The role of single-nucleotide variants of the energy metabolism-linked genes <i>SIRT3</i>, <i>PPARGC1A</i> and <i>APOE</i> in amyotrophic lateral sclerosis risk

Abstract

Amyotrophic lateral sclerosis (ALS) is a multifactorial disease, possibly with contributions from genetics and lifestyle. We examined variants in genes relevant to energy metabolism and physical activity in a case-control association study, with the aim of assessing genetics and physical activity as contributors to ALS risk. A well-characterized sample of Italian ALS patients (101) and controls (101) from the EURALS Consortium underwent a questionnaire interview on demographic, physical and other lifestyle habits, and venipuncture for DNA extraction. The genes selected were sirtuin 3 (SIRT3), peroxisome proliferator-activated receptor-γ coactivator-1α (PPARGC1A) and apolipoprotein E (APOE). Genetic studies suggested, for the first time, a protective role of the SIRT3 single-nucleotide polymorphism rs4980329 in ALS risk, and a contribution of the APOE-ε2 allele, which was more frequent in ALS patients than in controls. A joint analysis coupling genetic data and sporting activity revealed opposite roles of APOE-ε2 and SIRT3 rs3825075, the former being more frequent in physically active ALS patients and the latter more frequent in physically inactive patients. These findings suggest a contribution to ALS risk of genetic and environmental factors involved in energy metabolism, and stress the importance of a multifactorial analysis for evaluating this risk.

Analysis of Single Nucleotide Polymorphisms of STK32B, PPARGC1A and CTNNA3 Gene With Sporadic Parkinson's Disease Susceptibility in Chinese Han Population

“…STK32B and CTNNA3 are two protein-coding genes, but the current study has not found any association with pathogenic pathways of Parkinson's disease. However, It is worth mentioning that among the 3 genes described above, PPARGC1A plays an important role in the development and progression of neurodegenerative diseases such as Amyotrophic lateral sclerosis and Huntington's disease ( 31 , 32 ). As we all known, mitochondrial dysfunction and oxidative stress have been strongly linked to PD ( 33 , 34 ).…”

Lipid Biomarkers for Amyotrophic Lateral Sclerosis

“…It was also found that individuals who had suffered from head trauma in the adulthood were more prone to have ALS, and this association was stronger in the presence of APOE ε4 (33). In contrast, the frequency of APOE ε2, which is a priori neuroprotective, was higher in ALS patients that had practiced sport regularly (30). APOE ε2 also increased the risk of developing FTD in a cohort of patients with ALS (34).…”

“…The identification of APOE ε4 as a risk factor for Alzheimer's disease represented a major breakthrough in the field [(26), and references therein]. On the contrary, most studies on ALS did not observe any association of APOE ε4 with an increased risk (27–30), excepted some recent findings (31). Additional reports showed complex interactions between particular APOE alleles and other genetic or physiopathological variables.…”

Multi-omics studies reveal ameliorating effects of physical exercise on neurodegenerative diseases

“…There is study showed that the overall effect of the ε4 allele alone seems non-significant ( Mui et al, 1995 ), while the possible protective role of the ε2 allele form was poorly explored ( Buée et al, 1996 ). Diego Albani et al highlighted an association between ALS and the ε2 allele, which was generally considered neuroprotective ( Albani et al, 2017 ). Their result showed that among the group of PA the ε2 allele was significantly more frequent in ALS patients than in physically inactive patients ( Albani et al, 2017 ).…”

“…Diego Albani et al highlighted an association between ALS and the ε2 allele, which was generally considered neuroprotective ( Albani et al, 2017 ). Their result showed that among the group of PA the ε2 allele was significantly more frequent in ALS patients than in physically inactive patients ( Albani et al, 2017 ). The ε4 allele of APOE has been associated with the development of the atherosclerosis ( Altenburg et al, 2007 ) and cardiovascular disease ( Lopez et al, 2014 ), both of which increase AD risk.…”