Background:Diabetic retinopathy is a leading cause of visual loss. Hypothesis-generating data from cardiovascular outcome trials suggest that fenofibrate therapy may reduce the progression of diabetic retinopathy. Objective:To determine whether treatment with fenofibrate reduces the progression of diabetic retinopathy. Design and methods:We conducted a parallel-group, double-masked, placebo-controlled clinical trial of fenofibrate. A web-based algorithm allocated participants to treatment arms by minimisation. Setting and participants:The trial was positioned within NHS Scotland's Diabetic Eye Screening Programme. Adults with diabetes and non-referable retinopathy or maculopathy (based on Diabetic Eye Screening retinal image grading) were eligible. Interventions:Study treatment was mailed to participants' homes. Participants who were eligible at the screening assessment entered an active pre-randomisation run-in during which they took 145 mg fenofibrate. After randomisation, participants received 145 mg fenofibrate tablets or placebo. Study treatment was taken daily in those with normal renal function, or on alternate days in those with impaired renal function. Main outcome measures:The primary outcome was a composite of developing referable diabetic retinopathy or maculopathy, or requiring treatment for diabetic retinopathy or maculopathy. Incremental cost-effectiveness was assessed in terms of the primary outcome and per modelled quality-adjusted life-year gained. Data sources:Data were obtained from 6-monthly interviews by research nurses and linkage to national healthcare data sets. Selected adverse events were adjudicated by study clinicians masked to treatment allocation. Results:One thousand four hundred and eighty-four participants entered the pre-randomisation run-in, of whom 1151 were randomised. The primary outcome occurred in 131 (22.7%) of 576 participants assigned fenofibrate and 168 (29.2%) of 575 participants assigned placebo (hazard ratio 0.73; 95% confidence interval 0.58 to 0.91; p = 0.006) over a median of 4.0 years. Any progression of retinopathy or maculopathy, and development of macular oedema were also reduced. There was no effect on visual function, quality of life, or visual acuity. Fenofibrate use resulted in a non-significant reduction in 6-monthly health service costs (mean difference -£101, 95% confidence interval -£243 to £42), leading to dominance over standard care and a high probability of cost-effectiveness. Based on modelling (assuming no difference in background healthcare costs by treatment allocation), fenofibrate led to a small increase (£6) in cost for a small gain (0.02) in quality-adjusted life-years; incremental cost-effectiveness ratio £406 per quality-adjusted life-year gained. The probability of cost-effectiveness was 79-86% at thresholds of £20,000-30,000 per quality-adjusted life-year gained. Limitations:Early Treatment Diabetic Retinopathy Study retinopathy grading is considered the gold standard, but it is not used in large-scale retinal screening programmes; Diabetic Eye Screening grading is based on Early Treatment Diabetic Retinopathy Study but is less granular. Conclusions:Fenofibrate was clinically effective and cost-effective for reducing the progression of diabetic retinopathy compared with placebo among participants with early retinal changes. Future work:LENS participants will be followed for 10 years to assess the long-term effects of fenofibrate therapy. Funding:This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 14/49/84.

Plasma levels of procollagen type 1 N-propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX) are bone turnover markers (BTM) used to predict risk of fracture. We compared the effects of vitamin D supplements on plasma levels of P1NP and CTX in the Biochemical Efficacy and Safety Trial of vitamin D (BEST-D) trial (305 participants) after treatment with 2000 IU/d or 4000 IU/d vitamin D3 or placebo. The results of BEST-D were combined in a meta-analysis of all trials of vitamin D v. placebo on levels of P1NP (12 trials, 2654 participants) or CTX (16 trials, 2695 participants). In BEST-D, allocation to vitamin D3 resulted in a dose-dependent increase in 25-hydroxy-vitamin D (25(OH)D) levels but had no effects on P1NP or CTX. Geometric mean (se) levels at 12 months were similar for P1NP (41·7 (0·7) v. 42·9 (1·0) ng/ml; P = 0·29: either dose v. placebo) and likewise for CTX (0·23 (0·01) v. 0·23 (0·01) ng/ml; P = 0·98). In a meta-analysis of eighteen trials, the average difference between the within-trial change in P1NP for allocated vitamin D and control was -3·3 % (95 % CI -5·6, -1·0, P < 0·005). For CTX, this difference was slightly greater (-3·8 % (-6·8, -0·8); P = 0·01). There was no significant heterogeneity between these trials after stratifying trials with or without Ca, higher or lower doses of vitamin D, or lower v. higher pre-treatment levels of 25(OH)D. Overall, vitamin D supplementation was associated with modest reductions in both P1NP and CTX, and results provide support for further trials of vitamin D for prevention of fracture in older people.

