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.

Background Genetic associations of rare coding variants often directly pinpoint causal genes and inform the direction of association and hence have potential to identify new drug targets. Rare variants are often restricted to specific ancestries due to population phenomena such as genetic drift. Thus, studying diverse populations is critical for human genetics-based drug target discovery. Here, we present an exome-wide association study (ExWAS) of smoking behavior in diverse ancestries that led to the discovery of a novel target for smoking addiction—CHRNB3. Methods We performed ExWAS of a quantitative smoking trait, number of cigarettes smoked per day (cig per day), in ∼70,000 individuals of admixed American ancestry from the Mexico City Prospective Study (MCPS) and ∼130,000 individuals of British European ancestry from the UK Biobank. Genetic analyses were performed using REGENIE accounting for relatedness, population stratification, age, sex, and other relevant covariates. Gene discovery was based on aggregate-level associations of rare (minor allele frequency (MAF) < 1%) predicted loss of function (pLOF) and deleterious missense variants in 17,066 unique genes across the genome. Statistical threshold for significance was set at P=5e-7 after multiple-testing correction. We further studied the associations of coding variants in the significant genes with cig per day in ∼75,000 individuals of East Asian ancestry using publicly available summary statistics from the Japan biobank. Results The ExWAS in admixed Americans revealed a strong protective burden association of rare pLOF and deleterious missense variants in CHRNB3 with cig per day (beta=-0.19 SD; P=3.6e-11). The signal was driven by a missense variant (p.Glu284Gly) that is enriched (MAF=1.3%) in admixed Mexican Americans but almost absent in other world populations. Heterozygous and homozygous carriers smoked on average 21% (mean=4.6 cig per day) and 78% (mean=1.3) fewer cigarettes compared to carriers of reference allele (mean=5.8). Further analysis revealed a pLOF variant (rs147306385, splice donor) in CHRNB3 that is enriched in East Asians (MAF=0.4%) but absent in other populations and showed a significant protective association with cig per day in Japanese (beta=-0.19 SD; P=3.9e-8) with almost the same effect size as p.Glu284Gly. Also, we found a nominal protective association of rare pLOF burden in CHRNB3 with cig per day in Europeans, further validating our discovery (beta=-0.27; P=0.002). Discussion Although early genome-wide association studies have implicated the 8p11.2 locus, containing CHRNB3 and CHRNA6, in smoking behavior, the causal gene(s) and mechanism have been unclear so far. Our findings based on rare variants from diverse ancestries point to a direct link between coding variation in CHRNB3 and number of cigarettes smoked per day. CHRNB3 encodes the beta-3 subunit of nicotinic acetylcholine receptors in the brain that bind nicotine and mediate its reinforcing properties leading to addiction. The strong protective effect displayed by rare variants suggests beta-3 inhibition is a novel therapeutic mechanism to treat smoking addiction. Disclosure Regeneron Genetics Center, Employee

