Recently admixed populations comprise a large portion of the human population worldwide, but are often excluded from Genome-Wide Association Studies (GWAS) due to analytic challenges. Our group has previously developed a local ancestry informed generalized linear model based method, Tractor, for GWAS in admixed samples, which produces accurate ancestry-specific effect sizes and boosts discovery power to identify ancestry-enriched loci. Tractor has been instrumental for elucidating the genetic architecture of complex traits across admixed cohorts, however it operates under an assumption of unrelated samples. As biobanks and other large-scale data sources continue to grow, increasing numbers of closely or cryptically related admixed samples are included. This brings new statistical challenges in conducting GWAS and motivates the timely development of novel tools that can model admixture in various cohort settings. Here, we propose a novel mixed model method, Tractor-Mix, that allows for well-calibrated association studies in datasets containing admixed samples with high degrees of relatedness. Similar to Tractor, our method conducts genetic association tests by leveraging local ancestry to produce more accurate effect sizes and boost power under heterogeneity while effectively controlling false positives. Extensive simulations show this enhanced method is competitive with other state-of-the-art approaches that do not produce ancestry-specific results. Empirical testing of Tractor-Mix on multiple cohorts, including admixed samples from the UK Biobank and Mexico City Prospective Study, highlight the value of the method, identifying ancestry-specific associations. In summary, Tractor-Mix is a powerful association framework that extends the capabilities of current models and will facilitate the inclusion of admixed samples in large-scale GWAS.

Rare coding variants that alter protein function and confer beneficial health effects can suggest potential drug targets. CHRNB3 encodes the β3 subunit of nicotinic acetylcholine receptors that bind nicotine and mediate its action in the brain. Here we report an exome-wide association study of number of cigarettes smoked per day (cig per day) in 37,897 current smokers from the Mexico City Prospective Study. We identify a deleterious missense variant in CHRNB3, p.Glu284Gly, that associates with a significant reduction in daily cigarette consumption. The missense variant is enriched in people of Indigenous Mexican ancestry but rare in other ancestries. We further identify a predicted loss-of-function variant in CHRNB3 that significantly associates with reduction in number of smoked cigarettes per day in participants of Japan Biobank. This variant is enriched in people of East Asian ancestry but is rare in other ancestries. Finally, we find that rare deleterious missense and predicted loss-of-function variants in aggregate associate with a reduction in the number of smoked cigarettes per day in individuals of European ancestry from the UK Biobank. Our results suggest that loss of function of CHRNB3 significantly associates with daily cigarette smoking, proposing β3 inhibition as a potential therapeutic strategy for nicotine addiction.

RATIONALE & OBJECTIVE:Chronic kidney disease (CKD) is a major cause of death in Mexico and blood pressure (BP) may be an important contributor. This study investigated the associations of BP with CKD, albuminuria, and death from kidney failure. STUDY DESIGN:Prospective cohort study. SETTING & PARTICIPANTS:133,470 adults aged ≥35 to <85 years without CKD or other chronic disease (except diabetes), recruited from two districts of Mexico City between 1998 and 2004, and who survived ≥5 years after recruitment. A random subset of 9198 underwent additional evaluation 2015-2019. EXPOSURES:Systolic BP (SBP), diastolic BP (DBP) and hypertension (participant report of taking blood pressure lowering medication or BP ≥140/90 mm Hg). OUTCOMES:Kidney failure mortality during follow-up, and CKD (self-report and/or eGFR <60 mL/min/1.73m2) and albuminuria at the time of repeat clinical evaluation. ANALYTICAL APPROACH:Multivariable Cox regression for the association of BP with kidney failure mortality and multivariable logistic regression for the association of baseline BP with CKD and albuminuria at the time of re-evaluation. RESULTS:Among all participants, SBP showed a continuous "log-linear" association with kidney failure mortality; each 20 mm Hg lower SBP being associated with 24% lower risk at ages 40-84 years (kidney failure death hazard ratio [HR] 0.76, 95% confidence interval 0.69-0.84). The association was stronger among those without diabetes (HR 0.54, 0.45-0.69) than with diabetes (HR 0.90, 0.80-1.01) but the absolute excess risk associated with higher BP was similar in these subgroups. Hypertension accounted for 9% of kidney failure deaths. Among those re-evaluated, 6% had developed CKD and 25% had albuminuria. 20 mm Hg lower baseline SBP was associated with 24% lower odds of both CKD (odds ratio [OR] 0.76, 0.68-0.85) and albuminuria (OR 0.76, 0.68-0.84) at the time of re-evaluation. Results were similar for DBP. LIMITATIONS:Baseline urine samples were unavailable and kidney function trends over time could not be assessed. CONCLUSIONS:This large prospective study in Mexican adults highlights elevated BP as a major modifiable risk factor for kidney failure mortality, CKD, and albuminuria.

