A deep catalogue of protein-coding variation in 983,578 individuals.

Rare coding variants that significantly impact function provide insights into the biology of a gene1-3. However, ascertaining their frequency 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. 23% of the Regeneron Genetics Center Million Exome data (RGC-ME) comes from non-European individuals of African, East Asian, Indigenous American, Middle Eastern, and South Asian ancestry. This catalogue includes over 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, we identify 3,988 loss-of-function intolerant genes, including 86 that were previously assessed as tolerant and 1,153 lacking established disease annotation. We also define regions of missense depletion at high resolution. Notably, 1,482 genes have regions depleted of missense variants despite being tolerant to 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 important resource of coding variation from the RGC-ME accessible via a public variant allele frequency browser.

Genotyping, sequencing and analysis of 140,000 adults from Mexico City.

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 City1. 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.

General and Abdominal Adiposity and Mortality in Mexico City: A Prospective Study of 150 000 Adults.

Background: Some reports suggest that body mass index (BMI) is not strongly associated with mortality in Hispanic populations. Objective: To assess the causal relevance of adiposity to mortality in Mexican adults, avoiding reverse causality biases. Design: Prospective study. Setting: 2 Mexico City districts. Participants: 159 755 adults aged 35 years and older at recruitment, followed for up to 14 years. Participants with a hemoglobin A1c level of 7% or greater, diabetes, or other chronic diseases were excluded. Measurements: BMI, waist-to-hip ratio, waist circumference, and cause-specific mortality. Cox regression, adjusted for confounders, yielded mortality hazard ratios (HRs) after at least 5 years of follow-up and before age 75 years. Results: Among 115 400 participants aged 35 to <75 years at recruitment, mean BMI was 28.0 kg/m2 (SD, 4.1 kg/m2) in men and 29.6 kg/m2 (SD, 5.1 kg/m2) in women. The association of BMI at recruitment with all-cause mortality was J-shaped, with the minimum at 25 to <27.5 kg/m2. Above 25 kg/m2, each 5-kg/m2 increase in BMI was associated with a 30% increase in all-cause mortality (HR, 1.30 [95% CI, 1.24 to 1.36]). This association was stronger at ages 40 to <60 years (HR, 1.40 [CI, 1.30 to 1.49]) than at ages 60 to <75 years (HR, 1.24 [CI, 1.17 to 1.31]) but was not materially affected by sex, smoking, or other confounders. The associations of mortality with BMI and waist-to-hip ratio were similarly strong, and each was weakened only slightly by adjustment for the other. Waist circumference was strongly related to mortality and remained so even after adjustment for BMI and hip circumference. Limitation: Analyses were limited to mortality. Conclusion: General, and particularly abdominal, adiposity were strongly associated with mortality in this Mexican population. Primary Funding Source: Mexican Health Ministry, Mexican National Council of Science and Technology, Wellcome Trust, Medical Research Council, and Kidney Research UK.

National panorama of adolescent pregnancy in Mexico: lessons learned in a six-year period.

Globally, adolescent pregnancy constitutes a serious public health problem of a multifactorial nature. Specifically for women, it entails various educational, economic and social implications that affect their life project and widen the social gaps in this age group. Furthermore, adolescent girls are more vulnerable because of the health risk involved with pregnancy at a younger age. According to the World Health Organization, "the probability of maternal death is twice as high in adolescents in comparison with women aged between 20 and 30 years, and for those younger than 15 years, the risks are five times higher". In general, adolescents are in great need for education on sexual and reproductive health issues, which should be aimed at increasing information and knowledge about correct use and access to modern contraceptive methods, as well as at demystifying fears and beliefs around their possible side effects. Ensuring proper counseling with trained personnel is equally vital. Public institutions have a social responsibility to support efforts aimed at preventing adolescent pregnancy, based on relevant lines of action and health policies.

