Parents' understanding of genetic risk data in genetic counseling.
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Comprehension↗
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Cardiovascular Risk Factors and Genetic Risk in Transthyretin V142I Carriers.
BACKGROUND: Nearly 3% to 4% of Black individuals in the United States carry the transthyretin V142I variant, which increases their risk of heart failure. However, the role of cardiovascular (CV) risk factors (RFs) in influencing the risk of clinical outcomes among V142I variant carriers is unknown. OBJECTIVES: This study aimed to assess the impact of CV RFs on the risk of heart failure in V142I carriers. METHODS: This study included self-identified Black individuals without prevalent heart failure from 6 TOPMed (Trans-Omics for Precision Medicine) cohorts, the REGARDS (Reasons for Geographic And Racial Differences in Stroke) study, and the All of Us Research Program. The cohort was stratified based on the V142I genotype and the number of CV RFs (hypertension, diabetes, obesity, and hypercholesterolemia). Adjusted Cox models were used to assess the association of heart failure with the V142I genotype and CV RF profile, taking noncarriers with a favorable CV RF profile as reference. RESULTS: The cross-sectional analysis, including 1,625 V142I carriers among 48,365 Black individuals, found that the prevalence of CV RFs did not vary by V142I carrier status. In the longitudinal analysis, there were 587 (3.2%) V142I carriers among 18,407 Black individuals (median age: 60 years [Q1-Q3: 52-68 years], 63.0% female). Among carriers, the heart failure risk was attenuated with a favorable (0 or 1 RF) CV RF profile (adjusted HR: 2.26; 95% CI: 1.58-3.23) compared with an unfavorable (3 or 4 RFs) CV RF profile (adjusted HR: 4.14; 95% CI: 2.79-6.14). CONCLUSIONS: A favorable CV RF profile lowers but does not abrogate V142I variant-associated heart failure risk. This study highlights the importance of having a favorable CV RF profile among V142I carriers for risk reduction of heart failure.
Aged↗
Nonuniform Association of Genetic Risk Scores for Intraocular Pressure.
IMPORTANCE: Elevated intraocular pressure (IOP) is a risk factor for primary open-angle glaucoma, and genetic risk scores hold promise as a tool for screening for ocular hypertension. However, genetic risk scores for IOP have a nonuniform association across the range of IOP, which reduces their accuracy. OBJECTIVE: To test the hypothesis that nonuniform behavior of genetic risk scores for IOP is associated with a specific type of genetic interaction. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional, post hoc genetic association studies were performed using linear and quantile regression in a sample of UK Biobank participants. Data were analyzed from January to September 2025. EXPOSURES: Ninety-eight genetic variants associated with IOP. MAIN OUTCOMES AND MEASURES: Tests were carried out for 98 genetic variants associated with IOP (P < 5.0 ×10-8) to examine (1) dominant or recessive genetic effects, (2) genotype × genotype interactions, (3) genotype × age interactions, and (4) genotype × sex interactions. RESULTS: A total of 98 235 participants (mean [SD] age, 58.1 [7.9] years; 52 168 female [53.1%]) were included in this analysis. More variants exhibited genotype × age interactions than expected by chance (14 of the 98 variants associated with IOP had at least nominal evidence of an interaction with age; P = 3.76 ×10-4). For 12 of these 14 variants, age increased rather than decreased the magnitude of the IOP vs genotype association. However, integrating age interactions into the genetic risk score construction process did not yield improved accuracy (incremental noninteraction model, R2 = 4.05; 95% CI, 3.82-4.31 and interaction model, R2 = 4.04; 95% CI, 3.80-4.27). There was little support for other types of genetic interaction. CONCLUSIONS AND RELEVANCE: In the current work, findings show minimal evidence that nonadditive allelic effects, genotype × genotype interactions, and genotype × sex interactions contributed to the nonuniform association of genetic variants with IOP across quantiles of IOP. Although a genetic risk score for IOP was more accurate in older vs younger individuals, efforts to account for genotype × age interactions in genetic risk score construction did not improve accuracy. These findings suggest other factors, such as gene-environment interactions, contribute to the nonuniform relationship of genetic variants with IOP.
Humans↗
Blood Pressure Genetic Risk and Incident Hypertension at 2 to 7 Years Post Partum.