ABSTRACTBACKGROUNDEvidence from low– and middle-income countries regarding the effect of smoking in people with diabetes is lacking. Here, we report the association of smoking with mortality in a large cohort of Mexican adults with diabetes.METHODSParticipants with diabetes mellitus (self-reported medical diagnosis, use of antidiabetic medications or HbA1c ≥6.5%) aged 35-74 years when recruited into the Mexico City Prospective Study were included. Cox regression confounder-adjusted mortality rate ratios (RRs) associated with baseline smoking status were estimated.FINDINGSAmong 15,975 women and 8225 men aged 35-74 years with diabetes but no other comorbidities at recruitment, 2498 (16%) women and 2875 (35%) men reported former smoking and 2753 (17%) women, and 3796 (46%) men reported current smoking. Smoking less than daily was common: 39.4% of female current smokers and 30.7% of male current smokers. During a median of 17 years of follow-up there were 5087 deaths at ages 35-74 years. Compared with never smoking, the all-cause mortality RR was 1.08 (95%CI 1.01–1.17) for former smoking, 1.09 (95%CI 0.99–1.20) for non-daily smoking, 1.06 (95%CI 0.96–1.16) for smoking <10 cigarettes per day (median during follow-up 4 cigarettes/day) and 1.28 (95% CI 1.14–1.43) for smoking ≥10 cigarettes/day (median during follow-up 15 cigarettes/day). Excess mortality among current daily smokers was greatest for COPD, lung cancer, cardiovascular diseases, and acute diabetic complications.INTERPRETATIONIn this cohort of Mexican adults with diabetes, low-intensity daily smoking was associated with increased mortality, despite observing smoking patterns which are different from other populations. Of those smoking ≥10 cigarettes per day, over one fifth were killed by their habit. Quitting substantially reduced these risks.RESEARCH IN CONTEXTEvidence before this studyWe conducted a search in PubMed to identify studies on smoking-related mortality in individuals with diabetes before September 1st, 2023, using the terms ((diabetes mellitus) OR (type 2 diabetes mellitus)) AND ((smoking) OR (tobacco)) AND ((mortality) OR (survival analysis) OR (death)). We identified a meta-analysis published in 2015 which analysed data from 1,132,700 participants with diabetes from 89 cohort studies. Among current and former smokers, the pooled adjusted relative risk for all-cause mortality was 1.55 (95% CI 1.46–1.64) and 1.19 (95% CI 1.11–1.28), respectively. Among current smokers, there was considerably higher risk of death due to cardiovascular disease, coronary heart disease, stroke, peripheral arterial disease, and heart failure. Most included studies were conducted in high income countries and only one was done in Latin America (Argentina, 1,730 participants). In Mexico, epidemiological studies related to smoking have been primarily descriptive in nature. A previous study of the MCPS that analysed all-cause smoking-related mortality among disease-free individuals found adjusted rate ratios among daily smokers of 1.17 (95% CI 1.10–1.25) for those using <10 cigarettes/day and 1.54 (95% CI 1.42–1.67) for those using ≥10 cigarettes/day. In this study, mortality risk in people with diabetes was not assessed separately. Instead, mortality risk estimates were obtained for several chronic diseases as a group. No other studies have analysed changes in smoking habits and smoking-related mortality in Mexican individuals with diabetes.Added value of this studyTo our knowledge, this is the first analysis of longitudinal data of Mexican adults with diabetes (n=24,200) followed over 17 years, to examine the association between smoking and all-cause and cause-specific mortality. Compared with never smokers with diabetes, former and daily smokers with diabetes had elevated mortality. Among daily smokers there was higher risk of death due to cardiovascular disease, acute diabetes complications, lung cancer and COPD. Our results are generally consistent with previous analyses that have found smoking as a significant risk factor for higher mortality in individuals with diabetes. Our estimates, however, are comparably lower for all-cause mortality, possibly related to distinct smoking habits specific to the Mexican population with diabetes.Implications of all available evidenceOur results confirm that smoking is a significant risk factor for all-cause and cause-specific mortality among Mexican adults with diabetes. Strategies to promote smoking cessation among individuals with diabetes should be encouraged, particularly given that tobacco use is a modifiable risk factor. This is especially meaningful in middle-to lower-income countries like Mexico, where diabetes prevalence is increasing and achieving glycaemic targets remains a challenge.

Rare coding variants that substantially affect function provide insights into the biology of a gene1-3. However, ascertaining the frequency of such variants requires large sample sizes4-8. Here we present a catalogue of human protein-coding variation, derived from exome sequencing of 983,578 individuals across diverse populations. In total, 23% of the Regeneron Genetics Center Million Exome (RGC-ME) data come from individuals of African, East Asian, Indigenous American, Middle Eastern and South Asian ancestry. The catalogue includes more than 10.4 million missense and 1.1 million predicted loss-of-function (pLOF) variants. We identify individuals with rare biallelic pLOF variants in 4,848 genes, 1,751 of which have not been previously reported. From precise quantitative estimates of selection against heterozygous loss of function (LOF), we identify 3,988 LOF-intolerant genes, including 86 that were previously assessed as tolerant and 1,153 that lack established disease annotation. We also define regions of missense depletion at high resolution. Notably, 1,482 genes have regions that are depleted of missense variants despite being tolerant of pLOF variants. Finally, we estimate that 3% of individuals have a clinically actionable genetic variant, and that 11,773 variants reported in ClinVar with unknown significance are likely to be deleterious cryptic splice sites. To facilitate variant interpretation and genetics-informed precision medicine, we make this resource of coding variation from the RGC-ME dataset publicly accessible through a variant allele frequency browser.