Importance:Excess body weight is a strong risk factor for atrial fibrillation (AF), and weight loss is recommended in clinical guidelines for all patients with obesity and AF. However, existing evidence derives from younger patients, and weight loss in older adults could precipitate frailty. Objective:To investigate whether weight loss is a safe and effective intervention in older patients with overweight and AF. Design, Setting, and Participants:Parallel-group, unblinded, randomized clinical trial conducted at 2 UK hospitals from November 14, 2018, to April 25, 2025. Approximately 1500 individuals undergoing electrical cardioversion for AF were assessed for eligibility, and approximately 500 aged 60 to 85 years with body mass index 27 or greater and without any exclusion criteria were invited to participate. Of these, 119 provided informed consent to enter the trial and 118 were randomized. Intervention:Participants were randomized to an 8-month low-calorie diet and behavioral support program (intervention, n = 59) or to usual care (control, n = 59). Main Outcome and Measure:Intention-to-treat analysis of the change in Atrial Fibrillation Severity Scale (AFSS) symptom severity score at 8 months after randomization. Results:Participants (n = 118) had a mean age of 68 years (SD, 6); 33% were female. The intervention resulted in significantly lower weight (baseline-adjusted mean weight at 8 months: 92.6 [SE, 0.85] kg vs 99.4 [SE, 0.85] kg; P < .001; estimated difference, -6.9 kg [95% CI, -9.2 to -4.5]). This corresponded to a weight reduction of 9.7% vs 3.1%, respectively (P < .001). However, there were no significant differences between the groups in AFSS symptom severity score (baseline-adjusted mean at 8 months, 7.9 [SE, 0.84] in the intervention group vs 8.9 [SE, 0.84] in the control group; between-group difference, -0.9 [95% CI, -3.3 to 1.4]; P = .43). No significant treatment effects were observed on physical performance, AF burden, cardiac imaging parameters, blood pressure, lipid profile, or incidence of repeat cardioversion or AF ablation during follow-up. No serious adverse events related to participation in the trial were reported in either group. Conclusions and Relevance:In older patients with overweight and persistent AF, a low-calorie diet and behavioral support program was associated with significant weight loss at 8 months with no safety concerns but did not affect AF symptoms, AF burden, cardiac remodeling, or the need for further rhythm control interventions. Trial Registration:ClinicalTrials.gov Identifier: NCT03713775.

Genome-wide association studies (GWAS) have substantially advanced our understanding of the genetic architecture underlying alcohol consumption. However, Latin American populations represent only ~ 1.8% of participants in current GWAS. Here, we present the largest GWAS meta-analysis of alcohol consumption in Latin American populations to date, analyzing 465,516 individuals through the Latin American Genomics Consortium (LAGC). We identified 14 independent loci, including 13 previously known associations and one novel locus in WRN . Multi-omic integrative network analysis revealed two functional modules: synaptic signaling pathways and inflammatory response mechanisms, extending beyond alcohol metabolism genes. Polygenic risk score (PRS) transferability varied substantially across Latin American subgroups. This study-derived PRS outperformed European-derived scores in South Americans and Puerto Ricans, while European PRS performed better in Mexicans and Cubans. Unsupervised genetic clustering confirmed that PRS performance depends on ancestral composition rather than geographic labels. These findings expand our understanding of the genetics of alcohol consumption in Latin Americans by identifying novel associations and demonstrating significant genetic heterogeneity within Latin American populations. Results underscore that population-specific approaches are essential to ensure broadly applicable genomic medicine.