IMPORTANCE: Hypertensive disorders of pregnancy (HDP; ie, preeclampsia/eclampsia and gestational hypertension) are associated with earlier development of chronic hypertension. Whether genetic risk for high systolic blood pressure (SBP) can stratify risk of new-onset hypertension after pregnancy is unclear. OBJECTIVE: To test the association of genetic risk for high SBP with new-onset hypertension at 2 to 7 years after delivery, independent of clinical characteristics and HDP history. DESIGN, SETTING, AND PARTICIPANTS: This was a cohort study of women enrolled during pregnancy between 2010 and 2013 and followed up at 2 to 7 years post partum. Included in the study were genotyped participants without pregestational chronic hypertension in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b) Heart Health Study. The setting included 8 US clinical sites. Study data were analyzed from October 2024 to January 2026. EXPOSURES: SBP genetic risk was calculated using a genome-wide SBP polygenic score and categorized as low (bottom quintile), intermediate (quintiles 2-4) or high (top quintile). MAIN OUTCOMES AND MEASURES: The primary outcome was stage 1+ hypertension (≥130/80 mm Hg or use of antihypertensive medication) at 2 to 7 years post partum. Logistic regression tested the association of SBP genetic risk with development of hypertension, adjusted for sociodemographic factors, prepregnancy diabetes, first-trimester BP, HDP history, and postpartum body mass index (BMI). Key secondary analyses were stratified by HDP history and compared population attributable risk for high SBP genetic risk, HDP history, and postpartum BMI. RESULTS: Among 2852 participants (mean [SD] age, 30.8 [5.5] years; 353 [12.4%] with prior HDP), 509 (17.8%) developed hypertension by 2 to 7 years (mean [SD], 3.2 [0.9] years) after delivery. SBP genetic risk was independently associated with incident hypertension (high vs low SBP genetic risk: adjusted odds ratio [aOR], 1.50; 95% CI, 1.09-2.07; P = .01). In stratified analyses, SBP genetic risk was associated with incident hypertension in those without prior HDP (aOR, 1.25; 95% CI, 1.12-1.40 per SD; P < .001) but not in those with prior HDP (aOR, 1.01; 95% CI, 0.79-1.28 per SD; P = .92; P for interaction = .10). High SBP genetic risk, HDP history, and BMI greater than or equal to 25 (calculated as weight in kilograms divided by height in meters squared) accounted for 4.7%, 10.8%, and 41.5%, respectively, of population attributable risk for hypertension. CONCLUSIONS AND RELEVANCE: Results of this cohort study reveal that higher SBP genetic risk was independently associated with higher risk of developing new-onset hypertension 2 to 7 years after delivery. However, HDP history and elevated BMI were more important contributors to hypertension risk.
Humans↗
Comprehension of skin cancer genetic risk feedback in primary care patients.
Few studies have examined comprehension and miscomprehension of genetic risk feedback for moderate-risk genes in the general population. We examined the prevalence and nature of accurate and inaccurate genetic risk feedback comprehension among those who received genetic testing for melanocortin-1-receptor (MC1R) gene variants that confer moderate melanoma risk. Participants (N = 145 Albuquerque, NM) were tested as part of a randomized controlled trial. Two weeks after receiving MC1R genetic risk feedback, participants answered open-ended questions regarding their reactions to the MC1R feedback report. Participants' comprehension of their feedback (average-risk or higher-risk for melanoma) was evaluated through qualitative analysis of open-ended responses. Most participants demonstrated comprehension of their feedback results (i.e., 63% of average-risk participants [ARPs]; 51% of higher-risk participants [HRPs]). Miscomprehension was evident in fewer participants (i.e., 16% of ARPs, 11% of HRPs). A few ARPs misunderstood the purpose of testing, whereas a few HRPs reported confusion about the meaning of their risk feedback. Some participants' responses to the open-ended questions were too ambiguous to ascertain comprehension or miscomprehension (i.e., 21% of ARPs, 38% of HRPs). Taken together, these findings suggest that genetic testing feedback for MC1R risk variants is largely comprehensible to general population participants. This study adds to the work examining comprehension and usage of common, moderate risk genetic information in public health contexts. However, to maximize the utility of genetic risk information in the general population, further research is needed to investigate and address areas where common genetic risk feedback misunderstandings occur.