En el mundo, el embarazo adolescente constituye un grave problema de salud pública de índole multifactorial. Específicamente para la mujer conlleva diversas implicaciones educativas, económicas y sociales que afectan su proyecto de vida y amplían las brechas sociales en este grupo etario. Asimismo, las adolescentes son más vulnerables por el riesgo en salud que implica un embarazo a corta edad; según la Organización Mundial de la Salud, "la probabilidad de muerte materna es dos veces más en las adolescentes respecto a las mujeres que se encuentran entre los 20 y 30 años de edad, y para las menores de 15 años los riesgos son cinco veces mayores". En general, las y los adolescentes experimentan una gran necesidad de educación en temas sobre salud sexual y reproductiva, la cual debe dirigirse al aumento de información y conocimientos sobre el uso correcto y acceso a métodos anticonceptivos modernos, así como a desmitificar los temores y creencias en torno a sus posibles efectos secundarios. Asegurar una consejería adecuada y con personal capacitado es igualmente vital. Las instituciones públicas tienen la responsabilidad social de respaldar los esfuerzos encaminados a prevenir el embarazo adolescente, con base en las líneas de acción y políticas sanitarias.

Diabetes and Cause-Specific Mortality in Mexico City.

BACKGROUND: Most large, prospective studies of the effects of diabetes on mortality have focused on high-income countries where patients have access to reasonably good medical care and can receive treatments to establish and maintain good glycemic control. In those countries, diabetes less than doubles the rate of death from any cause. Few large, prospective studies have been conducted in middle-income countries where obesity and diabetes have become common and glycemic control may be poor. METHODS: From 1998 through 2004, we recruited approximately 50,000 men and 100,000 women 35 years of age or older into a prospective study in Mexico City, Mexico. We recorded the presence or absence of previously diagnosed diabetes, obtained and stored blood samples, and tracked 12-year disease-specific deaths through January 1, 2014. We accepted diabetes as the underlying cause of death only for deaths that were due to acute diabetic crises. We estimated rate ratios for death among participants who had diabetes at recruitment versus those who did not have diabetes at recruitment; data from participants who had chronic diseases other than diabetes were excluded from the main analysis. RESULTS: At the time of recruitment, obesity was common and the prevalence of diabetes rose steeply with age (3% at 35 to 39 years of age and >20% by 60 years of age). Participants who had diabetes had poor glycemic control (mean [±SD] glycated hemoglobin level, 9.0±2.4%), and the rates of use of other vasoprotective medications were low (e.g., 30% of participants with diabetes were receiving antihypertensive medication at recruitment and 1% were receiving lipid-lowering medication). Previously diagnosed diabetes was associated with rate ratios for death from any cause of 5.4 (95% confidence interval [CI], 5.0 to 6.0) at 35 to 59 years of age, 3.1 (95% CI, 2.9 to 3.3) at 60 to 74 years of age, and 1.9 (95% CI, 1.8 to 2.1) at 75 to 84 years of age. Between 35 and 74 years of age, the excess mortality associated with previously diagnosed diabetes accounted for one third of all deaths; the largest absolute excess risks of death were from renal disease (rate ratio, 20.1; 95% CI, 17.2 to 23.4), cardiac disease (rate ratio, 3.7; 95% CI, 3.2 to 4.2), infection (rate ratio, 4.7; 95% CI, 4.0 to 5.5), acute diabetic crises (8% of all deaths among participants who had previously diagnosed diabetes), and other vascular disease (mainly stroke). Little association was observed between diabetes and mortality from cirrhosis, cancer, or chronic obstructive pulmonary disease. CONCLUSIONS: In this study in Mexico, a middle-income country with high levels of obesity, diabetes was common, glycemic control was poor, and diabetes was associated with a far worse prognosis than that seen in high-income countries; it accounted for at least one third of all deaths between 35 and 74 years of age. (Funded by the Wellcome Trust and others.).

Perfil clínico-epidemiológico de las defunciones por influenza con antecedente de vacunación oportuna, México 2010-2018.