AIMS:The LENS trial demonstrated that fenofibrate slowed the progression of diabetic retinopathy compared to placebo in participants with early diabetic eye disease. We assessed its cost-effectiveness for reducing the progression of diabetic retinopathy versus standard care from a UK National Health Service perspective. METHODS:Resource use and outcome data were collected over follow-up for participants enrolled in LENS. Mean costs were compared at 2 years and per 6-month follow-up (median 4.0 years). Within the trial, cost-effectiveness was assessed in terms of the incremental cost per case of referable disease averted. A microsimulation model, with inputs derived primarily from LENS trial data, was used to assess the incremental cost per quality-adjusted life year (QALY). RESULTS:Fenofibrate resulted in a mean (95% confidence interval) reduction in health service costs of -£254 (-1062 to 624) at 2 years and -£101 (-243 to 42) per 6-month follow-up. This was accompanied by a 4.4% (1.3% to 8.0%) absolute reduction in any referable diabetic retinopathy or treatment thereof at 2 years, and a 27% (9%-42%) relative reduction over follow-up. Modelled over 10 years, fenofibrate use cost an additional £6 per patient for an expected QALY gain of 0.02, costing £406 per QALY versus standard care under base case assumptions. The probability of cost-effectiveness varied from 70% to 79% at a threshold of £20,000 per QALY, depending on the price discount applied to anti-VEGF drugs. CONCLUSIONS:Fenofibrate is likely to offer a cost-effective treatment for slowing the progression of diabetic retinopathy in people with early to moderate diabetic retinopathy or maculopathy.

SUMMARYBackgroundSotrovimab is a neutralising monoclonal antibody that has been proposed as a treatment for patients admitted to hospital with COVID-19.MethodsIn this randomised, controlled, open-label platform trial, several possible treatments were compared with usual care in patients hospitalised with COVID-19 pneumonia. In the sotrovimab comparison, eligible and consenting patients were randomly allocated to either usual care alone or usual care plus a single 1g dose of sotrovimab, using web-based unstratified randomisation. Participants were retrospectively categorised according to their baseline serum SARS-CoV-2 nucleocapsid antigen concentration as ‘high-antigen’ or ‘low-antigen’, using the median concentration as a cut-off. The primary outcome was 28-day mortality assessed by intention to treat. Secondary outcomes were time to discharge alive from hospital, and, among those not on invasive ventilation at baseline, progression to invasive ventilation or death. Recruitment closed on 31 March 2024 when funding ended. ISRCTN (50189673) andclinicaltrials.gov(NCT04381936).FindingsFrom 4 January 2022 to 19 March 2024, 1723 patients were recruited to the sotrovimab comparison. 720 (42%) were classified as high-antigen, 717 (42%) as low-antigen, and 286 (17%) had unknown antigen status. Over 80% of patients were vaccinated, over 80% had anti-spike antibodies at randomisation, and almost all were infected with Omicron variants. In the prespecified primary efficacy population of high-antigen patients, 82/355 (23%) allocated sotrovimab versus 106/365 (29%) allocated usual care died within 28 days (rate ratio 0.75; 95% CI 0.56-0.99; p=0.046). In an analysis of all randomised patients (regardless of antigen status), 177/828 (21%) allocated sotrovimab versus 201/895 (22%) allocated usual care died within 28 days (rate ratio 0.95; 95% CI 0.77-1.16; p=0.60).InterpretationIn patients hospitalised with COVID-19, sotrovimab was associated with reduced mortality in the primary analysis population of patients with a high serum SARS-CoV-2 antigen concentration at baseline, but not in the overall population.FundingUK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056).

To assess the contribution of rare coding germline genetic variants to prostate cancer risk and severity, we perform here a meta-analysis of 37,184 prostate cancer cases and 331,329 male controls from five cohorts with germline whole exome or genome sequencing data, and one cohort with imputed array data. At the gene level, our case-control collapsing analysis confirms associations between rare damaging variants in four genes and increased prostate cancer risk: SAMHD1, BRCA2 and ATM at the study-wide significance level (P < 1x10(-8)), and CHEK2 at the suggestive threshold (P < 2.6x10(-6)). Our case-only analysis, reveals that rare damaging variants in AOX1 are associated with more aggressive disease (OR = 2.60 [1.75-3.83], P = 1.35x10(-6)), as well as confirming the role of BRCA2 in determining disease severity. At the single-variant level, our study reveals that a rare missense variant in TERT is associated with substantially reduced prostate cancer risk (OR = 0.13 [0.07-0.25], P = 4.67x10(-10)), and confirms rare non-synonymous variants in a further three genes associated with reduced risk (ANO7, SPDL1, AR) and in three with increased risk (HOXB13, CHEK2, BIK). Altogether, this work provides deeper insights into the genetic architecture and biological basis of prostate cancer risk and severity, with potential implications for clinical risk prediction and therapeutic strategies.