Genetic testing↗
Genetic risk scores, perceived neighborhood disorder, and sleep duration.
STUDY OBJECTIVES: Most studies of neighborhood context and sleep health emphasize direct effects and fail to account for the role of genetics. In this paper, we draw on the socioecological model to examine the interplay of genetics, neighborhood context, and sleep health. We specifically examine the independent and joint effects of genetic risk scores (GRS) and perceived neighborhood disorder on sleep duration. METHODS: We combine genomic and cross-sectional survey data from the All of Us Research Program, a non-probability sample of 22 575 adults of European ancestry living in the United States. We use the sleep duration-increasing risk allele count for 78 genome-wide single nucleotide polymorphisms (SNPs) to construct weighted genetic risk scores. Our analyses include an index of perceived neighborhood disorder and an objective measure of sleep duration based on wrist actigraphy. RESULTS: Genetic risk scores are inversely associated with neighborhood disorder, positively associated with continuous sleep duration, and inversely associated with the odds of short sleep. Neighborhood disorder is inversely associated with continuous sleep duration and positively associated with the odds of short and long sleep. The association between genetic risk scores and sleep duration (continuous and categorical) is invariant across levels of neighborhood disorder. CONCLUSIONS: Our analyses confirm the independent direct effects of genetic risk scores and neighborhood disorder on sleep duration. Our findings extend the socioecological model by assessing the role of genetics in the study of neighborhood context and sleep health. Although we observed a gene-environment correlation between genetic risk scores and perceived neighborhood disorder, there was little indication of genetic confounding and no evidence of gene-environment interaction.
Humans↗
Are There Any Effective Behavior Change Strategies for Communicating Genetic Risk in Obesity Prevention and Body Weight Reduction Interventions?
This systematic review examined how differences in intervention components may contribute to inconsistent findings in genetic risk communication studies, addressing obesity-related outcomes (e.g., weight reduction, nutrition behavior, exercise). The review was preregistered (PROSPERO #CRD42024524026) and followed PRISMA guidelines. Searches across eight databases identified 23 randomized controlled trials, covering 18 intervention trials. Risk of bias was assessed using the Risk of Bias 2 tool. A narrative synthesis was used to cluster studies by the content of intervention and control groups. Genetic risk communication alone (no behavioral counseling, addressing nutrition and exercise) or combined with phenotype-based risk was ineffective and sometimes counterproductive among low-risk individuals. When combined with personalized behavioral counseling, effectiveness improved, but only when compared to waitlist control groups or non-personalized behavioral counseling. Significant effects emerged in high-genetic risk subgroups within personalized behavioral counseling, using behavior change techniques such as problem-solving, feedback on behavior, self-monitoring, and environmental changes. The most promising results emerged from complex interventions integrating genetic risk communication into multiple sessions and combining numerous additional behavioral change techniques, such as social reward, cues/prompts, self-reward. Complex personalized interventions combining multiple behavior change techniques and prompting experiential genetic risk awareness show promise for improving weight, nutrition, and exercise-related outcomes.
Humans↗
[Genetic risk in cases of reciprocal translocation (author's transl)].
The analysis of 206 families with reciprocal translocations revealed thanks to a patient who was a carrier of an unbalanced translocation demonstrated the risk of a child suffering from the disease at about 16.4%, in the case of a meiotic segregation 2 : 2. In the case of translocation with meiotic segregation 3 : 1, the risk is much less, i.e. 7.6% for female carriers and significantly less than 3/83 for male carriers. It is extremely important to take this difference into account when evaluating the risks during genetic counselling. On the other hand, the freqeuncy of spontaneous abortions is practically the same for carriers of translocations with these two types of segregation and rises to nearly 23%; i.e. the postzygotic selection influences, to the same degree, zygotes with one chromosome too many, one two few, and zygotes with 46 chromosomes, but of which one has a defect or an excess of genetic material. Such selection depends rather on an interaction between the abnormal genome of the zygote (embryo) and the genome of the mother, whilst the prezygotic selection operates against the gametes having one chromosome too many or one too few. A large asymmetry in the length of the exchanged fragments could be one of the causes of the 3 : 1 segregation. This is proved by a more frequent participation (48/60) of the acrocentric chromosomes in the translocations with segregation 3 : 1. On the other hand, in translocations with segregation 2 : 2, acrocentrics are found much more rarely (66/146).