Abstract Background There is limited population-based evidence on the prevalence of cognitive impairment in Mexico, a country with a rapidly aging population and where key risk factors, such as diabetes and obesity, are common. This study describes the distribution of cognitive impairment in adults from Mexico City. Methods This cross-sectional population-based study included participants from the Mexico City Prospective Study which recruited 150,000 adults aged ≥ 35 years in 1998–2004. In 2015–2019 about 10,000 survivors were resurveyed with identical information from the original survey and additional assessments including a cognitive assessment. The main analyses included those aged 50–89 years with complete cognitive assessment and covariate data at resurvey. Cognitive impairment was defined by a score ≤ 24 on the Mini Mental State Examination (MMSE). The distribution of MMSE scores and cognitive impairment by age, sex, and major disease risk factors (diabetes, hypertension, and adiposity) was analyzed among those with complete MMSE data and some degree of self-reported formal education. Results Of the 9,288 participants aged 50–89 years at the 2015–2019 resurvey with complete data, 8,197 reported having at least some years of formal education. Among these (mean age 66 years; 31% men), their mean MMSE score was 26.2 (SD 3.6) points, 1,941 (24%) had cognitive impairment, their mean body-mass index (BMI) was 28.6 (SD 5.5) kg/m2, 3,008 (37%) had hypertension and 2,467 (30%) had diabetes. The sex- and district-standardised prevalence of cognitive impairment increased strongly with age, from 10% in those 50–59 years to 55% in those aged 80–89. At any given age, the prevalence of cognitive impairment was higher in women than in men. After accounting for the effects of age, sex, and district there was little difference in the prevalence of cognitive impairment between participants with or without diabetes, hypertension, overweight or obesity (BMI ≥ 25 km/m2), or high levels of fat mass. Conclusions In this population of adults aged 50–89 years from Mexico City, the prevalence of cognitive impairment was high, particularly among women. The extent to which cognitive impairment relates to health outcomes in this population needs to be investigated.

The etiology of prostate cancer, the second most common cancer in men globally, has a strong heritable component. While rare coding germline variants in several genes have been identified as risk factors from candidate gene and linkage studies, the exome-wide spectrum of causal rare variants remains to be fully explored. To more comprehensively address their contribution, we analysed data from 37,184 prostate cancer cases and 331,329 male controls from five cohorts with germline exome/genome sequencing and one cohort with imputed array data from a population enriched in low-frequency deleterious variants. Our gene-level collapsing analysis revealed that rare damaging variants in SAMHD1 as well as genes in the DNA damage response pathway (BRCA2, ATM and CHEK2) are associated with the risk of overall prostate cancer. We also found that rare damaging variants in AOX1 and BRCA2 were associated with increased severity of prostate cancer in a case-only analysis of aggressive versus non-aggressive prostate cancer. At the single-variant level, we found rare non-synonymous variants in three genes (HOXB13, CHEK2, BIK) significantly associated with increased risk of overall prostate cancer and in four genes (ANO7, SPDL1, AR, TERT) with decreased risk. Altogether, this study provides deeper insights into the genetic architecture and biological basis of prostate cancer risk and severity.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

BACKGROUND:Alcohol consumption is a leading cause of premature death globally, but there is no large-scale prospective evidence from Mexico. METHODS:The Mexico City Prospective Study recruited 150 000 adults aged 35 years or older between 1998 and 2004. Participants were followed up until Oct 1, 2022 for cause-specific mortality. Cox regression in those with no self-reported chronic disease at entry (adjusted for age, sex, district, education, physical activity, smoking, and diabetes) was used to relate baseline-reported alcohol consumption (never, former, occasional [less than monthly], and regular [at least monthly, split into <70, ≥70 to <140, ≥140 to <210, and ≥210 g/week]) to mortality at ages 35-74 from all causes, and from a pre-specified alcohol-related set of underlying causes. Heavy episodic drinking (normally consuming >5 [men] or >4 [women] drinks on a single occasion) and type of preferred drink were also examined. FINDINGS:Among 138 413 participants aged 35-74 years at recruitment, 21 136 (15%) were regular alcohol drinkers (14 863 [33%] men, 6273 [7%] women), of whom 13 383 (63%) favoured spirits and 6580 (31%) favoured beer. During follow-up, there were 13 889 deaths at ages 35-74 years, including 3067 deaths from the pre-specified alcohol-related causes. Overall, J-shaped associations with mortality were observed. Compared with occasional drinkers, those with baseline-reported consumption ≥210 g/week had 43% higher all-cause mortality (rate ratio [RR] 1·43 [95% CI 1·30-1·56]) and nearly three times the mortality from the pre-specified alcohol-related causes (2·77 [2·39-3·20]). Death from liver disease was strongly related to alcohol consumption; the RR comparing regular drinkers of ≥140 g/week with occasional drinkers was 4·03 (3·36-4·83). Compared with occasional light drinking, occasional heavy episodic drinking was associated with 20% higher alcohol-related mortality (1·20 [1·06-1·35]), and regular heavy episodic drinking was associated with 89% higher alcohol-related mortality (1·89 [1·67-2·15]). Drinks with alcohol percentages higher than spirits were associated with the greatest increased mortality risk, even after accounting for the total alcohol consumed. INTERPRETATION:In this Mexican population, higher alcohol consumption, episodic drinking, and very high percentage alcoholic products were all associated with increased mortality. FUNDING:Wellcome Trust, the Mexican Health Ministry, the National Council of Science and Technology for Mexico, Cancer Research UK, British Heart Foundation, and the UK Medical Research Council. TRANSLATION:For the Spanish translation of the abstract see Supplementary Materials section.