The impact of genetic ancestry on the development of clonal hematopoiesis (CH) remains largely unexplored. Here, we compared CH in 136,401 participants from the Mexico City Prospective Study (MCPS) to 416,118 individuals from the UK Biobank (UKB) and observed CH to be significantly less common in MCPS compared to UKB (adjusted odds ratio = 0.59, 95% confidence interval (CI) = [0.57, 0.61], P = 7.31 × 10-185). Among MCPS participants, CH frequency was positively correlated with the percentage of European ancestry (adjusted beta = 0.84, 95% CI = [0.66, 1.03], P = 7.35 × 10-19). Genome-wide and exome-wide association analyses in MCPS identified ancestry-specific variants in the TCL1B locus with opposing effects on DNMT3A-CH versus non-DNMT3A-CH. Meta-analysis of MCPS and UKB identified five novel loci associated with CH, including polymorphisms at PARP11/CCND2, MEIS1 and MYCN. Our CH study, the largest in a non-European population to date, demonstrates the power of cross-ancestry comparisons to derive novel insights into CH pathogenesis.

The high prevalence of obesity in Mexican-American populations in the United States has suggested that the different genetic composition of the Mexican population may be related to the high prevalence of obesity in Mexico. Recently, the genome of 140,000 individuals in the Mexico City Prospective Study (MCPS) cohort was explored, and it was found that the average Amerindian ancestry (AMR) was 66.2%, followed by European (29.2%), African (3.7%), and Asian (0.8%) ancestries. However, the proportions of ancestry vary by geographic region of the country, with an increasing gradient of AMR from north to south. Despite the importance of this relationship, there are few studies that have analyzed the relationship between obesity and AMR, and the results are controversial. The relationship between AMR and central obesity has been more consistent, especially in women. Few genetic variants associated with obesity have been found in Mexico, due to the small number of individuals analyzed. Future analysis of the MCPS cohort will likely clarify the relationship between AMR and obesity, and identify genetic variations and genes associated with obesity and other metabolic diseases, specific to the Amerindian genome.

Background. Hyperuricaemia and gout are common in chronic kidney disease (CKD). We aimed to assess the effects of sodium- glucose co-transporter-2 (SGLT2) inhibition on uric acid (urate) and gout in patients with CKD. Methods. The EMPA-KIDNEY trial randomised 6609 patients with CKD to receive either empagliflozin 10 mg daily or matching placebo over a median of 2 years of follow-up. Serum uric acid was measured at randomisation then at 2 and 18 months of follow-up and the effects of empagliflozin were analysed using a pre-specified mixed model repeated measures approach. Participant-reported gout events were analysed in Cox regression models (first events) with the Andersen-Gill extension (total events). A post hoc composite outcome included new initiation of uric acid-lowering therapy or colchicine. EMPA-KIDNEY primary and kidney disease progression outcomes were also assessed in subgroups of baseline serum uric acid. Results. Baseline mean +/- standard deviation serum uric acid concentration was 431 +/- 114 mu mol/l. Allocation to empagliflozin resulted in a study-average between-group difference in serum uric acid of -25.6 mu mol/l [95% confidence interval (CI) -30.3 to -21.0], with larger effects in those with higher eGFR (trend P < .001) and without diabetes (heterogeneity P < .001). Compared with placebo, empagliflozin did not significantly reduce first or total gout events [hazard ratio 0.87 (95% CI 0.74-1.02) for the 595 first events and 0.86 (0.72-1.03) for the 869 total events] with similar hazard ratios for the post hoc composite and across subgroups, including by diabetes and eGFR. The effect of empagliflozin on the primary outcome and kidney disease progression outcomes were similar irrespective of the baseline level of uric acid. Conclusions. SGLT2 inhibition reduces serum uric acid in patients with CKD, with larger effects at higher eGFR and in the absence of diabetes. However, the effect on uric acid is modest and did not translate into reduced risk of gout in EMPA-KIDNEY.