Female↗
Family genetic risk communication and reverse cascade testing in the BabySeq project.
PURPOSE: Genomic sequencing of newborns can initiate disease surveillance and therapy for children and may identify at-risk relatives through reverse cascade testing. We explored genetic risk communication and reverse cascade testing among families of newborns who underwent exome sequencing and were identified as having a risk for an autosomal dominant disease. METHODS: We conducted semistructured interviews with parents of newborns enrolled in the BabySeq Project who had a pathogenic or likely pathogenic variant associated with an autosomal dominant childhood- and/or adult-onset disease returned. We used directed content analysis to derive themes. RESULTS: From 11 families, all first-degree relatives (n = 32, 100%), 29 second-degree relatives (76%), and 26 third-degree relatives (43%) were informed of their risk. All parents (n = 22, 69% of first-degree relatives), 4 (11%) second-degree relatives, and 1 (2%) third-degree relatives underwent cascade testing. Most parents preferred to handle risk communication themselves. Parents with positive cascade testing but no associated symptoms were less inclined to share findings with relatives but highly motivated to share results if the variant's associated disease severity was high, as perceived with adult-onset conditions. One new subtheme, family member traits, was identified and defined as a relative's propensity to anxiety/concern after risk communications but did not diminish risk communication. CONCLUSION: Findings can inform more effective notification and testing practices for families of newborns at risk for hereditary genetic conditions.
Humans↗
[The mutagenic effect of x-rays iii. radiation genetic risks].
In the estimation of radiation genetic risks, the results must be derived from animal experiments. According to recently performed investigations, humans have almost the same mutation sensibility like mice. In risk estimations, it is necessary to take into account the factors which influence the mutation rate induced per unit dose. Risk estimations are carried out by comparing the effect per unit dose with the risk of the same effect, which is caused by unknown natural influences. The reader is reffered to data derived from humans.
Animals↗
A simple combinatorial method for calculating genetic risks.
A method is presented whereby genetic counsellors can calculate genetic risks in a wide variety of circumstances using only arithmetics. The method is general in that it can handle such information as gene frequency, mutation rate, mode of inheritance, penetrance, pedigree to which the consultand belongs, phenotype of the consultand and his relatives, biochemical findings, etc. Each of the possible combinations of genotypes which may be present in the pedigree is listed and considered in turn. The method consists of a series of simple steps leading mechanically to the right answer.
Computers↗
Osteoporosis genetic risk prediction using bone mineral density polygenic scores in Japanese: TMM CommCohort study.
Osteoporosis and fractures are major health concerns. We developed and validated a polygenic score (PGS) for quantitative ultrasound (QUS)-defined osteoporosis risk in Japanese individuals using heel QUS-derived T-scores. Genome-wide association study summary statistics from up to 10,794 participants in the Tohoku Medical Megabank Community-Based Cohort identified genome-wide significant loci, including MBL2, TMEM135, and WNT16. PGS models were constructed and evaluated using independent datasets for model selection (n = 1419) and validation (n = 8711). Adding the PGS to age and sex yielded only modest improvements in discrimination, whereas PGS quintiles supported genetic risk stratification. Compared with the intermediate group, individuals in the lowest PGS quintile had higher odds of the outcome (1.22, 95% confidence interval [CI]: 1.07-1.40), whereas those in the highest quintile had lower odds (0.85, 95% CI: 0.74-0.98). During prospective follow-up (mean 3.5 years), a similar gradient was observed, with higher incidence rate ratios in the lowest quintile (1.42, 95% CI: 1.17-1.73) and lower incidence rate ratios in the highest quintile (0.70, 95% CI: 0.54-0.89). No statistically significant interaction between age and PGS was observed, and age-T-score regression analyses showed no differences in age-related T-score decline across genetic risk groups. However, analyses in young adults (20-44 years) and extrapolation to age 20 suggested lower bone status around peak bone mass in individuals at high genetic risk for QUS-defined osteoporosis. These findings suggest that a Japanese-specific PGS may help identify individuals at elevated genetic risk earlier in adulthood.