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 115,919 adults without diabetes (diagnosed or undiagnosed) aged 35-84 years who participated in the Mexico City Prospective Study between 1998 and 2004. Participants were followed until January 1st, 2021 for cause-specific mortality. We defined prediabetes according to the American Diabetes Association (ADA, HbA1c 5.7% to 6.4%) and the International Expert Committee (IEC, HbA1c 6.0-6.4%) definitions. Cox regression adjusted for confounders was used to estimate all-cause and cause-specific mortality rate ratios (RR) at ages 35-74 years associated with prediabetes. FINDINGS:During 2,085,392 person-years of follow-up (median in survivors 19 years), there were 6,810 deaths at ages 35-74, including 1,742 from cardiovascular disease, 892 from renal disease and 108 from acute diabetic crises. Of 110,405 participants aged 35-74 years at recruitment, 28,852 (26%) had ADA-defined prediabetes and 7,203 (7%) had IEC-defined prediabetes. Compared with those without prediabetes, individuals with prediabetes had higher risk of all-cause mortality at ages 35-74 years (RR 1.13, 95% CI 1.07-1.19 for ADA-defined prediabetes and RR 1.28, 1.18-1.39 for IEC-defined prediabetes), as well as increased risk of cardiovascular mortality (RR 1.22 [1.10-1.35] and 1.42 [1.22-1.65], respectively), renal mortality (RR 1.35 [1.08-1.68] and 1.69 [1.24-2.31], respectively), and death from an acute diabetic crisis (RR 2.63 [1.76-3.94] and 3.43 [2.09-5.62], respectively). RRs were larger at younger than at older ages, and similar for men compared to women. The absolute excess risk associated with ADA and IEC-defined prediabetes at ages 35-74 accounted for6% and 3% of cardiovascular deaths respectively, 10% and 5% of renal deaths respectively, and 31% and 14% of acute diabetic deaths respectively. INTERPRETATION:Prediabetes is a significant risk factor for all-cause, cardiovascular, renal, and acute diabetic deaths in Mexican adults. Identification and timely management of individuals with prediabetes for targeted risk reduction could contribute to reducing premature mortality from cardiometabolic causes in this population. FUNDING:Wellcome Trust, the Mexican Health Ministry, the National Council of Science and Technology for Mexico, Cancer Research UK, British Heart Foundation, UK Medical Research Council. Instituto Nacional de Geriatría (Mexico City).

Purpose A variable number of tandem repeats (VNTR) in the insulin gene ( INS ) control region may be involved in type 2 diabetes (T2D). The TH01 microsatellite is near INS and may regulate it. We investigated whether the TH01 microsatellite and INS VNTR, assessed via the surrogate marker single nucleotide polymorphism rs689, are associated with T2D and serum insulin levels in a Mexican population. Methods We analyzed a main case–control study (n = 1986) that used univariate and multivariate logistic regression models to calculate the risk conferred by TH01 and rs689 loci for T2D development; rs689 results were replicated in other case–control (n = 1188) and cross-sectional (n = 1914) studies. Results TH01 alleles 6, 8, 9, and 9.3 and allele A of rs689 were independently associated with T2D, with differences between sex and age at diagnosis. TH01 alleles with ≥ 8 repeats conferred an increased risk for T2D in males compared with ≤ 7 repeats (odds ratio, ≥ 1.46; 95% confidence interval, 1.1–1.95). In females, larger alleles conferred a 1.5-fold higher risk for T2D when diagnosed ≥ 46 years but conferred protection when diagnosed ≤ 45 years. Similarly, rs689 allele A was associated with T2D in these groups. In males, larger TH01 alleles and the rs689 A allele were associated with a significant decrease in median fasting plasma insulin concentration with age in T2D cases; the reverse occurred in controls. Conclusion Larger TH01 alleles and rs689 A allele may potentiate insulin synthesis in males without T2D, a process disabled in those with T2D.

