Association of the COQ2 V393A variant with risk of multiple system atrophy in East Asians: a case–control study and meta-analysis of the literature

Abstract

Recent studies in Japan have associated multiple system atrophy (MSA), a neurodegenerative disease of uncertain etiology, with polymorphism in the COQ2 gene. This led us to explore whether the same polymorphism is associated with MSA in Han Chinese and more broadly in East Asians. We conducted a case-control study with 82 Han Chinese with probable MSA and 484 gender- and age-matched healthy subjects, genotyping them using the ligase detection reaction. The results were meta-analyzed together with data from four previous studies to gain a broader picture of possible disease associations in East Asian populations. The COQ2 variants M78V and R337X were not detected in our Han Chinese patients or controls; only the heterozygous V393A variant (CT genotype) was detected. The frequency of this genotype was significantly higher in patients (7.3%) than in controls (1.86%; OR 4.17, 95% CI 1.44-12.04, p = 0.004). Subgroup analysis among patients showed a significant association of V393A with MSA involving cerebellar signs (MSA-C; OR 4.59, 95% CI 1.36-15.48, p = 0.007), but not with MSA involving parkinsonism (MSA-P). Meta-analysis of our results in Han Chinese with data from case-control studies in Japan, Korea, mainland China and Taiwan showed a significant association of V393A with MSA (OR 2.05, 95% CI 1.29-3.25, p = 0.002), which subgroup analysis showed to be significant for MSA-C (OR 2.75, 95% CI 1.98-3.84, p < 0.001) but not for MSA-P (OR 1.25, 95% CI 0.64-2.46, p = 0.51). These findings provide evidence that the previously reported association of COQ2 V393A polymorphism with increased risk of MSA in Japanese also applies to Han Chinese, as well as more broadly to other East Asian populations. This association may be particularly strong for MSA-C.

A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders

“…in an unchanged diagnostic interpretation in 58 of 76 cases (76%), and reclassification in the remaining 18 cases (24%, Previously reported as a risk variant for multiple system atrophy (Zhao et al, 2016).…”

Coenzyme Q10 as a Peripheral Biomarker for Multiple System Atrophy

“…1 Heterozygous mutations of COQ2 , in particularly the V393A mutation, are genetic risk factors for sporadic MSA in Japan but not in Europe or North America. Follow-up studies confirmed the association of COQ2 with MSA in a Taiwanese cohort and a Chinese cohort, 2,3 but the association was not replicated in other studies from East Asia. 4-6 Other European and North American studies also did not find the association between COQ2 mutations and MSA.…”

“…A meta-analysis of East Asian cohorts (Japan, Taiwan, Korea, and China) supports the association of COQ2 mutations and MSA. 3 Indeed, patients with MSA in different geographic regions have diverse clinical presentations: Japanese patients have primarily the cerebellar subtype, whereas European patients have mostly the parkinsonism subtype. Consistent with this finding, COQ2 mutations seem to be more common in patients with the cerebellar subtype of MSA.…”

Understanding Multiple System Atrophy—Could Genetics Lead the Way?

“…An association between sporadic MSA and CoQ2 variants was found in Japanese, Taiwanese and Chinese populations, but these results were not replicated in other cohorts. [26][27][28][29][30][31] Further studies have revealed reduction in CoQ10 levels in the cerebellum and serum of patients with MSA. 32,33 These findings may be particularly important in implicating CoQ10 supplementation as a therapeutic option in MSA, though this has not yet been systematically studied.…”