variants across the genome, and represents a continuum of genetic susceptibility with an approximately normal distribution. Clinically relevant differences are typically observed in individuals in the highest and lowest percentiles of the PRS distribution, while relative risk gradients depend on the cancer type, the specific PRS model, and the reference population used. PRS is not a single test but rather a family of statistical models that differ in their design, predictive performance, and transferability across populations, underscoring the need for external validation and population-specific calibration of absolute risk. Broader implementation is thus still held back by differences between individual PRS models, limited transferability, and the lack of harmonized guidance on indication, reporting, and clinical decision-making. Consequently, clinical use in the European Union remains largely confined to pilot studies and local projects. Within these initiatives, PRS is most commonly applied in two main ways - either as a triage tool for intensified diagnostics or screening in higher-risk groups, or as a component of multifactorial absolute-risk models (e. g. BOADICEA/CanRisk) that integrate PRS with other risk factors such as pathogenic variants in moderate-penetrance genes (e. g. ATM or CHEK2), family history, or lifestyle factors. By refining absolute-risk estimates, PRS may shift individuals across clinical decision thresholds for more intensive surveillance and preventive strategies. AIM: This review summarizes the principles of PRS, the main sources of variability between models, and its potential applications in risk stratification and personalized cancer screening. It also addresses limitations in transferability, the need for calibration, and the currently limited evidence for improvements in hard clinical outcomes.

Humans↗

PubMed2025

Genetic Predisposition to Low-Density Lipoprotein Cholesterol and Incident Type 2 Diabetes.

IMPORTANCE: Treatment to lower high levels of low-density lipoprotein cholesterol (LDL-C) reduces incident coronary artery disease (CAD) risk but modestly increases the risk for incident type 2 diabetes (T2D). The extent to which genetic factors across the cholesterol spectrum are associated with incident T2D is not well understood. OBJECTIVE: To investigate the association of genetic predisposition to increased LDL-C levels with incident T2D risk. DESIGN, SETTING, AND PARTICIPANTS: In this large prospective, population-based cohort study, UK Biobank participants who underwent whole-exome sequencing and genome-wide genotyping were included. Participants were separated into 7 groups with familial hypercholesterolemia (FH), predicted loss of function (pLOF) in APOB or PCSK9 variants, and LDL-C polygenic risk score (PRS) quintiles. Data were collected between 2006 and 2010, with a median follow-up of 13.7 (IQR, 12.9-14.5) years. Data were analyzed from March 1 to November 1, 2024. EXPOSURES: LDL-C level, LDL-C PRS, FH, or pLOF variant status. MAIN OUTCOMES AND MEASURES: Cox proportional hazards regression models adjusted for age, sex, genotyping array, lipid-lowering medication use, and the first 10 genetic principal components were fitted to assess the association between LDL-C genetic factors and incident T2D and CAD risks. RESULTS: Among the 361 082 participants, mean (SD) age was 56.8 (8.0) years, 194 751 (53.9%) were female, and mean (SD) baseline LDL-C level was 138.0 (33.6) mg/dL. During the follow-up period, 22 619 (6.3%) participants developed incident T2D and 17 966 (5.0%) developed incident CAD. The hazard ratio for incident T2D was lowest in the FH group (0.65; 95% CI, 0.54-0.77), while the highest risk was in the pLOF group (1.48; 95% CI, 1.18-1.86). The association between LDL-C PRS and incident T2D was 0.72 (95% CI, 0.66-0.79) for very high LDL-C PRS, 0.87 (95% CI, 0.84-0.90) for high LDL-C PRS, 1.13 (95% CI, 1.09-1.17) for low LDL-C PRS, and 1.26 (95% CI, 1.15-1.38) for very low LDL-C PRS. CAD risk increased directly with the LDL-C PRS. CONCLUSIONS AND RELEVANCE: In this cohort study, LDL-C and T2D risks were inversely associated across genetic mechanisms for LDL-C variation. Further elucidation of the mechanisms associating low LDL-C risk with increased risk of T2D is warranted.

Humans↗

PubMed2025

Polygenic Prediction of Peripheral Artery Disease and Major Adverse Limb Events.