Latin American populations remain underrepresented in genomic research. To help address this, we present an analysis of high-coverage whole-genome data from 1481 volunteers recruited as part of the oriGen Project. We identify over 47.2 million SNVs and 8.1 million short indels, including nearly 3 million non-singleton short variants absent from dbSNP and the Mexico City Prospective Study. Admixture analysis indicates that a Mexican training dataset is needed to more accurately estimate ancestry compositions by genetic similarity. Analysis of copy number variation associated with MX-AMR highlights several loci, including LCE1D and RHD. Interestingly, while 3.1% of participants carry homozygous deletions in the RHD gene, which determines the Rh blood group, this frequency dropped to 0.6% among individuals with high MX-AMR. Since the RHD deletion is rare in East Asians, and the Rh-negative phenotype is rare in Indigenous American populations, our results support the hypothesis that the Rh-negative blood group increased in frequency during the Spanish conquest rather than by genetic drift. We also find that 10% of volunteers are heterozygotes for the 22-42128945-C-T Loss of Function variant in CYP2D6, an enzyme involved in metabolizing painkillers, and tamoxifen. This work helps address the underrepresentation of Mexican populations in genomic research. Mexican populations remain underrepresented in genomics. Here, Aguilar-Ordoñez et al. report on 1,481 whole-genomes from the oriGen project, identifying key variants like a CNV driving the Rh-negative blood group.

OBJECTIVE:The Mexican population experiences a notably high prevalence of type 2 diabetes (T2D) and high T2D-associated disease risks. We used targeted plasma nuclear magnetic resonance metabolomics data within a Mendelian randomization framework to characterize the metabolomic profile of genetically predicted liability to T2D in this population. RESEARCH DESIGN AND METHODS:Between 1998 and 2004, 50,000 men and 100,000 women aged ≥35 years were recruited from Mexico City. Mendelian randomization analyses used a genetic risk score (GRS) comprising 1,055 established T2D-associated risk variants and eight pathway-specific T2D GRSs constructed from nonoverlapping subsets of these variants to estimate associations with 143 metabolic biomarkers (including lipids, lipoproteins, fatty acids, amino acids, ketone bodies, and other low-molecular-weight biomarkers). RESULTS:Among 125,587 included participants, the T2D GRS explained 6.0% of T2D liability and was not associated with major potential confounders of the relationships of T2D with the circulating metabolome. Genetically predicted liability to T2D was strongly positively associated with concentrations of VLDL particles and lipids within these, with triglycerides, branched-chain amino acids, and glycoprotein acetyls, and more modestly positively associated with intermediate-density lipoprotein and LDL, particularly small LDL, particles. Inverse associations were found with relative concentrations of several fatty acids. Pathway-specific T2D GRSs all associated with higher T2D risk but showed differential relationships with circulating metabolic biomarkers. CONCLUSIONS:T2D is associated with widespread changes in the circulating metabolome among adults in Mexico, reflecting diverse biological mechanisms and highlighting the importance of effective T2D management, including control of T2D-associated dyslipidemia, in this population.