Background and aims In the primary prevention setting, low-dose aspirin reduces major vascular events (MVEs) by approximately 11% but increases major bleeding (MB) by 40–50%, implying that net benefit will be most evident when the MVE-to-MB ratio is >4. This study aimed to derive cross-validated risk scores for MB and MVE and use the MVE-to-MB ratio to identify groups who may derive differing net benefits from treatment. Methods 431 167 UK Biobank participants without known atherosclerotic cardiovascular disease at baseline were followed through record linkage for incident MVEs (myocardial infarction, non-haemorrhagic stroke, transient ischaemic attack, arterial revascularisation or vascular death) and MB (gastrointestinal and intracranial bleeds with hospital admission for ≥2 days). Risk scores were derived for MVE and MB using Cox proportional hazards models with cross-validation. Ratios of observed MVE-to-MB rates were calculated across risk categories. Results During a median follow-up of 12 years, 18 310 participants suffered an MVE and 5352 an MB. MB risk was highest among participants with frailty, prior bleeds, cancer, liver disease or renal dysfunction, with a 4.3-fold difference in risk between the highest and lowest fifths of MB risk (HR 4.3, 95% CI 3.87 to 4.77). The MVE-to-MB ratio was ≤2.6 in the highest MB risk groups and ≥4 in lower MB risk categories. Conclusions The derived models using routinely available disease history and laboratory measurements improved distinction of the MVE-to-MB ratio compared with using conventional models for MB risk including vascular risk factors. Such models can help identify those with moderate MVE risk but low MB risk who may benefit from low-dose aspirin.

Introduction and Objective: Latin American (LAm) populations are disproportionately affected by type 2 diabetes (T2D) but are underrepresented in genome-wide association studies (GWAS). Polygenic risk scores (PRS) constructed using European (EUR) GWAS exhibit limited predictive accuracy in other populations. We aim to improve the performance of a T2D PRS in individuals of LAm ancestry by increasing their representation in GWAS. Methods: We conducted the largest T2D GWAS meta-analysis for LAm individuals (N=207,055) using 17 datasets, including the Mexico City Prospective Study (N=125,042). We used this data to develop a new genome-wide LAm PRS and compare its performance with a previous PRS derived from a smaller LAm GWAS meta-analysis (N=82,013). We also combined the new LAm GWAS with those from four other ancestries (N=2,310,590, 9% LAm) to construct a multi-ancestry PRS. PRSs were evaluated in independent LAm cohorts (N=11,377). Results: The new LAm PRS, based on 200K LAm GWAS sample, showed a 30% increase in the proportion of variance explained by the additive genetic model (liability r2=7% vs. 5% in the previous LAm PRS). Compared with individuals in the interquartile range, those above the 95th percentile of the new LAm PRS had 3.4 times higher T2D odds (95% CI: 2.8-4.2). In contrast, the odds ratio for the same comparison using the previous LAm PRS was 1.8 (95% CI: 1.5-2.1). Integrating the LAm GWAS into a multi-ancestry PRS further improved the performance, explaining up to 16% of the variance (vs. 14% with a EUR PRS, GWAS N=1,486,934). Individuals above the 95th percentile of the multi-ancestry PRS distribution had a 6.7-fold higher T2D odds [95% CI: 5.3-8.4] compared to those in the interquartile range. Conclusion: This study demonstrates the improved predictive power of a T2D PRS achieved by a 60% increased sample size of an LAm GWAS and underscores the importance of further expanding the representation of LAm populations in genetic research. A. Huerta: None. P. Baca Peynado: None. F. Rivas: None. M. Ng: None. R. Mandla: None. J. Kim: None. Y. Lu: None. J.E. Below: None. R. Tapia-Conyer: None. J. Berumen: None. J. Alegre-Diaz: None. J. Emberson: Research Support; Regeneron Pharmaceuticals, AstraZeneca. J.M. Torres: None. P. Kuri: None. J.M. Mercader: None. NIDDK (UM1-DK078616); American Diabetes Association Innovative and Clinical Translational Award (1-19-ICTS-068); American Diabetes Association (11-22-ICTSPM-16); NHGRI (U01HG011723)

