Molecular Ancestry Across Allelic Variants of SLC22A1, SLC22A2, SLC22A3, ABCB1, CYP2C8, CYP2C9, and CYP2C19 in Mexican-Mestizo DMT2 Patients

Abstract

Background/Aims: across protein-coding genes, single nucleotide allelic variants (SNVs) affect antidiabetic drug pharmacokinetics, thus contributing to interindividual variability in drug response. SNV frequencies vary across different populations. Studying ancestry proportions among SNV genotypes is particularly important for personalising diabetes mellitus type 2 (DMT2) treatment. Methods: a sample of 249 Mexican DMT2 patients was gathered. SNVs were determined through real-time PCR (RT-PCR). Molecular ancestries were determined as 3 clusters (Native-American, European, and African) based upon 90 ancestry markers (AIMS). Statistical inference tests were performed to analyse ancestry across 23 SNV genotypes. Allele and ancestry distributions were analysed through Spearman's correlation. Results: ancestry medians were 65.48% Native-American (NATAM), 28.34% European (EUR), and 4.8% African (AFR). CYP2C8*3 and CYP2C8*4 were negatively correlated to NATAM, whereas positively to EUR. The activity score of CYP2C9 was correlated to NATAM (Rho = 0.131, p = 0.042). CYP2C19*17 and the activity score of CYP2C19 were negatively correlated to NATAM. The correlation throughout SLC22A1 variants, such as GAT in rs72552763, was positive by EUR, while A in rs594709 was negative thereby and positive by NATAM. SLC22A3 variant C in rs2076828 was positively correlated to NATAM. NATAM patients present higher HbA1c levels with respect to Mestizo patients (p = 0.037). Uncontrolled patients (HbA1c ≥ 7%) have a larger NATAM ancestry (p = 0.018) and lower EUR (p = 0.022) as compared to controlled patients (HbA1c < 7%). Conclusions: there is a correlation between ancestry and some pharmacokinetically relevant alleles among Mexican DMT2 patients. Ethnicity is relevant for personalised medicine across different populations.

Keywords: CYP2C19; CYP2C8; CYP2C9; SLC22 family; antidiabetic drugs.

Figure 1

Reference panels and resulting clusters by using ADMIXTURE among Mexican DMT2 patients (n = 238).

Figure 2

Ancestry proportion comparison (NATAM, EUR, and AFR) across our DMT2 patient sample, grouped by genotype and CYP2C8 activity score. Panels (A–C) are genotype groupings (*1/*1, *1/*3, *1/*4, and *3/*4). Panels (D–F) are activity score groupings (1, 1.5, and 2). The p value corresponds to Bonferroni’s post hoc adjustment test. * p < 0.05, NS.: not significant.

Figure 3

Ancestry proportion comparison (NATAM, EUR, and AFR) across our DMT2 patient sample, grouped by genotype and CYP2C9 activity score. Panels (A–C) are genotype groupings (*1/*1, *1/*2, *1/*3, *2/*2, and *2/*3). Panels (D–F) are activity score groupings (0.5, 1, 1.5, and 2). The p value corresponds to Bonferroni’s post hoc adjustment test. NS.: not significant.

Figure 4

Ancestry proportion comparison (NATAM, EUR, and AFR) across our DMT2 patient sample, grouped by genotype and CYP2C19 activity score. Panels (A–C) are genotype groupings (*1/*1, *1/*17, *1/*2, *17/*17, *2/*17, and *2/*2). Panels (D–F) are activity score groupings (PM, 1, 1.5, 2, and UM). The p value corresponds to Bonferroni’s post hoc adjustment test. * p < 0.05, NS.: not significant.

Figure 5

Ancestry proportion comparison (NATAM, EUR, and AFR) across our DMT2 patient sample, grouped by OCT variant genotypes. Panels (A–C) show genotype groupings of rs72552763 in SLC22A1 (GAT/GAT, GAT/del, and del/del). Panels (D–F) show genotype groupings of rs594709 in SLC22A1 (C/C, A/G, and G/G). Panels (G–I) show genotype groupings of rs2076828 in SLC22A3 (C/C, C/G, and G/G). The p value corresponds to Bonferroni’s post hoc adjustment test. * p < 0.05, NS.: not significant.

Figure 6

Activity score of cytochromes coded by CYP2C8, CYP2C9, and CYP2C19, hereby grouped according to ancestry proportion (NATAM, EUR, and AFR). Panels (A–C) show the relevant points and the adjusted by linear regression in accordance with ancestry. The path represents the adjusted regression line for ancestry proportion and activity score of each cytochrome in a linear model. The shaded areas represent the line’s 95% confidence interval. Rho corresponds to Spearman’s correlation coefficient. Panels (D–F) show the relevant points and the adjusted regression line’s facets in accordance with ancestry. Blue dots correspond to AFR ancestry, pink dots correspond to EUR ancestry, and purple dots correspond to NATAM ancestry. * p < 0.05.