INTRODUCTION: Influenza epidemics are of higher risk at the extremes of life and in people with comorbidities. Effective -vaccination prevents the occurrence of serious cases and decreases mortality. OBJECTIVE: To describe deaths from influenza with a history of timely vaccination, from the 2010 to the 2018 season in Mexico. METHOD: Cross-sectional, descriptive study where the Influenza Epidemiological Surveillance System database was used. RESULTS: From 2010 to 2018, 65 vaccinated individuals died from influenza, from which 55% of cases (n = 36) were due to type A (H1N1), 51% (n = 33) were females, median age was 57 years, 21 % (n = 14) did not meet the operational definition of influenza-like illness or severe acute respiratory infection, 83% (n = 54) had at least one comorbidity, with the most common being diabetes mellitus and hypertension (32% each); 55% (n = 36) of deaths received antiviral treatment and only 8% (n = 5) had no comorbidities and received treatment with oseltamivir. CONCLUSIONS: Deaths from influenza with timely vaccination represent a very low percentage of the totality. Vaccination against influenza has been a specific prevention strategy that decreases disease burden.

INTRODUCCIÓN: Las epidemias de influenza son de mayor riesgo en los extremos de la vida y en personas con comorbilidades. La vacunación efectiva previene la aparición de casos graves y disminuye la mortalidad. OBJETIVO: Describir las defunciones por influenza en México con antecedente de vacunación oportuna, de 2010 a 2018. MÉTODO: Estudio transversal descriptivo en el que se utilizó la base de datos del Sistema de Vigilancia Epidemiológica de Influenza. RESULTADOS: De 2010 a 2018 fallecieron por influenza 65 personas con vacunación, 55 % (n = 36) de las cuales por tipo A (H1N1), 51 % (n = 33) del sexo femenino, la mediana de edad fue de 57 años, 21 % (n = 14) no cumplía la definición operacional de enfermedad tipo influenza o infección respiratoria aguda grave, 83 % (n = 54) tenía al menos una comorbilidad; las comorbilidades más frecuentes fueron diabetes mellitus e hipertensión arterial (32 % cada una); 55 % (n = 36) recibió tratamiento antiviral y solo 8 % (n = 5) no presentaba comorbilidades y tenía tratamiento con oseltamivir. CONCLUSIONES: Las defunciones por influenza con vacunación oportuna representan un porcentaje muy bajo del total. La vacunación contra influenza ha sido una estrategia de prevención específica que disminuye la carga de la enfermedad.

Clinical-epidemiological profile of deaths from influenza with a history of timely vaccination, Mexico 2010-2018.

INTRODUCTION: Influenza epidemics are of higher risk at the extremes of life and in people with comorbidities. Effective vaccination prevents the occurrence of serious cases and decreases mortality. OBJECTIVE: To describe deaths from influenza with a history of timely vaccination, from the 2010 to the 2018 season in Mexico. METHOD: Cross-sectional, descriptive study where the Influenza Epidemiological Surveillance System database was used. RESULTS: From 2010 to 2018, 65 vaccinated individuals died from influenza, from which 55% of cases (n = 36) were due to type A (H1N1), 51% (n = 33) were females, median age was 57 years, 21 % (n = 14) did not meet the operational definition of influenza-like illness or severe acute respiratory infection, 83% (n = 54) had at least one comorbidity, with the most common being diabetes mellitus and hypertension (32% each); 55% (n = 36) of deaths received antiviral treatment and only 8% (n = 5) had no comorbidities and received treatment with oseltamivir. CONCLUSIONS: Deaths from influenza with timely vaccination represent a very low percentage of the totality. Vaccination against influenza has been a specific prevention strategy that decreases disease burden.

Use of HPV testing in cervical cancer screening services in Mexico, 2008-2018: a nationwide database study.