IMPORTANCE: Peripheral artery disease (PAD) is a heritable atherosclerotic condition associated with functional decline and high risk for limb loss. With growing knowledge of the genetic basis for PAD and related risk factors, there is potential opportunity to identify individuals at high risk using polygenic risk scores (PRSs). OBJECTIVE: To develop a novel integrated, multiancestry polygenic score for PAD (PRS-PAD) and evaluate its risk estimation for PAD and major adverse limb events in 3 populations. DESIGN, SETTING, AND PARTICIPANTS: This longitudinal cohort study was conducted among individuals with genotyping and electronic health record data in the UK Biobank (2006-2021), All of Us (AoU, 2018-2022), and the Mass General Brigham Biobank (MGBB, 2010-2023). Data were analyzed from July 2023 to February 2025. EXPOSURES: PRS-PAD, previously published PAD polygenic scores, and clinical risk factors. MAIN OUTCOMES AND MEASURES: The primary outcomes were PAD and major adverse limb events, defined as a surrogate of major amputation and acute limb ischemia. RESULTS: The study populations included 400 533 individuals from the UK Biobank (median [IQR] age, 58.2 [45.0-71.4] years; 216 215 female participants [53.9%]), 218 500 from AoU (median [IQR] age, 53.6 [37.7-65.0] years; 132 647 female participants [60.7%]), and 32 982 from MGBB (median [IQR] age, 56.0 [32.0-80.0] years; 18 277 female participants [55.4%]). In the UK Biobank validation cohort, PRS-PAD was associated with an odds ratio [OR] per SD increase of 1.63 (95% CI, 1.60-1.68; P < .001). After adjusting for clinical risk factors, the OR for the top 20% of PRS-PAD was 1.68 (95% CI, 1.62-1.74; P < .001) compared to the remainder of the population. Among PAD cases without a history of diabetes, smoking, or chronic kidney disease (n = 3645), 1097 individuals (30.1%) had a high PRS-PAD (top 20%). In incident disease analysis, PRS-PAD improved discrimination (C statistic, 0.761), which was nearly equivalent to the performances of diabetes (C statistic, 0.760) and smoking (C statistic, 0.765). Among individuals with prevalent PAD, high PRS-PAD was associated with an increased risk of incident major adverse limb events in the UK Biobank (hazard ratio [HR], 1.75; 95% CI, 1.18-2.57; P = .005), MGBB (HR, 1.56; 95% CI, 1.06-2.30; P = .02), and AoU (HR, 1.57; 95% CI, 1.06-2.33; P = .03). CONCLUSIONS AND RELEVANCE: This cohort study develops a new PRS that stratifies risk of PAD and adverse limb outcomes. Incorporating polygenic risk into PAD care warrants further investigation to guide screening and tailor management to prevent major adverse limb events.

Humans↗

PubMed1976

Dependence of reward contingent positive variation (RCPV) and cortical synchronization on visual input in the cat.

Cats trained to press a lever for milk reward display high amplitude low frequency electrocorticographic post-reinforcement synchronization (PRS) associated with epicortical steady potential shift, termed Reward Contingent Positive Variation (RCPV), over the parieto-occipital cortex. Previously, it was found that the PRS-RCPV phenomenon depends on unpatterned light input devoid of any conceivable information or conditional property. Although training in the dark most likely eliminated the "novelty" factor and the resulting orienting reaction to "light off" as a cause of PRS-RCPV suppression, a possibility could not be excluded that the absence of light had a negatively reinforcing property preventing the emergence of PRS-RCPV. Hence, in the present study an experimental paradigm was used in which "light off" and/or "tone on" cues signalled the availability of reward, the "light off" periods extending through the consummatory response. Seven out of 9 cats, despite 2-4 months of daily training, and 85% correct timing of bar press performance, never showed a PRS-RCPV response (one animal showed only sporadic and poorly developed patterns.) However, when the light was turned on during consumption, in 85% of such tests a fully developed PRS-RCPV emerged in a stimulus-bound manner. One animal was an exception and showed PRS-RCPV both in the absence and presence of light. It was concluded that light input plays a crucial role in the emergence of the PRS-RCPV phenomenon and therefore also participates in the integration of gustatory input.