Background Lipoprotein (a) [Lp(a)] is an independent atherosclerotic cardiovascular disease risk factor, with levels largely determined by variation in the LPA gene. Despite interests in therapeutic Lp(a) lowering, the phenotypic effects of very low Lp(a) are incompletely characterized, with some studies suggesting increased type 2 diabetes risk. Objectives Estimate associations between very low Lp(a), inferred by LPA loss of function variant rs41272114, with type 2 diabetes and glycemic biomarkers. Methods A multi-population study of European, Hispanic/Latino, and South Asian populations from five cohort studies was assembled. Effects of the null allele rs41272114 (CC, wild-type; T, null allele) on type 2 diabetes and glycemic biomarkers (fasting glucose, fasting insulin, glycosylated hemoglobin (HbA1c), triglyceride-to-high-density lipoprotein ratio, and HOMA-IR) were estimated using multivariable-adjusted and cohort-specific linear or logistic regression models that were combined using inverse variance meta-analysis. Results Of n=519,892 participants, the T null allele was common (n=49,841 CT and n=2,039 TT) and n=38,320 participants had type 2 diabetes (prevalence range: 4.7, 29.5%). Participants with the TT genotype had a median Lp(a) ranging 1.5-1.9 nmol/L compared to median Lp(a) ranging 15.8-30.0 nmol/L in participants with the CC genotype. We did not observe increased odds of type 2 diabetes by rs412722114 genotype (ORCTvs.CC = 0.97, 95% CI: 0.94, 1.00; ORTTvs.CC = 1.01, 95% CI: 0.89, 1.15). Mean levels of glycemic biomarkers also did not differ by rs41272114 genotype. Conclusions In a large multi-population study with high burdens of type 2 diabetes, life-long very low Lp(a) did not increase type 2 diabetes risk.

Background:Cardiovascular disease (CVD) is the leading cause of mortality in Latin America, yet most CVD risk equations were developed in high-income countries with limited validations in these settings. Here, we externally validated CVD risk prediction models for fatal CVD, and recalibrated the Globorisk-fatal model in Mexican population. Methods:We analyzed 112,262 adults ≥40 years, 67% (75,320) female and 33% (36,942) males, mean age 54.6 ± 10.7 years without prior CVD from the Mexico City Prospective Study. The primary outcome was 10-year fatal CVD, including myocardial infarction (MI) and stroke. CVD risk was estimated using the laboratory- and office-based Framingham, Globorisk, Globorisk-LAC, WHO, and SCORE2 equations. Discrimination was assessed with Harrell's c-statistic and AUROCs, calibration with mean estimates, slopes, and calibration curves, and overall performance with Brier scores. Sex-specific recalibration of the Globorisk-fatal model was performed using observed risks of fatal CVD. Findings:During 10 years of follow-up, 2429 fatal CVD events were recorded (1667 MI, 762 stroke). All models showed good discrimination, with c-statistics ranging from 0.761 to 0.805 in males and 0.797-0.831 in females. The Globorisk-fatal model had the highest c-statistic in females (0.831, 95% CI 0.821-0.841), and the laboratory-based WHO-MI model in males (0.805, 95% CI 0.783-0.827). Despite this, all equations consistently overestimated CVD risk, particularly in females. Calibration analyses revealed systematic overprediction at higher risk levels. Recalibration of the Globorisk-fatal model improved agreement between predicted and observed risks. Interpretation:CVD risk models showed good discrimination but consistently overestimated risk in this Mexican cohort. The recalibrated Globorisk-fatal model improves risk estimation of fatal CVD in Mexican adults. Funding:This research was supported by Instituto Nacional de Geriatría in Mexico.

BACKGROUND:Visceral adipose tissue (VAT) has been associated with cardiovascular disease (CVD) mortality. However, the comparative performance of VAT-related clinical surrogates remains poorly characterised. OBJECTIVES:To evaluate the performance of seven VAT-related clinical surrogates for predicting cause-specific CVD mortality. METHODS:We analysed data from the Mexico City Prospective Cohort, a population-based prospective cohort study, with baseline recruitment between 1998 and 2004 and ongoing mortality follow-up. CVD mortality included deaths from cardiac, stroke-related and other vascular causes. Seven VAT-related surrogates (METS-VF, CVAI, EVA, DAAT, LAP, VAI and DAI) were estimated using clinical, biochemical and anthropometric data at baseline. Associations with outcomes were evaluated using Cox regression models to estimate adjusted hazard ratios (aHR). Discrimination was assessed with Harrell's C-statistic (Cs) and calibration with slope plots. RESULTS:In a subsample of 102 385 participants without diabetes (median age: 47 years; 67% female) followed through a median of 20.13 years, 4068 (3.97%) died from any CVD causes. An increase in 1-SD unit of METS-VF (Cs: 0.73; aHR: 1.23, 95% CI: 1.18-1.29), EVA (Cs: 0.73; aHR: 1.19, 1.15-1.24), CVAI (Cs: 0.71; aHR: 1.19, 1.15-1.23) and DAAT (Cs: 0.63; aHR: 1.18, 1.14-1.23) was associated with CVD mortality and showed the highest predictive capacity and good calibration among the surrogates. Adding METS-VF to the Globorisk score among individuals classified as intermediate risk slightly improved discrimination for CVD mortality. CONCLUSIONS:In this large cohort of Mexican adults, four VAT-related clinical surrogates, particularly METS-VF, showed good discriminatory performance for long-term CVD mortality. Our results could support future studies that could incorporate VAT estimation to improve CVD risk stratification.