OBJECTIVE: To describe the methods of a study aimed at evaluating high risk-HPV (hrHPV)-based screening and cervical cytology as triage compared to conventional cervical cytology as primary screening in the detection of grade 2+ cervical intraepithelial neoplasia in the National Cancer Screening Program (NCSP) of Mexico. MATERIALS AND METHODS: We will use information originated from the Womens Cancer Information System of Mexico regarding cervical cancer from 2008 to 2018. The database includes cytology results, diagnostic confirmation by histopathology and/or treatment colposcopy. We will then carry out statistical analyses on approximately 15 million hrHPV. RESULTS: We will evaluate the overall performance of hrHPV-based screening as part of the NCSP and compare hrHPV-based to cytology-based screening under real-life conditions. To guarantee an unbiased comparison between hrHPV with cytology triage and conventional cytology we will use propensity score matching. CONCLUSIONS: ytology we will use propensity score matching. Conclusion. Decision makers may use our results to identify areas of opportunity for improvement in NCSP processe.

OBJETIVO: Describir los métodos de un estudio que busca comparar el beneficio de la introducción de la prueba de VPH de alto riesgo como prueba primaria frente a la citología convencional para la detección de la neoplasia intraepitelial cervical grado 2 o mayor, dentro del Programa de Prevención y Control del Cáncer de la Mujer, para el periodo de 2008 a 2018. MATERIAL Y MÉTODOS: Se utilizarán los registros del Sistema de Información de Cáncer de la Mujer, se realizarán los análisis estadísticos con aproximadamente 15 millones de resultados de VPH-alto riesgo, además se utilizarán los resultados de citología, colposcopia, histología y los casos referenciados al centro oncológico para tratamiento. Para comparar ambos grupos usaremos "propensity score matching". RESULTADOS: Se evaluará el desempeño general de la prueba de VPH-alto riesgo, en condiciones reales dentro del Programa Nacional de Prevención y Control de la Mujer y su tendencia en el tiempo. CONCLUSIONES: Los resultados de estudio ayudarán a los tomadores de decisiones a identificar áreas de oportunidad para mejorar el programa en México.

[Clinical and epidemiological characterization of chikungunya fever in Mexico]. / Caracterización clínica y epidemiológica de fiebre chikungunya en México.

On 6 December 2013, the Pan American Health Organization (PAHO) and the World Health Organization (WHO) reported confirmation of the first two cases of indigenous transmission of chikungunya fever (CHIK) in the Region of the Americas on the island of Sint Maarten (Netherlands Antilles). For the period 2013-2014, a total of 25 627 confirmed autochthonous cases were distributed in 43 countries, with Mexico reporting 155 cases in five states. Information on cases of CHIK in Mexico was obtained from the database of the General Directorate of Epidemiology (Ministry of Health of Mexico). The distribution of confirmed autochthonous cases of CHIK for 2015, by sex, was 64% female (5 583) and 36% male (3 085). The most frequent symptoms were fever in 98% of cases (8 564), followed by headache in 91.6% (7 941), myalgia in 89.9% (7 792), mild arthralgias in 73.5% (6 367), severe polyarthralgia in 72.6% (6 295), and exanthema in 58% (5 032). The clinical presentation of autochthonous cases of CHIK in Mexico has shown several clinical manifestations different from those seen in outbreaks in African and Asian countries and other regions in the Americas; for example, a greater percentage of cases with headache and myalgia and a smaller percentage of cases with arthralgia.

[Behavior of influenza seasons in Mexico from 2010 to 2016: Analysis and prospective]. / Comportamiento de las temporadas de influenza en México de 2010 a 2016, análisis y prospectiva.

