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.

Large-scale human exome sequencing can identify rare protein-coding variants with a large impact on complex traits such as body adiposity. We sequenced the exomes of 645,626 individuals from the United Kingdom, the United States, and Mexico and estimated associations of rare coding variants with body mass index (BMI). We identified 16 genes with an exome-wide significant association with BMI, including those encoding five brain-expressed G protein–coupled receptors (CALCR, MC4R, GIPR, GPR151, and GPR75). Protein-truncating variants in GPR75 were observed in ~4/10,000 sequenced individuals and were associated with 1.8 kilograms per square meter lower BMI and 54% lower odds of obesity in the heterozygous state. Knock out of Gpr75 in mice resulted in resistance to weight gain and improved glycemic control in a high-fat diet model. Inhibition of GPR75 may provide a therapeutic strategy for obesity.

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Background: While most of the global burden from chronic diseases, and especially vascular diseases, is now borne by low and middle-income countries, few large-scale epidemiological studies of chronic diseases in such countries have been performed.

SummaryBackgroundDiabetes is a cause of at least a third of all deaths in Mexican adults aged 35–74 years, with the excess mortality due mainly to vascular disease, renal disease, infection, and acute diabetic crises. We aimed to analyse the effect of diabetes duration and glycaemic control on death rate ratios (RRs) for these causes and to assess the relevance to cause-specific mortality of undiagnosed diabetes.MethodsAbout 100 000 women and 50 000 men aged 35 years or older from Mexico City were recruited into a blood-based prospective study between April 14, 1998, and Sept 28, 2004, and followed up until Jan 1, 2016, for cause-specific mortality. Participants who, at recruitment, reported any chronic disease other than diabetes and those who had missing data for HbA1c or diabetes duration were excluded. We used Cox models to estimate the associations of undiagnosed or previously diagnosed diabetes (almost all type 2) with risk of mortality from vascular disease, renal disease, and infection, exploring among those with previously diagnosed diabetes the independent relevance of diabetes duration (<5 years, ≥5 to <10 years, or ≥10 years) and HbA1c (<9%, ≥9% to <11%, or ≥11%). We also estimated the association of HbA1c with mortality in participants without diabetes at recruitment.Findings133 662 participants were aged 35–74 years and had complete data and no other chronic disease. 16 940 (13%) had previously diagnosed diabetes, 6541 (5%) had undiagnosed diabetes, and 110 181 (82%) had no diabetes. Among participants with previously diagnosed diabetes, glycaemic control was poor (median HbA1c 8·9% [IQR 7·0–10·9]), and was worse in those with longer duration of disease at recruitment. Compared with participants without diabetes, the death RRs at ages 35–74 years for the combination of vascular, renal, or infectious causes were 3·0 (95% CI 2·7–3·4) in those with undiagnosed diabetes, 4·5 (4·0–5·0) for the 5042 participants with a diabetes duration of less than 5 years, 6·6 (6·1–7·1) for the 7713 participants with a duration of 5 years to less than 10 years, and 11·7 (10·7–12·7) for the 4185 participants with a duration of at least 10 years. Similarly, the death RRs were 5·2 (4·8–5·7) for those with HbA1c less than 9%, 6·8 (6·2–7·4) for those with HbA1c of 9% to less than 11%, and 10·5 (9·7–11·5) for those with HbA1c of at least 11%. Diabetes was not strongly associated with the combination of deaths from other causes apart from acute glycaemic crises. Among participants without diabetes, higher HbA1c was not positively related to mortality.InterpretationIn Mexico, the rates of death from causes strongly associated with diabetes increased steeply with duration of diabetes and were higher still among people with poor glycaemic control. Delaying the onset of type 2 diabetes, as well as improving its treatment, is essential to reduce premature adult mortality in Mexico.FundingWellcome Trust, the Mexican Health Ministry, the Mexican National Council of Science and Technology, Cancer Research UK, British Heart Foundation,...

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Body fat distribution is a major, heritable risk factor for cardiometabolic disease, independent of overall adiposity. Using exome-sequencing in 618,375 individuals (including 160,058 non-Europeans) from the UK, Sweden and Mexico, we identify 16 genes associated with fat distribution at exome-wide significance. We show 6-fold larger effect for fat-distribution associated rare coding variants compared with fine-mapped common alleles, enrichment for genes expressed in adipose tissue and causal genes for partial lipodystrophies, and evidence of sex-dimorphism. We describe an association with favorable fat distribution (p = 1.8 × 10−09), favorable metabolic profile and protection from type 2 diabetes (~28% lower odds; p = 0.004) for heterozygous protein-truncating mutations in INHBE, which encodes a circulating growth factor of the activin family, highly and specifically expressed in hepatocytes. Our results suggest that inhibin βE is a liver-expressed negative regulator of adipose storage whose blockade may be beneficial in fat distribution-associated metabolic disease.

The Mexico City Prospective Study (MCPS) is a prospective cohort of over 150,000 adults recruited two decades ago from the urban districts of Coyoacán and Iztapalapa in Mexico City. We generated genotype and exome sequencing data for all individuals, and whole genome sequencing for 10,000 selected individuals. We uncovered high levels of relatedness and substantial heterogeneity in ancestry composition across individuals. Most sequenced individuals had admixed Native American, European and African ancestry, with extensive admixture from indigenous groups in Central, Southern and South Eastern Mexico. Native 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 population specific allele frequencies at 142 million genomic variants, with an effective sample size of 91,856 for Native Mexico at exome variants, all available via a public browser. Using whole genome sequencing, we developed an imputation reference panel which outperforms existing panels at common variants in individuals with high proportions of Central, South and South Eastern Native Mexican ancestry. Our work illustrates the value of genetic studies in populations with diverse ancestry 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.