Introduction: Somatic mutations in blood stem cells can drive clonal expansion and result in clonal haematopoiesis (CH). CH is a precursor to myeloid malignancies, and is increasingly also recognised as a risk factor for non-malignant diseases. CH has been investigated in Europeans, but remains understudied in non-European populations. Here, we investigate the causes and consequences of CH in two large prospective cohort studies, specifically the Mexico City Prospective Study (MCPS) and UK Biobank (UKB). MCPS represents the largest CH study in a non-European population to date. Methods: Admixed Americans were identified from MCPS (n=136,401) while Europeans were identified from the UKB (n=419,228) participants. Somatic variant calling was performed using Mutect2 on whole exome sequencing (WES) data across a selected panel of genes to identify putative CH driver mutations. WES was performed at an average depth of 55x, and CH was defined using a variant allele frequency of ≥3%. Genome-wide association studies (GWAS) for CH were performed using imputed array data, and exome-wide association studies (ExWAS) and gene-level association analyses using WES data. Global/Continental-level ancestry was assigned based on peddy score ≥95% while local ancestry was inferred using RFMix (Ziyatdinov et al., 2022). Results: The most recurrently mutated genes in MCPS and UKB were DNMT3A, TET2, ASXL1, PPM1D, TP53, SF3B1 and SRSF2. The prevalence of CH increased progressively with age to approximately 8/22 (36%) detected as carriers at age 100 and above. CH was 40% more prevalent in age-matched Europeans (4.96%) compared to Admixed Americans (3.10%). Inter-population comparison revealed overall CH, DNMT3A-, TET2-, ASXL1-, PPM1D-, TP53-, JAK2-, and SRSF2-mutant CH to be more prevalent in UKB relative to MCPS (Figure A). Intra-population analysis of the Admixed American cohort further revealed that individuals with a higher fraction of European ancestry were at higher risk of overall CH, DNMT3A-, ASXL1-, and SRSF2-mutant CH, but not TET2-, PPM1D-, TP53-, and JAK2-mutant CH. These suggest differences in relative contribution of genetic, lifestyle or environment factors to specific CH genes. CH GWAS performed in Admixed Americans recapitulated previously reported variants in Europeans, and also identified novel, ancestry-specific variants associated with CH risk, including SNPs upstream of TCL1B (rs968294563: OR=1.79, P=2.01x10 -9; rs187319135: OR=1.85, P=2.69x10 -9). Notably, TCL1B variants were associated with an increased risk of TET2- and ASXL1-mutant CH (rs968294563: OR=3.17, P=3.82x10 -16 for TET2; OR=2.36, P=2.40x10 -3 for ASXL1), but a decreased risk of DNMT3A-mutantCH (rs968294563: OR=0.51, P=6.32x10 -4) (Figure B). The minor allele frequency (MAF) of the most common TCL1B variant in Admixed Americans was 1.23% but was virtually absent in Europeans. CH ExWAS can identify rare causal variants not captured by genotyping or imputation, and these variants may be in linkage disequilibrium with common variants detectable via GWAS. Indeed, ExWAS in Admixed Americans identified one rare SNP on the TCL1B promoter (rs774615666: OR=2.24, P=1.94x10 -8) that was associated with an increased risk of TET2-mutantCH (OR=4.19, P=2.77x10 -10) and a decreased risk of DNMT3A-mutantCH (OR=0.13, P=1.65x10 -4), mirroring our GWAS findings. The rs774615666 risk allele was >200-fold more common in Admixed Americans (MAF: 0.33%) compared to Europeans (MAF: 0.0011%) and was not in linkage disequilibrium with the previously reported TCL1A promoter CH risk SNP in Europeans (Weinstock et al., 2023). Meta-analyses were performed using 555,629 individuals, from both MCPS Admixed American CH GWAS and UKB European CH GWAS. Of the 11 loci reported for overall CH, one was novel, namely GACAT3/ CYRIA. Lastly, we investigated the phenotypic associations of CH in Admixed Americans. Gene-specific CH was associated with increased risk of death from haematological malignancies ( TET2, TP53, SF3B1, and SRSF2), other cancer types ( ASXL1, DNMT3A, and SRSF2) and cardiovascular diseases( DNMT3A, TP53). Conclusions: The substantial difference in CH prevalence between populations and the ancestry-specific genetic associations, demonstrate how the analysis of non-European cohorts can generate novel insights and highlights the importance of such analyses in advancing health equality amongst different human populations.