The influenza virus spreads rapidly through recurring seasonal outbreaks during the fall and winter. Our country has the Epidemiological Surveillance System for Influenza (SISVEFLU), in operation since 2006, which has records of 558 health units of Influenza. According to the information recorded in it, we can see that the 2010-2016 influenza seasons have a biannual behavior, and that in the 2010-2011, 2012-2013, and 2014-2015 seasons, the predominant viral subtype was A (H3N2), while in the 2011-2012, 2013-2014, and 2015-2016 seasons, the predominant subtype was A (H1N1) pdm09, which was associated with an increased number of influenza cases and deaths. It is expected that the 2016-2017 season will have predominance of subtype A (H3N2) and in 2017-2018 the expected will be subtype A (H1N1) pmd09. During the 2010-2016 seasons, 53.5% of cases of influenza were women; 77% had no history of vaccination, and 36% had one or more comorbidities. As for deaths, 55% was observed in males, 85% had not been vaccinated, and 71.5% had one or more comorbidities.

Evidence of the presence of the Zika virus in Mexico since early 2015.

To assess the possible circulation of Zika virus (ZIKV) prior to the first documented case in Mexico, we reanalyzed the stored samples from the states of Veracruz and Yucatán, which were originally collected to test for dengue (DENV) and chikungunya (CHIKV) but were negative for these viruses despite the symptomatology. The samples were originally collected between the 30 and 46 epidemiological weeks (EW) when the ZIKV was not yet declared as a Public Health Emergency of International Concern (PHEIC). From the total 4016 negative samples, a total of one hundred samples, 50 from Veracruz (CHIK- DENV-) and 50 from Yucatán (4 CHIK- DENV- and 46 CHIK- or DENV-), were tested for Zika virus by using RT-PCR. Results showed that in Veracruz and Yucatán, 20 % (10/50) and 70 % (35/50) were, respectively, ZIKV positive, indicating unequivocally the presence of ZIKV at least since July 2015. We also tested non-confirmed suspect measles cases from early 2015 for ZIKV by RT-PCR. Remarkably in 11 Mexican states, 86 % (18/21) were positive with the earlier symptoms onset as early as May 2015. Finally, RT-PCR analyses on RNA extracted from Aedes aegypti mosquitoes captured from January to March 2015 showed the presence of ZIKV, strongly suggesting that the vector was already carrying the virus at the start of 2015.

Identification of Asian genotype of chikungunya virus isolated in Mexico.

We identified 25 autochthonous chikungunya virus cases in Mexico, initially detected by RT-PCR targeting the E1 gene and propagated in C6/36 Aedes albopictus cells, in 2014. To determine the type of virus found, in a previous report, the genomes of 2 CHIKV strains were fully sequenced. Genome sequence analysis revealed that these isolates from Mexico belonged to the Asian genotype, and a phylogenetic association with the circulating strain in the British Virgin Islands was also established in the same year. This was further supported by changes in specific amino acids, E2-V368A and 6K-L20M. For these reasons, it can be inferred that the route of virus entry to Mexico was held across the countries in the Caribbean and Central America. The presence of E1-A226V mutation associated with more efficient replication in the salivary gland of the A. albopictus mosquito was not observed. Interestingly, a newly acquired NSP4-S399C mutation was observed; however, the significance of changes in amino acid found in non-structural proteins in autochthonous strains remains to be elucidated.

Day-to-Day Population Movement and the Management of Dengue Epidemics.

Dengue is a growing public health problem in tropical and subtropical cities. It is transmitted by mosquitoes, and the main strategy for epidemic prevention and control is insecticide fumigation. Effective management is, however, proving elusive. People's day-to-day movement about the city is believed to be an important factor in the epidemiological dynamics. We use a simple model to examine the fundamental roles of broad demographic and spatial structures in epidemic initiation, growth and control. We show that the key factors are local dilution, characterised by the vector-host ratio, and spatial connectivity, characterised by the extent of habitually variable movement patterns. Epidemic risk in the population is driven by the demographic groups that frequent the areas with the highest vector-host ratio, even if they only spend some of their time there. Synchronisation of epidemic trajectories in different demographic groups is governed by the vector-host ratios to which they are exposed and the strength of connectivity. Strategies for epidemic prevention and management may be made more effective if they take into account the fluctuating landscape of transmission intensity associated with spatial heterogeneity in the vector-host ratio and people's day-to-day movement patterns.

