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

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.

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