The effect of Indigenous American genomic ancestry on type 2 diabetes in Mexico: an analysis of 134 548 individuals from the Mexico City Prospective Study.

BACKGROUND: The prevalence of type 2 diabetes in Mexico is among the highest in the world and a major public health problem. The aim of this study was to examine the association between the percentage of Indigenous American genomic ancestry (AMR) and the prevalence of both prediabetes and type 2 diabetes in a large study of Mexican adults. METHODS: In this cross-sectional study, we analysed data from 134 548 individuals from the Mexico City Prospective Study (MCPS), including sociodemographic, clinical, and genetic data. Type 2 diabetes was defined as a self-reported previous diagnosis, glucose-lowering medication, or glycated hemoglobin (HbA1c) of at least 6·5%. Prediabetes was defined as HbA1c between 5·7% and less than 6·5%. Individuals with probable type 1 diabetes were excluded. Logistic regression models were used to estimate associations between higher AMR ancestry percentage and prediabetes and type 2 diabetes, after adjustment for age, sex, and other diabetes risk factors. FINDINGS: Between April 14, 1998, and Sept 28, 2004, 159 755 participants were recruited into MCPS. Among these, 134 548 participants were selected for subsequent analyses (mean age 52 years [SD 12·6]; 90 688 [67·4%] women and 43 860 [32·6%] men); mean AMR ancestry percentage was 66·2% (SD 17·9). Across AMR tenths (mean AMR ranging from 34·8% [SD 7·9] to 94·7% [SD 2·7]), the prevalence of prediabetes increased from 19·2% (2573 of 13 376) to 26·3% (3529 of 13 421) and of type 2 diabetes from 13·5% (1805 of 13 376) to 23·4% (3142 of 13 421). After adjustment for age and sex, each 20% absolute increase in AMR was associated with substantially increased odds of type 2 diabetes (odds ratio [OR] 1·45 [95% CI 1·43-1·48]) and of prediabetes (OR 1·28 [1·26-1·30]). Further adjustment for socioeconomic status, lifestyle factors, and adiposity reduced these ORs to 1·33 (1·31-1·36) for type 2 diabetes and 1·18 (1·16-1·20) for prediabetes. Consequently, at the population mean AMR ancestry percentage, these fully adjusted ORs were 2·59 (2·44-2·75) for type 2 diabetes and 1·75 (1·65-1·85) for prediabetes, whereas among Indigenous populations with 100% AMR ancestry, ORs were 4·23 (3·85-4·64) for type 2 diabetes and 2·33 (2·14-2·54) for prediabetes. ORs for type 2 diabetes and prediabetes associated with higher AMR were higher for women than for men, for younger than for older participants, and were further reduced in magnitude following additional adjustment for a type 2 diabetes polygenic risk score. INTERPRETATION: The percentage of inherited AMR ancestry is strongly associated with prediabetes and type 2 diabetes in this admixed Mexican population. These findings suggest that most of the Mexican population has a higher genetic susceptibility to type 2 diabetes than European-ancestry populations, underscoring the need for health systems to implement earlier, more intensive, and population-targeted preventive strategies. FUNDING: Mexican Health Ministry, National Council of Science and Technology for Mexico, Wellcome Trust, Cancer Research UK, British Heart Foundation, Kidney Research UK, and UK Medical Research Council.