# Type 2 diabetes and cause-specific mortality in Mexico City: a Mendelian randomisation analysis

## TL;DR

This study shows that type 2 diabetes causes higher death rates from kidney, vascular, and infectious diseases in Mexico.

## Contribution

The study uses genetic data to establish a causal link between type 2 diabetes and specific causes of death.

## Key findings

- Genetically predicted type 2 diabetes increases the risk of death from renal disease by 2.29 times.
- Type 2 diabetes is strongly linked to death from acute diabetic crises and vascular disease.
- No clear causal link was found between type 2 diabetes and death from cancer or cirrhosis.

## Abstract

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.

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.

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]).

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.

10.13039/100010269Wellcome Trust, the Mexican Health Ministry, the 10.13039/501100003141National Council for Science and Technology (CONACyT) for Mexico, Cancer Research UK, 10.13039/501100000274British Heart Foundation, Kidney Research UK, UK 10.13039/501100000265Medical Research Council, 10.13039/100004325AstraZeneca, Regeneron.