Journal Article↗
Genetic Risk Factors for Kidney Function in Individuals with Type 1 Diabetes.
KEY POINTS: Previous research has identified polygenic risk scores that are associated with low eGFR and albuminuria in the general population. We observed that these eGFR and albuminuria polygenic risk scores were associated with eGFR and albuminuria, respectively, in type 1 diabetes. Associations were independent of glycemic control and suggest shared genetic kidney risk factors between type 1 diabetes and the general population. BACKGROUND: Genetic risk factors underlying kidney disease in type 1 diabetes (T1D) remain poorly understood. We examined whether previously established polygenic risk scores (PRS) for eGFR and albuminuria are associated with these measures in adults with T1D in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications study. METHODS: We applied eGFR and albuminuria PRS derived in general population cohorts to 1304 DCCT/Epidemiology of Diabetes Interventions and Complications participants with genome-wide genotyping. We tested PRS associations with eGFR and urine albumin excretion rate (AER) as well as incident eGFR <60 ml/min per 1.73 m 2 , AER ≥30 mg/24 h, and AER ≥300 mg/24 h. For consistency, PRS values were linearly transformed so higher scores corresponded to higher eGFR and AER. We also examined associations of kidney outcomes with rs55703767 in COL4A3 , which has previously been associated with CKD in T1D. RESULTS: At DCCT baseline, participants had a mean age of 27 years; 53% were male. 49% of participants were randomized to intensive versus conventional glucose-lowering therapy. Participants were followed for median of (first-third quartiles) 35 (33-37) years. The eGFR PRS was significantly associated with continuous eGFR (per one SD higher PRS 2.72 ml/min per 1.73 m 2 higher [95% confidence interval (CI), 2.05 to 3.40]) and incident eGFR <60 ml/min per 1.73 m 2 (hazard ratio [HR]=0.82 [95% CI, 0.73 to 0.92]), but not consistently with albuminuria. There was no association with quantitative AER (2.42 mg/24 h [95% CI, -1.86 to 6.89]) or sustained AER ≥30 mg/24 h (HR=1.03; [95% CI, 0.94 to 1.14]). The albuminuria PRS was significantly associated with incident AER ≥30 mg/24 h (HR=1.12 [95% CI, 1.02 to 1.22]) but not continuous eGFR (0.49 ml/min per 1.73 m 2 higher [95% CI, -0.23 to 1.21]) or incident eGFR <60 ml/min per 1.73 m 2 (HR=0.96 [95% CI, 0.85 to 1.08]). Associations were similar in analyses stratified by DCCT treatment group assignment. rs55703767 was associated with lower incident macroalbuminuria in the overall cohort (HR=0.77 per minor allele [95% CI, 0.59 to 0.99]), and upon stratification by DCCT treatment group assignment, only within the conventional and not intensive glucose-lowering therapy group. CONCLUSIONS: PRS associated with eGFR and albuminuria in the general population were associated with corresponding measures in adults with T1D. The results suggest shared genetic risk factors for kidney disease between T1D and the general population but different genetic risk factors for albuminuria and eGFR in T1D. CLINICAL TRIALS REGISTRATION NUMBERS: NCT00360893 , NCT00360815 .
Adult↗
Patient stratification by genetic risk in Alzheimer's disease is only effective in the presence of phenotypic heterogeneity.
Case-only designs in longitudinal cohorts are a valuable resource for identifying disease-relevant genes, pathways, and novel targets influencing disease progression. This is particularly relevant in Alzheimer's disease (AD), where longitudinal cohorts measure disease "progression," defined by rate of cognitive decline. Few of the identified drug targets for AD have been clinically tractable, and phenotypic heterogeneity is an obstacle to both clinical research and basic science. In four cohorts (n = 7241), we performed genome-wide association studies (GWAS) and Mendelian randomization (MR) to discover novel targets associated with progression and assess causal relationships. We tested opportunities for patient stratification by deriving polygenic risk scores (PRS) for AD risk and severity and tested the value of these scores in predicting progression. Genome-wide association studies identified no loci associated with progression at genome-wide significance (α = 5×10-8); MR analyses provided no significant evidence of an association between cognitive decline in AD patients and protein levels in brain, cerebrospinal fluid (CSF), and plasma. Polygenic risk scores for AD risk did not reliably stratify fast from slow progressors; however, a deeper investigation found that APOE ε4 status predicts amyloid-β and tau positive versus negative patients (odds ratio for an additional APOE ε4 allele = 5.78 [95% confidence interval: 3.76-8.89], P<0.001) when restricting to a subset of patients with available CSF biomarker data. These results provided no evidence for large-effect, common-variant loci involved in the rate of memory decline, suggesting that patient stratification based on common genetic risk factors for progression may have limited utility. Where clinically relevant biomarkers suggest diagnostic heterogeneity, there is evidence that a priori identified genetic risk factors may have value in patient stratification. Mendelian randomization was less tractable due to the lack of large-effect loci, and future analyses with increased samples sizes are needed to replicate and validate our results.
