Abstract
Purpose
Type 2 diabetes (T2D) and low serum concentration of high-density lipoprotein cholesterol (HDL-c) are common coexisting metabolic disorders. ABCA1 variants have been shown to be associated to these conditions. We sought to test the combined effect of two ABCA1 gene common variants, rs2422493 (− 565C > T) and rs9282541 (R230C) on HDL-c levels and T2D risk.
Methods
Path analysis was conducted in 3,303 Mexican-mestizos to assess the specific contributions of rs2422493 and rs9282541 ABCA1 variants, insulin resistance, waist-to-height ratio (WHtR), and age on HDL-c levels and T2D risk. Participants were classified into four groups according to their ABCA1 variants carrier status: (i) the reference group carried wild type alleles for both ABCA1 variants (−/−), (ii) +/– were carriers of rs2422493 but non-carriers of rs9282541, (iii) −/+ for carriers of rs9282541 but not carriers of rs2422493 and (iv) carriers of minor alleles for both SNPs (+/+). Principal components from two previous genome-wide association studies were used to control for ethnicity.
Results
We identified significant indirect effects on T2D risk mediated by HDL-c in groups −/+ and +/+ (β = 0.04; p = 0.03 and β = 0.06; p < 0.01, respectively) in comparison to the −/− reference group. Low concentrations of HDL-c were directly and significantly associated with increased T2D risk (β = −0.70; p < 0.01). WHtR, male gender, age, and insulin resistance were also associated with T2D risk (p < 0.05). There was no significant direct effect for any of the ABCA1 groups on T2D risk: p = 0.99, p = 0.58, and p = 0.91 for groups +/–, −/+, and +/+ respectively.
Conclusions
The ABCA1 rs9282541 (R230C) allele is associated with T2D in Mexicans through its effect on lowering HDL-c levels. This is the first report demonstrating that HDL-c levels act as an intermediate factor between an ABCA1 variant and T2D.
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Acknowledgements
Ana Ochoa-Guzmán is a PhD student from Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM) and she was supported by Consejo Nacional de Ciencia y Tecnología (CONACyT) fellowship 468294. We thank Saúl Cano-Colín, José Luis Ventura-Gallegos, Maribel Rodríguez-Torres, Salvador Ramírez and Irma Mitre for technical assistance.
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We thank Consejo Nacional de Ciencia y Tecnología (CONACyT) for financial support (Project 128877).
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AO-G and HM-M designed, analyzed data and wrote the manuscript. DG-Q, OC-T, MLO-S, YS-K, VO, ED-D, LM-H, AG, and OP-M recollected patient’s data and/or contributed to the manuscript. AZ-D and CAA-S designed and supervised the research and edited the manuscript. MTT-L designed, supervised the research and wrote the manuscript. MTT-L is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
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All procedures performed in human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments ethical standards. The study was approved by The Committee of Ethics and the Institutional Review Board of the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ).
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Ochoa-Guzmán, A., Moreno-Macías, H., Guillén-Quintero, D. et al. R230C but not − 565C/T variant of the ABCA1 gene is associated with type 2 diabetes in Mexicans through an effect on lowering HDL-cholesterol levels. J Endocrinol Invest 43, 1061–1071 (2020). https://doi.org/10.1007/s40618-020-01187-8
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DOI: https://doi.org/10.1007/s40618-020-01187-8