Background:Cardiovascular disease (CVD) is a leading cause of diabetes-related mortality in Mexico. Although diabetes subgroups capture underlying disease heterogeneity, their association and utility for risk prediction for fatal CVD in Mexican adults remain unclear. Here, we aimed to assess the risk of fatal CVD risk and their complementary role for fatal CVD risk prediction across diabetes subgroups in Mexican adults. Methods:We included adults with diabetes from the Mexico City Prospective Study (MCPS). Participants were classified into mild obesity-related (MOD), severe insulin-deficient (SIDD), severe insulin-resistant (SIRD), and mild age-related (MARD) diabetes using a self-normalizing neural network algorithm. Fatal CVD was defined as death from ischemic heart disease or stroke (ICD-10 I20-I25, I60-I69). SCORE2-Diabetes was internally recalibrated for fatal CVD outcomes only for use within MCPS, as this does not represent a formal validation of the original composite endpoint. Cause-specific Cox proportional hazards and Fine & Gray competing risk regression models were used to estimate subgroup-specific risk, and sequential models evaluated the incremental predictive value of diabetes subgroups combined with SCORE2-Diabetes and traditional risk factors. Findings:We analyzed data from 24,943 adults living with diabetes (mean age 58 ± 12, 67% female, no ethnicity data available). Over a median follow-up of 19.3 years (IQR 12.7-20.6), 2218 fatal CVD events (8.9%) were recorded. SIDD was the most prevalent subgroup (50.0%), followed by SIRD (14.1%), MARD (17.7%), and MOD (18.3%). SIDD and MARD showed the highest adjusted risk of fatal CVD (HR 1.58 [95% CI 1.38-1.81] and 1.35 [1.13-1.60]), whereas MOD and SIRD had lower risk, even when considering competing causes of non-CVD deaths. Recalibrated SCORE2-Diabetes demonstrated adequate discrimination overall (c-statistic 0.748, 95% CI 0.734-0.762) and for most diabetes subgroups but underperformed in MARD, with internal recalibration for fatal CVD outcomes improving risk assessment. The combination of diabetes subgroups and SCORE2-Diabetes modestly improved prediction for fatal CVD outcomes. Interpretation:Diabetes subgroups show heterogeneity in fatal CVD risk in Mexican adults. SIDD and MARD identify high-risk individuals and integration subgroup classification with SCORE2-Diabetes is complementary for fatal CVD risk prediction. Funding:This research was supported by a grant provided by the Bernard Lown Scholars in Cardiovascular Health Program grant number BLSCHP-2403.

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.

