ABCB1 gene variants as risk factors and modulators of age of onset of demyelinating disease in Mexican patients

J L Guerrero Camacho; T Corona Vázquez; J J Flores Rivera; A Ochoa Morales; L Martínez Ruano; I Torres Ramírez de Arellano; D J Dávila Ortiz de Montellano; A Jara Prado

doi:10.1016/j.nrl.2020.05.013

ABCB1 gene variants as risk factors and modulators of age of onset of demyelinating disease in Mexican patients

Neurologia (Engl Ed). 2020 Sep 7:S0213-4853(20)30216-4. doi: 10.1016/j.nrl.2020.05.013. Online ahead of print.

[Article in English, Spanish]

Authors

J L Guerrero Camacho¹, T Corona Vázquez², J J Flores Rivera², A Ochoa Morales¹, L Martínez Ruano¹, I Torres Ramírez de Arellano¹, D J Dávila Ortiz de Montellano¹, A Jara Prado³

Affiliations

¹ Departamento de Genética, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, México.
² Laboratorio Clínico de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, México.
³ Departamento de Genética, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, México. Electronic address: aureliojara@yahoo.com.mx.

PMID: 32912743
DOI: 10.1016/j.nrl.2020.05.013

Abstract

Introduction: The C1236T, G2677T/A, and C3435T variants of the ABCB1 gene alter the functioning of P-glycoprotein and the transport of endogenous and exogenous substances across the blood-brain barrier, and act as risk factors for some neurodegenerative diseases. This study aimed to determine the association between demyelinating disease and the C1236T, G2677T/A, and C3435T variants of ABCB1 and its haplotypes and combinations of genotypes.

Methods: Polymerase chain reaction with restriction fragment length polymorphism analysis (PCR-RFLP) and Sanger sequencing were used to genotype 199 patients with demyelinating disease and 200 controls, all Mexicans of mixed race; frequencies of alleles, genotypes, haplotypes, and genotype combinations were compared between patients and controls. We conducted a logistic regression analysis and calculated chi-square values and 95% confidence intervals (CI); odds ratios (OR) were calculated to evaluate the association with demyelinating disease.

Results: The TTT and CGC haplotypes were most frequent in both patients and controls. The G2677 allele was associated with demyelinating disease (OR: 1.79; 95% CI: 1.12-2.86; P=.015), as were the genotypes GG2677 (OR: 2.72; 95% CI: 1.11-6.68; P=.025) and CC3435 (OR: 1.82; 95% CI: 1.15-2.90; P=.010), the combination GG2677/CC3435 (OR: 2.02; 95% CI, 1.17-3.48; P=.010), and the CAT haplotype (OR: 0.21; 95% CI: 0.05-0.66; P=.001). TTTTTT carriers presented the earliest age of onset (23.0±7.7 years, vs. 31.6±10.7; P=.0001).

Conclusions: The GG2677/CC3435 genotype combination is associated with demyelinating disease in this sample, particularly among men, who may present toxic accumulation of P-glycoprotein substrates. In our study, the G2677 allele of ABCB1 may differentially modulate age of onset of demyelinating disease in men and women.

Keywords: ABCB1 gene; Análisis de asociación; Análisis de haplotipos; Association analysis; Demyelinating disease; Enfermedad desmielinizante; Esclerosis múltiple; Gen ABCB1; Glicoproteína P; Haplotype analysis; Multiple sclerosis; P-glycoprotein.