Challenges in the development and implementation of the National Comprehensive Cancer Control Program in Mexico.

Chronic noncommunicable diseases (NCDs), including cancer, have become the leading cause of human morbidity and mortality. In Mexico, cancer is the third leading cause of death, with a high incidence among the economically active population, a high proportion of advanced stages at diagnosis and limited care coverage for patients. However, no public policy aimed at managing this important public health problem has been developed and implemented to date. This manuscript describes the first interinstitutional proposal of a National Program for Cancer Control, considering the known risk factors, early detection, treatment, palliative care and patient rehabilitation. This manuscript also outlines a series of thoughts on the difficulties and needs that the Mexican health system faces in achieving the main objectives of the program: to decrease the incidence of cancer, to increase survival and to improve the quality of life for this group of patients.

[Emerging and reemerging diseases]. / Enfermedades emergentes y reemergentes.

Emerging and reemerging diseases are the result of the interaction of multiple factors, such as social determinants of health, climate change, and conditions that prevail and are identifiable in some populations. As a consequence, there may be situations that by their nature are defined as a health emergency, impacting directly on the health of a population, either because they are not known or due to their rapid spread, resulting in a health security problem. Examples of these diseases are described in this article, starting with their origin, their impact on the population, and the response necessary in order to contain or prevent damage of a greater magnitude. The presence of these agents and their consequent damage to the population should lead efforts towards comprehensive prevention and appropriate containment strategies to ensure the protection of public health. Endeavors should be directed not only to a specific agent, but rather to factors that determine their reemergence, such as Ebola, or their permanence, such as the binomial infection of tuberculosis-AIDS. In order to correctly implement strategies, training and availability of supplies play a crucial role in facing the challenges that lie ahead.

Outbreak of Vibrio cholerae serogroup O1, serotype Ogawa, biotype El Tor strain--La Huasteca Region, Mexico, 2013.

On September 2 and 6, 2013, Mexico's National System of Epidemiological Surveillance identified two cases of cholera in Mexico City. Rectal swab cultures from both patients were confirmed as toxigenic Vibrio cholerae serogroup O1, serotype Ogawa, biotype El Tor. Pulsed-field gel electrophoresis and virulence gene amplification (ctxA, ctxB, zot, and ace) demonstrated that the strains were identical to one another but different from strains circulating in Mexico previously. The strains were indistinguishable from the strain that has caused outbreaks in Haiti, the Dominican Republic, and Cuba. The strain was susceptible to doxycycline, had intermediate susceptibility to ampicillin and chloramphenicol, was less than fully susceptible to ciprofloxacin, and was resistant to furazolidone and trimethoprim-sulfamethoxazole. An investigation failed to identify a common source of infection, additional cases, or any epidemiologic link between the cases. Both patients were treated with a single, 300-mg dose of doxycycline, and their symptoms resolved.

Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease.

Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare loss-of-function variants in two genes (BSN and APBA1) with effects substantially larger than those of well-established obesity genes such as MC4R. In contrast to most other obesity-related genes, rare variants in BSN and APBA1 were not associated with normal variation in childhood adiposity. Furthermore, BSN protein-truncating variants (PTVs) magnified the influence of common genetic variants associated with BMI, with a common variant polygenic score exhibiting an effect twice as large in BSN PTV carriers than in noncarriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion in human induced pluripotent stem cell-derived hypothalamic neurons. Collectively, our findings implicate degenerative processes in synaptic function in the etiology of adult-onset obesity.

Characterising the contribution of rare protein-coding germline variants to prostate cancer risk and severity in 37,184 cases.

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.

Prediabetes as a risk factor for all-cause and cause-specific mortality: a prospective analysis of 115,919 adults without diabetes in Mexico City.

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).