Rationale & Objective:Reduced kidney function is strongly associated with higher mortality, but most evidence is from high-income populations. This study evaluated the relevance of kidney function to cause-specific mortality in Mexico, a country where diabetes is common and chronic kidney disease (CKD) is a major cause of morbidity and mortality. Study Design:Prospective study of Mexican adults aged ≥35 years at recruitment (1998-2004) who were followed until October 2022. Setting & Participants:Participants recruited into the Mexico City Prospective Study. Analyses focused on 126,245 participants aged 35-74 years at recruitment without prior disease (except diabetes or CKD). Exposures:Estimated glomerular filtration rate (eGFR). Outcomes:Cause-specific mortality. Analytical Approach:Cox regression was used to relate eGFR to cause-specific mortality. Analyses were adjusted for sociodemographic and lifestyle factors, anthropometry, and diabetes. Results:Among 40,996 men and 85,249 women aged 35-74 years, median eGFR was 102 (IQR, 91-110) mL/min/1.73 m2, mean body mass index was 29.1 (SD 4.9) kg/m2, 1% had self-reported CKD, 13% had previously diagnosed diabetes, and 12,590 died at ages 35-74 years over a median follow-up of 20.4 years. For those with eGFR <105 mL/min/1.73 m2, each 15-mL/min/1.73 m2 lower eGFR was associated with 32% higher all-cause mortality (RR, 1.32; 95% CI, 1.30-1.35). The strongest associations were for kidney (RR, 1.75; 95% CI, 1.69-1.80), infective (RR, 1.34; 95% CI, 1.24-1.44), and vascular deaths (RR, 1.28; 95% CI, 1.24-1.33). Compared with participants with eGFR 90-104 mL/min/1.73 m2, those with eGFR <30 mL/min/1.73 m2 had almost 7 times the all-cause mortality rate (RR, 6.5; 95% CI, 5.7-7.3). For participants with eGFR >105 mL/min/1.73 m2, higher eGFR was associated with higher mortality. The absolute excess mortality risk associated with reduced eGFR was particularly high for those with diabetes. Limitations:Data on urinary albumin and nonfatal disease outcomes were unavailable. Conclusions:In Mexico, decreased kidney function is strongly associated with premature mortality, mainly from vascular, kidney, and infective causes. Prevention and management of CKD, particularly in individuals with diabetes, should be central to disease-prevention policies.

BACKGROUND:Observational studies relating blood pressure in middle age to mortality may underestimate lifelong effects. Mendelian randomization can reduce the impact of confounding and reverse causality and may better estimate lifelong effects of blood pressure on mortality. METHODS:Mendelian randomization analyses used 125 895 Mexico City Prospective Study participants aged 35 to 74 years at recruitment with valid genetic and other data. Cox regression, adjusted for confounders and regression dilution bias, related blood pressure to mortality in 133 027 participants aged 35 to 74 years without prior chronic disease (other than diabetes) at recruitment. RESULTS:In the genetic analyses (40 560 [32%] men; mean age 50 years, mean body mass index 29 kg/m2) there were 13 153 deaths before age 75 years (3478 cardiovascular, 2053 kidney, and 7622 other). Each 10 mm Hg higher genetically predicted lifelong systolic blood pressure was associated with 73% higher cardiovascular mortality at ages 35 to 74 years (rate ratio, 1.73 [95% CI, 1.44-2.06]), 42% higher kidney death (1.42 [95% CI, 1.15-1.75]), but no clear increase in death from other causes. These lifelong rate ratios were higher than those estimated by observational analyses relating blood pressure in middle age to risk. Mendelian randomization analyses of lifelong diastolic blood pressure confirmed strong associations with cardiovascular but not kidney death. Mortality rate ratios were similar for men and women and in those with versus without diabetes, and broadly similar at different ages and at different proportions of Indigenous American ancestry. Sensitivity analyses gave consistent results. CONCLUSIONS:In this Mexican population, genetically informed lifelong differences in blood pressure were strongly related to death from cardiovascular and kidney disease.