Animals↗

PubMed1995

Mammalian phosphoribosyl-pyrophosphate synthetase.

PRPP synthetase from rat liver exists as large molecular weight aggregates composed of at least three different components. Cloning of cDNA for the catalytic subunit revealed the presence of two highly homologous isoforms of 34 kDa, designated as PRS I and PRS II. Northern blot analysis showed tissue-differential expression of the two isoform genes. cDNA was expressed in E. coli and studies on the recombinant isoforms showed differences in sensitivity to inhibition by ADP and GDP and to heat inactivation. The rat gene for PRS I has 22 kb and is split into 7 exons. cDNAs for human enzymes were also cloned. Human genes for PRS I and PRS II are localized at different regions on the X-chromosome and their promoter regions were examined. Another component, PRPP synthetase-associated protein of 39 kDa (PAP39), was cloned from cDNA library of the rat liver. The deduced amino acid sequence of PAP39 is remarkably similar to those of PRS I and PRS II. Evidence indicated molecular interaction between PAP39 and the catalytic subunits and an inhibitory effect of PAP39 on the catalytic activity. Expression of the PAP39 gene is tissue-differential like the PRS genes, indicating that the composition of PRPP synthetase may differ with the tissue, hence properties of the enzyme would differ. Further studies on these components and their interaction are expected to reveal various mechanisms governing mammalian PRPP synthetase.

Amino Acid Sequence↗

PubMed1982

Variant T47D human breast cancer cells with high progesterone-receptor levels despite estrogen and antiestrogen resistance.

In target tissues for estrogen, including breast cancer cells, the synthesis of progesterone receptors (PRs) is controlled by estradiol acting through estrogen receptors (ERs). We describe studies with T47D human breast cancer cells, whose PRs are not regulated by estradiol, though present in extraordinary amounts (300,000 sites per cell). These cells have no ERs sedimenting at 8S on sucrose density gradients, and no unfilled cytoplasmic or nuclear ERs; some apparently hormone-filled nuclear sites, with KD congruent to 0.7 nM, can be demonstrated by exchange. The nuclear ER sites are not processed after estradiol treatment. Nafoxidine, however, doubles nuclear estrogen binding in 6 hr, in a cycloheximide-insensitive step that may represent a reversal of processing. T47D cells are profoundly resistant to estrogens and antiestrogens; estradiol does not stimulate PRs, and nafoxidine concentrations that are cytotoxic to ER-positive cells have no effect on cell growth or on PR levels. Yet the PRs are normal by several criteria, and they can be stoichiometrically translocated to, and extracted from, nuclei in the first 3 min after progesterone addition. If progesterone treatment exceeds 10 min, rapid nuclear turnover prevents quantitative PR recovery. Cytoplasmic PRs are replenished in 10 to 24 hr, and this cycloheximide-sensitive step is also estrogen- and nafoxidine-resistant. However, despite their insensitivity to estradiol or antiestrogen, PRs are not constitutively synthesized; 5-bromodeoxyuridine and sodium butyrate can selectively inhibit PR production. Thus, since PRs retain some characteristics of inducible proteins, the persistent nuclear estrogen-binding sites may be stimulating PRs continuously, even in the absence of exogenous estradiol.

Breast Neoplasms↗

PubMed2006

Mandibular morphology and growth with and without hypodontia in subjects with Pierre Robin sequence.

