Alzheimer Dis Assoc Disord. 2016 Oct-Dec;30(4):305-309.

Association Analysis of Polymorphisms in TOMM40, CR1, PVRL2, SORL1, PICALM, and 14q32.13 Regions in Colombian Alzheimer Disease Patients.

Jenny Ortega-Rojas, BSc, MSc,* Luis Morales, MD, MSc,* Esneyder Guerrero, MSc,Carlos E. Arboleda-Bustos, BSc, MSc, PhD,*  Adriana Mejia, BSc, MSc,* Diego Forero, MD, PhD,z Luis Lopez, PhD,Rodrigo Pardo, MD,*y Gonzalo Arboleda, MD, PhD,*Juan Yunis, MD, MSc,* and Humberto Arboleda, MD*

Neurosciences Research Group, Genetics Institute †Departament of Statistics, Universidad Nacional de Colombia, Bogotá Departments of §Internal Medicine ∥Pathology ¶Pediatrics, School of Medicine, Universidad Nacional de Colombia ‡Laboratory of Neuropsychiatric Genetics, Biomedical Sciences Research Group, School of Medicine, Universidad Antonio Nariño, Bogotá, Colombia.

 

Abstract

OBJECTIVE:

We evaluated the association of several single-nucleotide polymorphisms in different genes including APOE, TOMM40, CR1, PVRL2, SORL1, PICALM, and GWA_14q32.13 in a Colombian sample of Late-Onset Alzheimer disease (LOAD) patients.

METHODS:

A case-control study was conducted in 362 individuals (181 LOADs and 181 controls) to determine the association of single-nucleotide polymorphisms in APOE (e2, e3, and e4), TOMM40 (rs2075650), CR1 (rs665640), PVRL2 (rs6859), SORL1 (rs11218304), PICALM (rs3851179), and GWA_14q32.13 (rs11622883) with LOAD in a sample from Colombia.

RESULTS:

We were able to confirm the previously reported association of the APOE4 allele with AD. In addition, we report a new significant association with rs2075650 of TOMM40 for LOAD in our sample. We did not detect any significant interaction between TOMM40 and APOE4 carriers (heterozygous or homozygous) for disease risk development. However, Kaplan-Meier survival analyses suggest that AD patients with TOMM40 allele rs2075650-G have an average age of disease onset of 6 years earlier compared with carriers of the A allele. In addition, the age of disease onset is earlier if APOE4/4 is present.

CONCLUSION:

Our findings suggest that rs2075650 of TOMM40 could be involved in earlier presentation of LOAD in the Colombian population.

PMID: 27023435

 

Supplement:

Late-Onset Alzheimer disease (LOAD) has a high prevalence in Latin America countries such as Colombia. However, the genes associated for LOAD in some regions are not consistent for others populations. So far the only gene related to LOAD is APOE gene. In the present study, we evaluated some single-nucleotide polymorphisms in APOE gene (e2, e3, and e4) and also in other genes associated with LOAD as: TOMM40 (rs2075650), CR1 (rs665640),PVRL2 (rs6859), SORL1 (rs11218304), PICALM (rs3851179), and GWA_14q32.13 (rs11622883) genes. Our results showed a correlation between disease age onset  and APOEe4 and rs2075650 of TOMM40 gene. Furthermore, we found that the G allele carriers of rs2075650 variant (OR = 4.05; 95% CI, 2.62-6.25, p=3.68e-07) have an elevated risk of developing AD. Also, patients that carried rs2075650-G-variant of TOMM40 gene and one APOEe4 allele, had on average, a disease onset 6 years earlier. The age of onset is 13 years earlier if the person is a carrier of two APOEe4 alleles.

The TOMM40 gene is located in the chromosomic region 19q13.2, spans 12 Kb and is in linkage disequilibrium with APOE [2].  On the mitochondrial surface, the precursors of the proteins are recognized by the TOM complex, constituted by the external membrane translocases. This complex contains at least seven subunits, being TOMM40 one of them [1]. APOE protein interacts with the mitochondria, specifically in the outer membrane. Isoform APOEe4 has a bigger affinity for the mitochondria, and can trigger mitotoxicity processes [3]. 

In brains of LOAD patients, TOM40 colocalizes with the Amyloid Precursor Protein (APP) inside of the mitochondria, in an isoform-dependent manner. Thus, it is suggested that TOMM40 could be a potential candidate gene in the development of AD [4]. The importance of TOM400 in LOAD is supported by many different case-control studies, as well as GWAS, that suggest TOMM40 as an important factor for the development of AD [5,6]. The polymorphism rs2075650 in the TOMM40 gen has been associated with LOAD in different populations [7]. Due to its intronic localization, rs2075650 could act as a regulatory element, modulating the expression of the gene, since it is part of an haplotypic block that forms a putative enhancer element (TOM40 IVS2-4) and that could modulate the expression, not only of TOMM40, but also neighboring genes such as APOE and APOC1 [2]. This TOMM40 variant has also been related to longevity, since the carriers of the minor allele have 29% less probability to reach 90 years old, an effect that is dependent on APOEe4 [8].

The potential association between TOMM40, longevity and Aβ could be important in future investigations, since it could promote the understanding of how different polymorphisms in this gene interact with APOEe4, and how these interactions affect the risk of developing AD and its age of onset in different populations, including ours.

 

References

[1] Rapaport, D. How does the TOM complex mediate insertion of precursor proteins into the mitochondrial outer membrane?. J Cell Biol (2005). 171(3): 419-423.

[2] Bekris, L. M., F. Lutz, et at . Functional analysis of APOE locus genetic variation implicates regional enhancers in the regulation of both TOMM40 and APOE. J Hum Genet (2012) 57(1): 18-25.

[3] Lutz MW, C. D., Saunders AM, Roses AD.. Genetic variation at a single locus and age of onset for Alzheimer’s Disease.  Alzheimers Dement (2010)  6(2): 125-131.

[4] Devi, L., B. M. Prabhu, et al. Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer’s disease brain is associated with mitochondrial dysfunction. J Neurosci  (2006) 26(35): 9057-9068.

[5] Feulner, T. M., S. M. Laws, et al. Examination of the current top candidate genes for AD in a genome-wide association study. Mol Psychiatry (2010)15(7): 756-766.

[6] Hong, M. G., A. Alexeyenko, et al. Genome-wide pathway analysis implicates intracellular transmembrane protein transport in Alzheimer disease. J Hum Genet (2010) 55(10): 707-709.

[7] Huang H , Zhao J , Xu B , Ma X, Dai Q, Li T, Xue F, Chen B. The TOMM40 gene rs2075650 polymorphism contributes to Alzheimer’s disease in Caucasian, and Asian populations. Neurosci Lett. 2016 Aug 15;628:142-6.

[8] Deelen, J., M. Beekman, et al. Genome-wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited. Aging Cell  (2011) 10(4): 686-698.