Previous observational studies suggested that vitamin D may control the absorption of iron (Fe) by inhibition of hepcidin, but the causal relevance of these associations is uncertain. Using placebo-controlled randomisation, we assessed the effects of supplementation with vitamin D on biochemical markers of Fe status and erythropoiesis in community-dwelling older people living in the UK. The BEST-D trial, designed to establish the optimum dose of vitamin D3 for future trials, had 305 participants, aged 65 years or older, randomly allocated to 4000 IU vitamin D3 (n 102), 2000 IU vitamin D3 (n 102) or matching placebo (n 101). We estimated the effect of vitamin D allocation on plasma levels of hepcidin, soluble transferrin receptor (sTfR), ferritin, Fe, transferrin, saturated transferrin (TSAT%) and the sTfR-ferritin index. Despite increases in 25-hydroxy-vitamin D, neither dose had significant effects on biochemical markers of Fe status or erythropoiesis. Geometric mean concentrations were similar in vitamin D3 arms v. placebo for hepcidin (20·7 [se 0·90] v. 20·5 [1·21] ng/ml), sTfR (0·69 [0·010] v. 0·70 [0·015] µg/ml), ferritin (97·1 [2·81] v. 97·8 [4·10] µg/l) and sTfR-ferritin ratio (0·36 [0·006] v. 0·36 [0·009]), respectively, while arithmetic mean levels were similar for Fe (16·7 [0·38] v. 17·3 [0·54] µmol/l), transferrin (2·56 [0·014] v. 2·60 [0·021] g/dl) and TSAT% (26·5 [0·60] v. 27·5 [0·85]). The proportions of participants with ferritin < 15 µg/l and TSAT < 16 % were unaltered by vitamin D3 suggesting that 12 months of daily supplementation with moderately high doses of vitamin D3 are unlikely to alter the Fe status of older adults.

La alta prevalencia de obesidad en las poblaciones mexicoamericanas en Estados Unidos ha sugerido que la composición genética diferente de la población mexicana podría estar relacionada con la alta prevalencia de obesidad en México. Recientemente, se exploró el genoma de 140 000 individuos en la cohorte Estudio Prospectivo de la Ciudad de México (MCPS, Mexico City Prospective Study) y se encontró que el promedio de ancestría amerindia (AMR) fue de 66.2 %, seguida de las ancestrías europea (29.2 %), africana (3.7 %) y asiática (0.8 %). Sin embargo, las proporciones de ancestría varían según la región geográfica del país, observándose un gradiente creciente de AMR de norte a sur. A pesar de la importancia de esta relación, existen pocos estudios que han analizado la relación entre obesidad y AMR; además, los resultados son controversiales. La relación entre AMR y obesidad central ha sido más consistente, especialmente en mujeres. Se han encontrado pocas variantes genéticas asociadas a la obesidad en México, debido principalmente al reducido número de individuos estudiados. Análisis futuros de la cohorte MCPS seguramente permitirán esclarecer con precisión la relación entre AMR y obesidad, e identificar variaciones genéticas y genes específicos del genoma amerindio asociados a la obesidad y a otras enfermedades metabólicas.