Alzheimer Disease↗
Linkage between HLA-B8 and HLA-DQ2.5 Contributes to Ancestry-Dependent Genetic Risk for Celiac Disease.
BACKGROUND: Most genetic studies on celiac disease (CeD) have focused on individuals of European descent. Limited data are available for the Hispanic and black populations. METHODS: We analyzed whole-genome sequencing data, electronic health records (EHR), and laboratory results from the All of Us Research Program. We identified 3,481 individuals with CeD through EHR, self-reporting, or both. Of these, 2,899 carried one of the four well-established risk haplotypes, including 262 of admixed American (89% Hispanic) and 108 of African (70% black) ancestry. Five sex-, age-, and ancestry-matched controls per case were selected for the assessment of genetic and clinical risk factors. RESULTS: An enrichment in the DQB1*02:01 allele was observed in CeD patients across all ancestries, with the strongest association in Europeans (32.3% vs. 11.6%), followed by Americans (18.5% vs. 8.1%) and Africans (15.7% vs. 8.1%). Among individuals carrying the DQ2.5 (DQA1*05:01-DQB1*02:01 haplotype), HLA-B8 was present in 72.3% of Europeans, 42.3% of Admixed Americans, and lower in Africans. This linkage disequilibrium was higher in CeD patients than in controls across all three ancestries. A polygenic risk score distinguished seropositive CeD from controls with 86% accuracy. Incorporating clinical risk factors, including family history, hypothyroidism, diarrhea, vitamin D deficiency, and anemia, increased predictive accuracy to 92%. The model identified 93% of CeD patients with tTG-IgA levels greater than 10 IU/mL. CONCLUSION: Linkage between HLA-B8 and DQ2.5 differs significantly among individuals of European, admixed American, and African ancestry, contributing to ancestry-dependent genetic risk for CeD.
Celiac disease↗
Genetic risk factors in rheumatoid arthritis: A Mendelian randomization study of chronic kidney disease in European populations.
Rheumatoid arthritis (RA) is a heritable autoimmune disease linked to chronic kidney disease (CKD) in observational studies. However, whether this association is causal and driven by shared genetic risk remains unclear, warranting genetic investigation. To investigate possible causal relationships between RA and different CKD subtypes, we used Mendelian randomization (MR) analyses with data from genome-wide association studies. The inverse variance weighted (IVW) methodology was the main method, and sensitivity analyses were added to improve the validity of the causal estimations. Our analysis predicted that RA significantly increases the risk of IgA nephropathy (IVW odds ratio [OR] = 1.041, 95% confidence interval [CI] = 1.018-1.065, P = 4.286e-04), diabetic nephropathy (IVW OR = 1.078, 95% CI = 1.009-1.152, P = .027), nephrotic syndrome (IVW OR = 1.164, 95% CI = 1.078-1.257, P = 1.012e-04), and chronic renal failure (IVW OR = 1.046, 95% CI = 1.018-1.075, P = 1.000e-03). MR analyses confirmed RA's positive causal effect on these CKD subtypes (all P < .05). While heterogeneity was observed for IgA nephropathy and chronic renal failure, sensitivity analyses (MR-Egger intercept, all P > .05) revealed no evidence of horizontal pleiotropy, supporting the robustness of our findings. Our findings suggest that in European-ancestry populations, a genetic predisposition to RA is causally associated with a higher risk of specific types of CKD. While these results require validation in diverse ethnic groups, they highlight the potential importance of renal monitoring for genetically susceptible RA patients, which may help mitigate the public health burden of CKD.
