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

• Published in: PloS one Vol. 16; no. 11; p. e0259663
• Main Authors: Hayashi, Koji, Noguchi-Shinohara, Moeko, Sato, Takehiro, Hosomichi, Kazuyoshi, Kannon, Takayuki, Abe, Chiemi, Domoto, Chiaki, Yuki-Nozaki, Sohshi, Mori, Ayaka, Horimoto, Mai, Yokogawa, Masami, Sakai, Kenji, Iwasa, Kazuo, Komai, Kiyonobu, Ishimiya, Mai, Nakamura, Hiroyuki, Ishida, Natsuko, Suga, Yukio, Ishizaki, Junko, Ishigami, Akihito, Tajima, Atsushi, Yamada, Masahito
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15-11-2021; Public Library of Science (PLoS)
• Subjects: Aged; Aging; Alleles; Alzheimer's disease; Alzheimers disease; Analysis; Apolipoprotein E4; Apolipoprotein E4 - genetics; Apolipoprotein E4 - metabolism; Apolipoproteins; Apolipoproteins E - genetics; Apolipoproteins E - metabolism; Ascorbic acid; Ascorbic Acid - blood; Bioinformatics; Biology and Life Sciences; Brain; Care and treatment; Case-Control Studies; Cognitive ability; Cognitive Dysfunction - blood; Cognitive Dysfunction - genetics; Cognitive Dysfunction - metabolism; Dementia; Dementia disorders; Diagnosis; Dosage and administration; Female; Funding; Gene expression; Genes; Genomics; Genotype; Genotypes; Glucose Transporter Type 1 - genetics; Glucose Transporter Type 3 - genetics; Homozygotes; Hospitals; Humans; Male; Maxillofacial surgery; Medicine and Health Sciences; Neurobiology; Neurology; Neurosciences; Nucleotides; Pharmaceuticals; Pharmacy; Research and Analysis Methods; Risk analysis; Risk factors; Sodium-Coupled Vitamin C Transporters - genetics; Supervision; Transporter; Transposons; University graduates; Vitamin C; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0259663

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.