Background Genome-wide association studies (GWAS) have made substantial contributions to our understanding of the genetic factors that influence alcohol consumption. However, most efforts have been made in populations of European ancestry, resulting in less representation of other populations, with Latin American (LA) populations among the least represented, comprising less than 2% of the total GWAS participants. LA populations are characterized by varying degrees of genetic admixture from Indigenous American, European, and African ancestries, which creates challenges when modeling the genetic architecture of complex traits. However, recently developed GWAS approaches, such as Tractor, that leverage local ancestry information (defined as the genetic ancestry of an individual at a particular genomic location) could help overcome this challenge. Methods This study, led by members of the Latin American Genomics Consortium (LAGC), is a meta-analysis of GWAS studies of self-reported alcohol consumption in 465,516 individuals from cohorts based in Latin American countries and the United States (US). We also conducted a local ancestry-aware GWAS on 11,655 LA individuals using Tractor. Results We replicated well-known genetic associations for alcohol consumption in genes that include the ADH locus (lead variant rs1229984, p-value = 1.12e-203) and others associated with psychiatric and behavioral traits, such as CADM2. We also identified a signal in the ALDH2 locus, previously associated only in East Asian populations. Using the local ancestry-aware GWAS, we identified associations in genes previously associated with the number of drinks consumed per week (Drkwk) by the GWAS and Sequencing Consortium of Alcohol and Nicotine use consortium (GSCAN), rs1874323 (p-value = 2.5860e-08) in the MAGI1 gene, and rs6833926 (p-value = 3.00e-08) in the ARAP2 gene. We also identified potential novel associations in the SLIT3 gene (rs73805262, p-value = 9.95e-09 and rs115143510, p-value = 1.23e-08), as well as one intergenic variant (rs3929849, p-value = 2.3930e-09) among segments of African-like ancestry. We also identified associations in intergenic regions of American-like descent (rs4130378, p-value = 9.673e-09; rs536315876, p-value = 4.3640e-09; rs115675116, p-value = 4.3190e-09). Nevertheless, given the small sample size in the local ancestry-aware GWAS, these results required further replication. We also compared the association of the polygenic risk score (PRS) derived from the European population using GSCAN (PRS-EUR) data with the PRS from our large-scale meta-analysis (PRS-LA), examining the relationship with drinks consumed per week in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) cohort, identifying a heterogeneity in the transferability of the PRS across geographical LA subgroups. We identified that both the PRS-EUR and PRS-La were associated with Drkwk in individuals from Puerto Rico (PRS-EUR, p-value = 7.40e-03; PRS-LA, p-value = 1.40e-02); meanwhile, only the PRS-EUR was associated in individuals from Mexico (p-value = 7.41e-3) and Cuba (p-value = 1.31e-02), and only the PRS-LA was associated in individuals from South America (p-value = 3.23e-02) Discussion Our study contributes to current efforts to elucidate the genetic architecture of alcohol consumption in Latin American populations, implicating novel genes (such as WRN) and revealing varying performance of PRS across different geographical subgroups.

This trial compared the effects of daily treatment with vitamin D or placebo for 1 year on blood tests of vitamin D status. The results demonstrated that daily 4000 IU vitamin D3 is required to achieve blood levels associated with lowest disease risks, and this dose should be tested in future trials for fracture prevention.

BACKGROUND:UK cardiovascular disease (CVD) incidence and mortality have declined in recent decades but socioeconomic inequalities persist. AIM:To present a new CVD model, and project health outcomes and the impact of guideline-recommended statin treatment across quintiles of socioeconomic deprivation in the UK. DESIGN AND SETTING:A lifetime microsimulation model was developed using 117 896 participants in 16 statin trials, 501 854 UK Biobank (UKB) participants, and quality-of-life data from national health surveys. METHOD:A CVD microsimulation model was developed using risk equations for myocardial infarction, stroke, coronary revascularisation, cancer, and vascular and non-vascular death, estimated using trial data. The authors calibrated and further developed this model in the UKB cohort, including further characteristics and a diabetes risk equation, and validated the model in UKB and Whitehall II cohorts. The model was used to predict CVD incidence, life expectancy, quality-adjusted life years (QALYs), and the impact of UK guideline-recommended statin treatment across socioeconomic deprivation quintiles. RESULTS:Age, sex, socioeconomic deprivation, smoking, hypertension, diabetes, and cardiovascular events were key CVD risk determinants. Model-predicted event rates corresponded well to observed rates across participant categories. The model projected strong gradients in remaining life expectancy, with 4-5-year (5-8 QALYs) gaps between the least and most socioeconomically deprived quintiles. Guideline-recommended statin treatment was projected to increase QALYs, with larger gains in quintiles of higher deprivation. CONCLUSION:The study demonstrated the potential of guideline-recommended statin treatment to reduce socioeconomic inequalities. This CVD model is a novel resource for individualised long-term projections of health outcomes of CVD treatments.