Mexico City Prospective Study

background

Between 1998 and 2004, over 150,000 middle-aged adults (including 100,000 women and 50,000 men) from two districts of Mexico City provided information about their lifestyle and disease history, had physical measurements recorded (including weight, waist and hip circumference, blood pressure) and had a blood sample taken.

A resurvey of 10,000 surviving participants (2015 - 2019) captured how lifestyles, physical and biological measurements and treatments for disease (e.g. diabetes) have changed over time. The resurvey also allowed us to better assess the relevance to premature death of characteristics that can vary over time (such as blood pressure and smoking) as well as including various enhancements (such as bioimpedance, an assessment of cognitive function and the collection of urine samples).

All participants are tracked for mortality through linkage to Mexican national mortality records. By January 2021 over 28,000 were confirmed to have died. MCPS offers the opportunity to study how social, lifestyle, physical, metabolic and genetic factors influence the major causes of death in Mexican adults in a single large cohort that has already been followed for two decades.

Major findings

discovery of link between gpr75 and obesity

In collaboration with scientists at the Regeneron Genetics Center® (RGC), we combined exome sequence data from the 150,000 participants in the MCPS with data from a further 500,000 people in the UK and the US. We discovered rare genetic mutations in the GPR75 gene that were associated with protection against obesity. Protective ‘loss of function’ mutations were found in about one in every 3,000 people sequenced. People with this genetic ‘superpower’ had 1.8 kg/m² lower BMI on average and a 54% reduced risk of obesity. The link between the mutations and lower BMI was cemented by studying mice in which the GPR75 gene had been disabled. The results suggest for the first time that pharmacological inhibition of GPR75 may be a therapeutic target both for obesity and the many diseases that result from obesity. Read full paper and press release.

Diabetes and cause-specific mortality

At recruitment, nearly half of women and one-third of men aged 50-59 were obese (ie, had a BMI ≥30 kg/m²) and by age 60 more than one in five had a confirmed diagnosis of diabetes. Of those with previously diagnosed diabetes, analysis of blood samples revealed that blood sugar was on average poorly controlled. Over the next 12 years, those with diabetes had four times the overall death rate at ages 35-74 compared with people without diabetes. In comparison, in high-income countries people with diabetes have been found to have only about twice the death rate of other people. The biggest excess risk of death among people with diabetes was from kidney disease, followed by heart and other vascular disease, infection and acute diabetic crises (also reflecting poor blood sugar control).

Overall, the excess mortality among people with diabetes accounted for at least one-third of all deaths between the ages 35-74 years, which is twice what previous studies had suggested. Read full paper.

Adiposity and cause-specific mortality

Obesity makes diabetes and several other chronic diseases more common, but these diseases may then result in substantial weight loss, thereby hiding the reason they arose in the first place. To avoid being misled by this reversal of causality, we looked at the association between adiposity and mortality excluding people who at the time of recruitment already had evidence of any chronic disease, and concentrated our attention on deaths more than five years after recruitment.

We found that both general obesity and carrying excess fat around the waist were major risk factors for premature death, with strengths of association that were similar to those observed in high-income populations. Among those with BMI>25 kg/m², each increase of 5 kg/m² was associated with a 30% increase in mortality.

In addition, among people whose BMI was similar, waist circumference was of additional relevance to mortality, suggesting that abdominal obesity is particularly harmful. Read full paper.

More recently we found that BMI was strongly associated with death due to COVID-19, with a fourfold difference in COVID-19 mortality risk between those with a BMI ≥40 versus <25 kg/m². However, even during 2020 other causes of death accounted for more than twice as many deaths as COVID-19, so the absolute relevance of BMI to mortality was greater for the aggregate of those other causes than for COVID-19. Read full paper.

Blood pressure and cause-specific mortality

Although elevated blood pressure is known to be a major cause of premature death in high-income populations, there is little direct evidence in studies of Hispanic populations. In our analysis, we confirmed that blood pressure was a major risk factor for death from a range of diseases among Mexicans. It was especially strongly related to death from vascular and kidney disease, with no ‘threshold’ levels below which lower blood pressure was not associated with lower risk.

Because those with diabetes were at substantially higher risk than those without diabetes, the absolute excess mortality rates associated with elevated blood pressure were much higher in individuals with diabetes. Read full paper.