Humans↗
Non-genetic Risk Factors for Allopurinol-Induced Severe Cutaneous Adverse Reaction (SCAR): A Systematic Review.
BACKGROUND: Allopurinol-induced severe cutaneous adverse reactions (SCARs) are rare but potentially life threatening, particularly in Asian populations. While the genetic marker HLA-B*58:01 is a well-established risk factor, non-genetic factors may also contribute. This systematic review synthesizes evidence on associations between non-genetic risk factors and allopurinol-induced SCAR. METHODS: We searched MEDLINE, Scopus, Cochrane Library and Web of Science from inception to 29 June 2026 for observational studies examining non-genetic risk factors for SCAR, defined as Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, Acute Generalised Exanthematous Pustulosis, or Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms. Adults aged ≥ 18 years were included. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a random-effects model; heterogeneity was assessed with I2. Mean differences were calculated for continuous variables. NIH Study Quality Assessment Tool was used for quality assessment of the studies. RESULTS: Twenty-six studies were included. Female sex (20 studies; 3340 SCAR cases, 562,647 controls) was associated with an increased risk of allopurinol-induced SCAR (OR 2.06; 95% confidence interval (CI) 1.25-3.38). Chronic kidney disease (16 studies; 1625 SCAR cases, 553,804 controls) was also significantly associated with SCAR (OR 3.78; 95% CI 1.99-7.17). Five studies (177 SCAR cases, 1368 controls) reported higher allopurinol doses among SCAR cases than tolerant controls (mean difference 19.61 mg; 95% CI 2.97-36.24). No significant associations were observed for age or concomitant diuretic use in the primary meta-analyses. Substantial heterogeneity was observed across studies. Sensitivity analyses demonstrated consistent findings for most factors, although concomitant diuretic use became significantly associated with SCAR after exclusion of non-Asian and zero-event studies. CONCLUSION: CKD, female sex, and higher allopurinol dose were identified as significant non-genetic risk factors for allopurinol-induced SCAR. These findings support consideration of non-genetic factors alongside pharmacogenomic screening in future risk-stratification strategies. However, substantial heterogeneity and potential publication bias limit the certainty of the available evidence. Well-designed studies evaluating non-genetic predictors as primary outcomes are needed to develop robust integrated risk prediction models for clinical decision making.
Journal Article↗
Single-cell transcriptomic atlas of Alzheimer's disease middle temporal gyrus reveals region, cell type, and sex specificity of gene expression with novel genetic risk for MERTK in female.
BackgroundAlzheimer's disease (AD), the most common age-related neurodegenerative disease, is closely associated with both amyloid-β plaque and neuroinflammation. Two thirds of AD patients are female, and they have a higher disease risk; women with AD have more extensive brain histological changes than men along with more severe cognitive symptoms and neurodegeneration.ObjectiveThis study aimed to determine how sex difference induces structural brain changes and molecular cell vulnerabilities in AD, with a focus on identifying sex-specific transcriptional alterations and genetic risk factors.MethodsWe performed single nucleus RNA sequencing on postmortem brains from individuals with AD and age- and sex-matched controls, focusing on the middle temporal gyrus, a cortical brain region strongly affected by the disease, and integrated single nucleus RNA sequencing results with genome-wide association study (GWAS) data using cell type-specific enrichment and generalized gene-set analysis approaches. The analysis pipeline is provided with threshold information.ResultsWe identified a selectively vulnerable subpopulation of layer 2/3 excitatory neurons that were RORB-negative and CDH9-expressing in both males and females. Disease-associated, but sex-independent, reactive astrocyte signatures were also present. In clear contrast, the microglia signatures of AD brains differed between males and females. Integrating single cell transcriptomic data with results from GWAS, we identified MERTK genetic variation as a candidate novel risk factor for AD selectively in females.ConclusionsTaken together, our single cell atlas of middle temporal gyrus revealed a unique cellular-level view of sex-specific transcriptional changes in AD, illuminating GWAS identification of sex-specific AD genes. These data serve as a rich resource for interrogation of the molecular and cellular basis of AD.
Alzheimer's disease↗