Background Social inequalities in adult mortality have been reported across diverse populations, but there is no large-scale prospective evidence from Mexico. We aimed to quantify social, including educational, inequalities in mortality among adults in Mexico City.Methods The Mexico City Prospective Study recruited 150 000 adults aged 35 years and older from two districts of Mexico City between 1998 and 2004. Participants were followed up until Jan 1, 2021 for cause-specific mortality. Cox regression analysis yielded rate ratios (RRs) for death at ages 35-74 years associated with education and examined, in exploratory analyses, the mediating effects of lifestyle and related risk factors.Findings Among 143 478 participants aged 35-74 years, there was a strong inverse association of education with premature death. Compared with participants with tertiary education, after adjustment for age and sex, those with no education had about twice the mortality rate (RR 184; 95% CI 171-198), equivalent to approximately 6 years lower life expectancy, with an RR of 178 (167-190) among participants with incomplete primary, 162 (153-172) with complete primary, and 134 (125-142) with secondary education. Education was most strongly associated with death from renal disease and acute diabetic crises (RR 365; 95% CI 305-438 for no education vs tertiary education) and from infectious diseases (267; 200-356), but there was an apparent higher rate of death from all specific causes studied with lower education, with the exception of cancer for which there was little association. Lifestyle factors (ie, smoking, alcohol drinking, and leisure time physical activity) and related physiological correlates (ie, adiposity, diabetes, and blood pressure) accounted for about four-fifths of the association of education with premature mortality.Interpretation In this Mexican population there were marked educational inequalities in premature adult mortality, which appeared to largely be accounted for by lifestyle and related risk factors. Effective interventions to reduce these risk factors could reduce inequalities and have a major impact on premature mortality.

The Mexico City Prospective Study is a prospective cohort of more than 150,000 adults recruited two decades ago from the urban districts of Coyoacán and Iztapalapa in Mexico City 1 . Here we generated genotype and exome-sequencing data for all individuals and whole-genome sequencing data for 9,950 selected individuals. We describe high levels of relatedness and substantial heterogeneity in ancestry composition across individuals. Most sequenced individuals had admixed Indigenous American, European and African ancestry, with extensive admixture from Indigenous populations in central, southern and southeastern Mexico. Indigenous Mexican segments of the genome had lower levels of coding variation but an excess of homozygous loss-of-function variants compared with segments of African and European origin. We estimated ancestry-specific allele frequencies at 142 million genomic variants, with an effective sample size of 91,856 for Indigenous Mexican ancestry at exome variants, all available through a public browser. Using whole-genome sequencing, we developed an imputation reference panel that outperforms existing panels at common variants in individuals with high proportions of central, southern and southeastern Indigenous Mexican ancestry. Our work illustrates the value of genetic studies in diverse populations and provides foundational imputation and allele frequency resources for future genetic studies in Mexico and in the United States, where the Hispanic/Latino population is predominantly of Mexican descent.