BACKGROUND:Prediabetes has been associated with increased all-cause and cardiovascular mortality. However, no large-scale studies have been conducted in Mexico or Latin America examining these associations. METHODS:We analyzed data from 114 062 adults without diabetes (diagnosed or undiagnosed) from the Mexico City Prospective Study. Participants were followed until January 1, 2021, for cause-specific mortality. We defined prediabetes according to the American Diabetes Association (ADA; HbA1c ≥ 5.7% to <6.5%) and the International Expert Committee (IEC; HbA1c ≥ 6.0 to <6.5%) definitions. Cox regression adjusted for confounders was used to estimate all-cause and cause-specific mortality rate ratios (RR) for deaths occurring at ages 35 to 74 years associated with prediabetes. RESULTS:After median 18.4 (IQR 17.6-19.7) years of follow-up, individuals with prediabetes had higher risk of all-cause mortality at ages 35 to 74 compared to those without prediabetes (RR 1.13 [1.07-1.20] for ADA-defined and 1.27 [1.17-1.38] for IEC-defined prediabetes), as well as higher risk of cardiovascular (RR 1.23 [1.11-1.37] and 1.44 [1.24-1.67], respectively), renal (RR 1.33 [1.06-1.66] and 1.62 [1.18-2.23], respectively), and acute diabetic deaths (RR 2.62 [1.75-3.93] and 3.42 [2.09-5.61], respectively). The absolute excess risk associated with ADA-defined prediabetes at ages 35 to 74 accounted for 7% of cardiovascular, 9% of renal, and 31% of acute diabetic deaths. IEC-defined prediabetes accounted for 4%, 5% and 14% of cardiovascular, renal, and acute diabetic deaths. Prediabetes-associated excess mortality risks were, at least in part, explained by adiposity. CONCLUSION:Prediabetes is a significant risk factor for all-cause, cardiovascular, renal, and acute diabetic deaths in Mexican adults. Early identification and timely management of prediabetes among individuals at risk of this condition could reduce premature mortality in this population.

BACKGROUND:Cardiovascular disease (CVD) is the leading cause of mortality in Latin America, yet most CVD risk prediction models were developed in high-income countries with limited validations in these settings. OBJECTIVES:To externally validate CVD risk prediction models for 10-year fatal CVD, and recalibrate the Globorisk-fatal model in Mexican population. METHODS:We analyzed 112,262 adults ≥40 years from the Mexico City Prospective Study. Outcomes were restricted to fatal CVD, including myocardial infarction (MI) and stroke, censored at 10 years. CVD risk was estimated using the laboratory- and office-based Framingham, Globorisk, Globorisk-LAC, WHO, and SCORE2 equations. Discrimination was assessed with Harrell's c-statistic and AUROCs, calibration with mean estimates, slopes, and calibration curves, and overall performance with Brier scores. Sex-specific recalibration of the Globorisk-fatal model was performed using observed 10-year risks. RESULTS:During 10 years of follow-up, 2,429 fatal CVD events were recorded (1,667 MI, 762 stroke). All models showed good discrimination, with c-statistics ranging from 0.761-0.805 in men and 0.797-0.831 in women. The Globorisk-fatal model had the highest c-statistic in women (0.831, 95%CI 0.821-0.841), and the laboratory-based WHO-MI model in men (0.805, 95%CI 0.783-0.827). Despite this, all equations consistently overestimated CVD risk, particularly in women. Calibration analyses revealed systematic overprediction at higher risk levels, more pronounced in men. Recalibration of the Globorisk-fatal model improved agreement between predicted and observed risks, reducing overestimation. CONCLUSIONS:CVD risk models showed good discrimination but consistently overestimated risk in this Mexican cohort. The recalibrated Globorisk-fatal model improves risk estimation of fatal CVD in Mexican adults.

Background:Observational epidemiological studies in Mexico have shown high mortality risks associated with type 2 diabetes (T2D). However, it is unclear whether these relationships are wholly causal. We aimed to assess the association of genetically-predicted T2D liability with risk of death in Mexico. Methods:Between 1998 and 2004, 150,000 men and women were recruited from Mexico City and followed-up until September 2022 for cause-specific mortality. Mendelian randomisation analyses, using a genetic risk score (GRS) comprising 1055 established T2D-associated risk variants, estimated associations with risk of all-cause and cause-specific mortality at ages 35-74. Findings:Among 121,433 included participants with a mean (standard deviation) age of 51 (11), 68% (n = 82,249) were women and 18% (n = 21,371) had T2D. The GRS explained 6.3% of T2D liability and was not associated with major potential confounders of the T2D-mortality relationship. During a median (interquartile range) of 20.2 (19.4-21.4) years' follow-up, 12,293 participants died. Genetically-predicted T2D liability was associated with a death rate ratio (RR) of 1.29 (95% confidence interval [CI] 1.23-1.36) per trebling in genetically-predicted odds of T2D. There were particularly strong associations with death from renal disease (n = 1696; RR 2.29 [95% CI 1.99-2.64]) and acute diabetic crises (n = 509; RR 2.27 [1.75-2.93]) and weaker, but still strong, associations with death from vascular disease (n = 3226; RR 1.31 [1.19-1.46]) and infection (n = 2437; RR 1.21 [1.07-1.36]). Genetically-predicted T2D liability was not clearly associated with death from cancer (n = 2016; RR 1.00 [95% CI 0.88-1.14]) or cirrhosis (n = 895; RR 0.90 [0.74-1.10]). Interpretation:T2D is causally associated with death from vascular, renal and infectious diseases. Its prevention and effective management could substantially reduce premature deaths in Mexico, where T2D is common. Funding:Wellcome Trust, the Mexican Health Ministry, the National Council for Science and Technology (CONACyT) for Mexico, Cancer Research UK, British Heart Foundation, Kidney Research UK, UK Medical Research Council, AstraZeneca, Regeneron.

