Effects of functional variants of vitamin C transporter genes on apolipoprotein E E4-associated risk of cognitive decline: The Nakajima study.

Kôji Hayashi ,Chiemi Abe,Yukio Suga,Chiaki Domoto,Takehiro Sato,Kazuyoshi Hosomichi,Mai Horimoto,Akihito Ishigami,Sohshi Yuki-Nozaki,Natsuko Ishida,Junko Ishizaki,Takayuki Kannon,Atsushi Tajima,Kenji Sakai,Hiroyuki Nakamura,Masahito Yamada,Kazuo Iwasa,Mai Ishimiya,Masami Yokogawa,Moeko Noguchi‐Shinohara ,Akira Mori ,Koichiro Komai

doi:10.1371/journal.pone.0259663

Abstract

Apolipoprotein E E4 (APOE4) is a risk factor for cognitive decline. A high blood vitamin C (VC) level reduces APOE4-associated risk of developing cognitive decline in women. In the present study, we aimed to examine the effects of functional variants of VC transporter genes expressed in the brain (SLC2A1, SLC2A3, and SLC23A2) on APOE4-associated risk of developing cognitive decline. This case–control study involved 393 Japanese subjects: 252 cognitively normal and 141 cognitively impaired individuals (87 mild cognitive impairment and 54 dementia). Database searches revealed that rs1279683 of SLC23A2, and rs710218 and rs841851 of SLC2A1 are functional variants that are significantly associated with the altered expression of the respective genes and genotyped as three single nucleotide variants (SNVs). When stratified by SNV genotype, we found a significant association between APOE4 and cognitive decline in minor allele carriers of rs1279683 (odds ratio [OR] 2.02, 95% CI, 1.05–3.87, p = 0.035) but not in the homozygote carriers of the major allele. Significant associations between APOE4 and cognitive decline were also observed in participants with major allele homozygotes of rs710218 (OR 2.35, 95% CI, 1.05–5.23, p = 0.037) and rs841851 (OR 3.2, 95% CI, 1.58–6.46, p = 0.0012), but not in minor allele carriers of the respective SNVs. In contrast, the three functional SNVs showed no significant effect on cognitive decline. Our results imply that functional SNVs of VC transporter genes can affect APOE4-associated risk of developing cognitive decline via altered VC levels in the brain.

Highlights

Cognitive decline in patients with mild cognitive impairment (MCI) and dementia is a complex trait resulting from the interaction between genetic and environmental factors
We hypothesized that genetic variants that alter the function of vitamin C (VC) transporters in the brain affect the VC level and Apolipoprotein E E4 (APOE4)-associated risk of developing cognitive decline
In the multivariate logistic regression analysis, none of the single nucleotide variants (SNVs) were significantly associated with cognitive decline in either models. This case–control study involved the Japanese cohort population to determine the association between VC transporter genes (SLC23A2, SLC2A1, and SLC2A3) and APOE4-associated risk of developing cognitive decline (MCI or dementia)

Summary

Introduction

Cognitive decline in patients with mild cognitive impairment (MCI) and dementia is a complex trait resulting from the interaction between genetic and environmental factors. The E4 variant of apolipoprotein E (APOE4) is a well-known strong genetic risk factor for Alzheimer’s disease (AD) [1] and confers susceptibility to MCI [2]. In our previous longitudinal study, we found that high serum vitamin C (VC) levels during normal cognition reduce APOE4-associated risk of cognitive decline, especially in women [8]. Studies in animal models have revealed that VC is maintained at relatively high concentrations in the brain during systematic VC deficiency, suggesting the vital role of VC in the brain [11, 12]. Acute administration of VC improved cognitive function in mouse models of AD and aging [15, 16]

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