BackgroundFive modifiable risk factors are associated with cardiovascular disease and death from any cause. Studies using individual-level data to evaluate the regional and sex-specific prevalence of the risk factors and their effect on these outcomes are lacking.MethodsWe pooled and harmonized individual-level data from 112 cohort studies conducted in 34 countries and 8 geographic regions participating in the Global Cardiovascular Risk Consortium. We examined associations between the risk factors (body-mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, current smoking, and diabetes) and incident cardiovascular disease and death from any cause using Cox regression analyses, stratified according to geographic region, age, and sex. Population-attributable fractions were estimated for the 10-year incidence of cardiovascular disease and 10-year all-cause mortality.ResultsAmong 1,518,028 participants (54.1% of whom were women) with a median age of 54.4 years, regional variations in the prevalence of the five modifiable risk factors were noted. Incident cardiovascular disease occurred in 80,596 participants during a median follow-up of 7.3 years (maximum, 47.3), and 177,369 participants died during a median follow-up of 8.7 years (maximum, 47.6). For all five risk factors combined, the aggregate global population-attributable fraction of the 10-year incidence of cardiovascular disease was 57.2% (95% confidence interval [CI], 52.4 to 62.1) among women and 52.6% (95% CI, 49.0 to 56.1) among men, and the corresponding values for 10-year all-cause mortality were 22.2% (95% CI, 16.8 to 27.5) and 19.1% (95% CI, 14.6 to 23.6).ConclusionsHarmonized individual-level data from a global cohort showed that 57.2% and 52.6% of cases of incident cardiovascular disease among women and men, respectively, and 22.2% and 19.1% of deaths from any cause among women and men, respectively, may be attributable to five modifiable risk factors. (Funded by the German Center for Cardiovascular Research (DZHK); ClinicalTrials.gov number, NCT05466825.) Harmonized individual-level data from a global cohort showed that more than half the cases of incident cardiovascular disease and one fifth of deaths may be attributable to five modifiable risk factors.

Background Body‐mass index is the sum of fat mass index (FMI) and lean mass index (LMI), which vary by age, sex, and impact on disease outcomes. We investigated the separate and joint relevance of FMI and LMI with vascular‐metabolic causes of death in Mexican adults. Methods and Results A total of 113 025 adults aged 35 to 74 years and free from diabetes or other chronic diseases when recruited into the Mexico City Prospective Study were followed for 19 years. Cox models estimated sex‐specific death rate ratios from vascular‐metabolic causes after adjustment for confounders and exclusion of the first 5 years of follow‐up. To account for the strong correlation between FMI and LMI, additional models estimated rate ratios associated with “residual FMI” and “residual LMI” (ie, the residuals from linear regression analyses of FMI on LMI, or vice versa). In both sexes, higher FMI and LMI were associated with higher risks of vascular‐metabolic mortality. For a given (ie, fixed) level of LMI, the rate ratio (95% CI) for vascular‐metabolic mortality per 1 kg/m 2 higher residual FMI strengthened and was higher in women (1.52 [1.38–1.68]) than in men (1.19 [1.13–1.25]). By contrast, for a given level of FMI, higher residual LMI was inversely associated with vascular‐metabolic mortality (rate ratio per 1 kg/m 2 0.67 [0.56–0.80] in women and 0.94 [0.90–0.98] in men). Conclusions In this study, higher residual FMI was more strongly associated with vascular‐metabolic mortality in women than in men. Conversely, higher residual LMI was inversely associated with vascular‐metabolic mortality, particularly in women.

Introduction Although higher risks of infectious diseases among individuals with diabetes have long been recognized, the magnitude of these risks is poorly described, particularly in lower income settings. This study sought to assess the risk of death from infection associated with diabetes in Mexico. Research design and methods Between 1998 and 2004, a total of 159 755 adults ≥35 years were recruited from Mexico City and followed up until January 2021 for cause-specific mortality. Cox regression yielded adjusted rate ratios (RR) for death due to infection associated with previously diagnosed and undiagnosed (HbA1c ≥6.5%) diabetes and, among participants with previously diagnosed diabetes, with duration of diabetes and with HbA1c. Results Among 130 997 participants aged 35–74 and without other prior chronic diseases at recruitment, 12.3% had previously diagnosed diabetes, with a mean (SD) HbA1c of 9.1% (2.5%), and 4.9% had undiagnosed diabetes. During 2.1 million person-years of follow-up, 2030 deaths due to infectious causes were recorded at ages 35–74. Previously diagnosed diabetes was associated with an RR for death from infection of 4.48 (95% CI 4.05–4.95), compared with participants without diabetes, with notably strong associations with death from urinary tract (9.68 (7.07–13.3)) and skin, bone and connective tissue (9.19 (5.92–14.3)) infections and septicemia (8.37 (5.97–11.7)). In those with previously diagnosed diabetes, longer diabetes duration (1.03 (1.02–1.05) per 1 year) and higher HbA1c (1.12 (1.08–1.15) per 1.0%) were independently associated with higher risk of death due to infection. Even among participants with undiagnosed diabetes, the risk of death due to infection was nearly treble the risk of those without diabetes (2.69 (2.31–3.13)). Conclusions In this study of Mexican adults, diabetes was common, frequently poorly controlled, and associated with much higher risks of death due to infection than observed previously, accounting for approximately one-third of all premature mortality due to infection.