INTRODUCTION: Mandibular micrognathia is the hallmark of Pierre Robin sequence (PRS). A high prevalence of mandibular hypodontia has been reported in subjects with PRS. The hypothesis of this study is that the morphology of the mandible in subjects with PRS and mandibular hypodontia is different from that in subjects with PRS but without mandibular hypodontia. METHODS: The study was conducted at the craniofacial center of The Hospital for Sick Children in Toronto. The study sample comprised 16 caucasian children with nonsyndromic PRS (7 boys, 9 girls) with mandibular hypodontia and 18 white children with nonsyndromic PRS (6 boys, 12 girls) without hypodontia. Longitudinal lateral cephalograms were available before orthodontic treatment (T1; mean age, 11.7 years) and after orthodontic treatment but before orthognathic surgery (T2; mean age, 16.6 years). A new, customized cephalometric analysis with additional landmarks and measurements to study mandibular morphology was performed. Differences in measurements were studied by using analysis of variance adjusted for age and sex. RESULTS: Cephalometric measurements were smaller in the group with mandibular hypodontia at T1: mandibular length (3.36 mm, P = .04), ramal length (2.78 mm, P = .04), posterior facial height (3.97 mm, P = .03), and mandibular molar eruption (1.96 mm, P = .02). At T2, the differences increased: mandibular length (4.56 mm, P = .02), ramal length (4.04 mm, P = .002), posterior facial height (5.98 mm, P = .001), and mandibular molar eruption (2.08 mm, P = .04). Comparison of growth increments between the 2 groups from T1 to T2 showed a greater cranial base deflection increment in the group with mandibular hypodontia (0.88 degrees, P = .02) and a larger posterior facial height increment in the group without mandibular hypodontia (2.02 mm, P = .04). CONCLUSIONS: Children with nonsyndromic PRS with mandibular hypodontia had smaller mandibles than children with nonsyndromic PRS and normal complements of mandibular teeth. Their patterns of growth did not improve during adolescence, and the magnitude of differences increased.

Adolescent↗

PubMed2026

Development and Validation of a Clinical Polygenic Risk Report in U.S.-Based Health Systems for 8 Cardiovascular Conditions.

BACKGROUND: Polygenic risk scores (PRS) stratify inherited cardiovascular risk, but their path to clinical implementation remains unclear. OBJECTIVES: We aimed to develop and validate integrated PRS for 8 cardiovascular conditions and outline a framework for their clinical reporting. METHODS: We analyzed genotype and clinical data from 245,394 All of Us Research Program participants. Publicly available PRS for 8 traits-coronary artery disease, atrial fibrillation, type 2 diabetes, venous thromboembolism (VTE), thoracic aortic aneurysm (TAA), extreme hypertension, severe hypercholesterolemia, and elevated lipoprotein(a)-were combined using PRSmix, an elastic-net approach. Integrated PRS were externally validated in 53,306 Mass General Brigham Biobank participants using logistic regression, adjusting for age, sex, and ancestry. RESULTS: Of 53,306 genotyped Mass General Brigham Biobank participants (55.6% women, mean age 53 ± 17 years), integrated PRS demonstrated robust discrimination and appropriate calibration across 8 cardiovascular traits. Comparing high genetic risk (top 10% of PRS distribution, or top 20% for rarer TAA and VTE) vs average risk (26th-75th percentiles, or 21st-80th percentiles for TAA and VTE) yielded ORs: coronary artery disease (3.7 [95% CI: 3.4-4.1]), type 2 diabetes (3.1 [95% CI: 2.8-3.3]), atrial fibrillation (3.0 [95% CI: 2.7-3.3]), VTE (1.9 [95% CI: 1.6-2.0]), TAA (1.7 [95% CI: 1.5-1.9]), hypertension (2.1 [95% CI: 1.8-2.3]), hypercholesterolemia (4.1 [95% CI: 3.7-4.5]), and lipoprotein(a) (41.0 [95% CI: 27.0-62.2]). Incorporating integrated PRS into clinical models improved risk classification, while prospective analyses confirmed significant associations with incident cardiovascular outcomes. CONCLUSIONS: Integrated PRS offer an implementable framework for genetic risk reporting, and are now available as a clinically orderable test. Broader prospective validation studies are needed to further establish clinical utility.

Humans↗

PubMed2003

Causes of postreperfusion syndrome in living or cadaveric donor liver transplantations.