Accurate eGFR is essential for identifying and managing CKD. The CKD Epidemiology Collaboration (CKD-EPI) 2021 equation removed the race coefficient from the 2009 version, but its effect in Mexican populations remains unclear. Here, we compared eGFR category prevalence, and predictive performance between the CKD-EPI 2009 and 2021 creatinine-based eGFR equations, as well as the prognostic relevance of reclassification in eGFR categories using the 2021 equation in Mexicans. We evaluated 25,110 adults who were at least aged 20 years from the 2016-2023 cycles of the Mexican National Health and Nutrition Survey to estimate national low eGFR and eGFR category prevalence using both equations. We also assessed 5-year and 10-year risk of all-cause, cardiovascular, and kidney-related mortality in 142,884 adults from the Mexico City Prospective Study using Cox proportional hazards and Fine and Gray regression models. In Mexican National Health and Nutrition Survey 2023, prevalence of eGFR <60 ml/min per 1.73 m 2 was lower with CKD-EPI 2021 (3%; 95% confidence interval [CI], 2% to 4%) compared with the 2009 equation (4%; 95% CI, 2% to 5%). Use of the 2021 equation resulted in upward eGFR reclassification in 7% (95% CI, 4% to 9%) of adults 20 years or older, particularly among older adults and those with hypertension or diabetes, yielding a reduction in 486,532 adults identified with eGFR <60 ml/min per 1.73 m 2 compared with the 2009 equation. In Mexico City Prospective Study, despite both equations showing similar C-statistics, the 2021 equation reclassified 8.3% of participants to higher eGFR categories, and reclassification was associated with lower risk of 5-year and 10-year all-cause, cardiovascular, and kidney-related mortality, particularly for participants reclassified upward from G3a to G5 categories. The CKD-EPI 2021 equation yields lower prevalence of low eGFR but leads to prognostically relevant eGFR category reclassification compared with the 2009 equation. Our findings support the implementation of the 2021 equation for population health monitoring in Mexico without compromising prognostic utility.

Background:We aimed to describe the frequency of deaths related to advanced HIV disease (AHD) and its associated characteristics, as well as the frequency of very early and early mortality after HIV diagnosis, among people with HIV in Mexico between 1998 and 2022. Methods:We used data from the Mexican National Death Registry. We defined deaths related to AHD as those listed in the AIDS-defining conditions of the Centers for Disease Control and Prevention, very early mortality as deaths occurring within the first month after HIV diagnosis, and early mortality as those occurring between the first month and the first year after HIV diagnosis. We used logistic regression models to describe trends of deaths related to AHD, early mortality, very early mortality, and specific causes of death over time. Results:There were 106 056 registered deaths among people with HIV, ranging from 507 to 5287 annually. The most common cause of death was related to AHD throughout the study period (54%). The predicted probability of death related to AHD decreased from 75% to 35% between 2000 and 2012 but increased after 2014 to 52% in 2022. Overall, 22% of deaths occurred very early and 25% early after HIV diagnosis. Calendar year was the only strong predictor of death due to AHD. Conclusions:A high and increasing proportion of deaths were attributed to advanced HIV disease in Mexico; a fifth of them occurred in the first month of HIV diagnosis and almost a half in the first year. In the context of universal access to antiretroviral therapy, these results suggest that additional components of the public health HIV response could be lacking.