OBJECTIVE: The postreperfusion syndrome (PRS) occurrence was evaluated in patients undergoing liver transplantation in our institution to determine the relationship between PRS and associated variables. METHODS: Of the 185 consecutive liver transplants, pediatric patients, patients with uncompleted data or retransplantations were excluded. The remaining 145 adult patients having 77 cadaveric and 68 living donor right lobe liver transplantations were studied. PRS was defined as a decrease in mean arterial pressure >30% below the baseline value. Logistic regression was used for statistical analyses. A P value <.05 was considered as significant. RESULTS: Total rate of PRS occurrence was 48.9% (71 patients) for the 145 patients. Logistic regression analyses revealed a significant relationship between the PRS and four of the variables: shorter duration of the anhepatic period, higher mean calcium requirement, higher mean heart rate difference from anhepatic to reperfusion period and lower central venous pressure at the dissection period during operations (P <.05). We could not demonstrate any significant effect of the operation type-surgical technique and duration of operations, blood and fresh frozen plasma volume transfused, demographic variables of the recipients, donor liver factors, other haemodynamic and metabolic variables at specific time periods (P >.05). CONCLUSIONS: In conclusion, it is important that PRS does not seem to occur in a predictable manner in this study except for the increased calcium requirements during the operations in PRS experienced patients. The clinical parameters as graft ischemia time, the type of the operation, demographic variables of the recipient, hemodynamic or metabolic variables and transfusion needs during the operations seemed to have no contribution to PRS occurrence.

Adult↗

PubMed1997

Partial reconstitution of mammalian phosphoribosylpyrophosphate synthetase in Escherichia coli cells. Coexpression of catalytic subunits with the 39-kDa associated protein leads to formation of soluble multimeric complexes of various compositions.

Rat liver phosphoribosylpyrophosphate (PRPP) synthetase exists as complex aggregates composed of 34-kDa catalytic subunits (PRS I and PRS II) and homologous 39- and 41-kDa proteins termed PRPP synthetase-associated proteins (PAPs). While a negative regulatory role was indicated for PAPs, the physiological function of PAPs is less well understood. We attempted to prepare recombinant 39-kDa PAP (PAP39) and to reconstitute the enzyme complex. Free PAP39 was poorly expressed in Escherichia coli, while expression of protein fused with glutathione S-transferase was successful. The purified fusion protein had no PRPP synthetase activity, and bound to dissociated PRS I and PRS II, with a similar affinity. A free form of PAP39 prepared from the fusion protein formed insoluble aggregates. The enzyme complex was then partially reconstituted in situ by coexpression of PAP39 with PRS I or PRS II in E. coli cells. This coexpression led to formation of soluble complexes of various compositions, depending on the conditions. When the relative amount of PAP39 was higher, specific catalytic activities, in terms of the amount of the catalytic subunit, were lowered. PAP39 complexed with PRS I was more readily degraded by proteolysis than seen with PRS II, in vivo and in vitro. These results provide additional, strong evidence for that PAP39 has no catalytic activity in the enzyme complex, but does exert inhibitory effects in an amount-dependent manner, and that composition of the enzyme complex varies, depending on the relative abundance of components present at the site of aggregate formation.

Adenosine Diphosphate↗

PubMed2003

Stress-induced visceral hypersensitivity in female rats is estrogen-dependent and involves tachykinin NK1 receptors.

Hormonal cycling may be related to a higher incidence of pain syndrome in female. As tachykinins are pivotal in stress-induced colonic dysfunction, we investigated whether ovarian steroids influence stress-induced visceral hypersensitivity to rectal distension (RD) in female rats and further, whether this influence involves NK1 receptors. Female Wistar rats, either intact or ovariectomized (OVX), were equipped for abdominal muscle electromyography and submitted to 2-h partial restraint stress (PRS) or sham-PRS. First, the effect of PRS was evaluated in intact rats. Second, abdominal response to RD was recorded in OVX rats treated with either, progesterone, 17beta-estradiol, 17beta-estradiol-plus-progesterone, or vehicle, in both basal and PRS conditions. Third, the NK1 receptor-antagonist, SR140333, was tested in PRS-intact and PRS-OVX rats under 17beta-estradiol or 17beta-estradiol-plus-progesterone treatment. PRS induced visceral hypersensitivity to RD and this effect was prevented by ovariectomy. OVX rats treated with 17beta-estradiol or 17beta-estradiol-plus-progesterone, but not progesterone alone, exhibited visceral hypersensitivity after PRS similar to that of intact rats. Both stress-induced visceral hypersensitivity in intact rats and the hormonally-restored visceral hyper-responsiveness of OVX rats were antagonized by SR140333. It is concluded, therefore, that stress-induced visceral hypersensitivity in female rats is estrogens-dependent and mediated through NK1 receptor activation.

Abdominal Muscles↗