BACKGROUND:Persistent hyperglycaemia in diabetes can cause weight loss, distorting the association of adiposity with mortality. We estimated the lifelong associations of genetically predicted body mass index (BMI) with 52 causes of death among 125 003 Mexican adults, in whom persistent hyperglycaemia in diabetes was common. METHODS:A trans-ancestry genetic instrument for BMI (from 724 BMI-associated single-nucleotide polymorphisms) estimated the causal relevance of BMI to mortality before age 75 years, stratified by sex and adjusted for age and underlying ancestry structure, using a one-sample Mendelian randomization (MR) approach. Two-sample MR and other sensitivity analyses were also performed. RESULTS:The genetic instrument explained 3% of the BMI variation and predicted BMI similarly in men and women. Each 5-kg/m2 higher genetically predicted BMI was associated with nearly a doubling in the risk of all-cause mortality at ages 35-74 years [13 066 deaths; hazard ratio (HR) 1.80, 95% confidence interval (CI) 1.63-2.00]. Hazard ratios were greater for vascular-metabolic (n =  7111; HR 2.15, 95% CI 1.87-2.48) than for non-vascular-metabolic causes (n =  5955; HR 1.47, 95% CI 1.27-1.71) and particularly strong for renal (n =  2034; HR 3.59, 95% CI 2.76-4.67), acute diabetic crises (n =  557; HR 2.70, 95% CI 1.64-4.44), and infective deaths (n =  811; HR 2.61, 95% CI 1.73-3.92). For all-cause mortality, HRs were somewhat greater at younger ages compared with older ages, and slightly larger in those with a higher proportion of Indigenous American ancestry. The strength of the association with mortality was reduced by more than half after simple adjustment for genetic predisposition to diabetes. Sensitivity analyses supported the main conclusions. CONCLUSION:In this Mexican population, genetically predicted lifelong BMI was strongly related to mortality and mediated substantially through diabetes.

Human populations differ in disease prevalences and in average values of phenotypes, but the extent to which differences are caused by genetic or environmental factors is unknown for most complex traits. Comparing phenotypic means across populations is confounded by environmental differences and comparisons based on polygenic predictors can lead to biased inference. Family-based analyses of genetically admixed individuals offer a powerful framework for disentangling the direct and associated effects of genetic ancestry on phenotypes. Here, we leverage genetic data from admixed adults in the Mexico City Prospective Study (MCPS) to estimate within-family ancestry effects. We quantified associations between genetic ancestry and 15 complex traits among 52,583 unrelated individuals and in 39,714 relatives across 17,627 families. At the population level, relative to a European ancestry baseline, we estimate an effect of Indigenous American (IAM) ancestry of -1.98 standard deviations (P < 2×10-16) for height and a natural log-odds ratio (lnOR) of 1.73 (95% confidence interval [CI] 1.54-1.92) for type 2 diabetes (T2D, P < 2×10-16), and multiple associations with other traits and ancestries. We estimated a within-family direct effect of IAM of -1.51 standard deviations (P = 1.02×10-8) for height and lnOR of 5.13 (95% CI 2.48-7.78, P = 1.51×10-4) for risk of T2D. These direct effects are supported by between-ancestry differences in polygenic burden and evidence of selection at trait-associated loci. In contrast, we found no evidence for a direct effect of ancestry on educational attainment or other study traits despite large and significant associations at the population level, implying environmental causes or confounding. Overall, this study provides an experimental design to study between- ancestry genetic effects for complex traits and reports significant ancestry differences for height, T2D, and metabolic-related traits in a genetically diverse population from Mexico City. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by funding from the Mexican Health Ministry; the National Council for Science and Technology (CONACyT) for Mexico; the Wellcome Trust [058299/Z/99]; Cancer Research UK; the British Heart Foundation [RE/13/1/30181]; and the UK Medical Research Council [MC\_UU\_00017/2, MR/Z504543/1]. Genotyping was supported through an academic partnership involving the National Autonomous University of Mexico, the University of Oxford, Regeneron Pharmaceuticals, and AstraZeneca. No authors received payment from a pharmaceutical company or other agency for writing this article. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics approval was obtained from the Mexican Ministry of Health, the Mexican National Council for Science and Technology, and the University of Oxford, UK. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors