Epistasis, physical capacity-related genes and exceptional longevity: FNDC5 gene interactions with candidate genes FOXOA3 and APOE

Noriyuki Fuku, Roberto Díaz-Peña, Yasumichi Arai, Yukiko Abe, Hirofumi Zempo, Hisashi Naito, Haruka Murakami, Motohiko Miyachi, Carlos Spuch, José A. Serra-Rexach, Enzo Emanuele, Nobuyoshi Hirose, Alejandro Lucia

Research output: Contribution to journalArticle

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Abstract

Background: Forkhead box O3A (FOXOA3) and apolipoprotein E (APOE) are arguably the strongest gene candidates to influence human exceptional longevity (EL, i.e., being a centenarian), but inconsistency exists among cohorts. Epistasis, defined as the effect of one locus being dependent on the presence of 'modifier genes', may contribute to explain the missing heritability of complex phenotypes such as EL. We assessed the potential association of epistasis among candidate polymorphisms related to physical capacity, as well as antioxidant defense and cardiometabolic traits, and EL in the Japanese population. A total of 1565 individuals were studied, subdivided into 822 middle-aged controls and 743 centenarians. Results: We found a FOXOA3 rs2802292 T-allele-dependent association of fibronectin type III domain-containing 5 (FDNC5) rs16835198 with EL: the frequency of carriers of the FOXOA3 rs2802292 T-allele among individuals with the rs16835198 GG genotype was significantly higher in cases than in controls (P<0.05). On the other hand, among non-carriers of the APOE 'risk' ε4-allele, the frequency of the FDNC5 rs16835198 G-allele was higher in cases than in controls (48.4% vs. 43.6%, P<0.05). Among carriers of the 'non-risk' APOE ε2-allele, the frequency of the rs16835198 G-allele was higher in cases than in controls (49% vs. 37.3%, P<0.05). Conclusions: The association of FDNC5 rs16835198 with EL seems to depend on the presence of the FOXOA3 rs2802292 T-allele and we report a novel association between FNDC5 rs16835198 stratified by the presence of the APOE ε2/ε4-allele and EL. More research on 'gene*gene' and 'gene*environment' effects is needed in the field of EL.

Original languageEnglish
Article number803
JournalBMC Genomics
Volume18
DOIs
Publication statusPublished - 2017 Nov 14

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Apolipoproteins E
Alleles
Apolipoprotein E2
Genes
Apolipoprotein E4
Gene Frequency
Modifier Genes
Antioxidants
Genotype
Phenotype
Research
Population
Fibronectin Type III Domain

Keywords

  • Ageing
  • APOE
  • Centenarians
  • Exceptional longevity
  • FNDC5
  • FOXO3A

ASJC Scopus subject areas

  • Biotechnology
  • Genetics

Cite this

Epistasis, physical capacity-related genes and exceptional longevity : FNDC5 gene interactions with candidate genes FOXOA3 and APOE. / Fuku, Noriyuki; Díaz-Peña, Roberto; Arai, Yasumichi; Abe, Yukiko; Zempo, Hirofumi; Naito, Hisashi; Murakami, Haruka; Miyachi, Motohiko; Spuch, Carlos; Serra-Rexach, José A.; Emanuele, Enzo; Hirose, Nobuyoshi; Lucia, Alejandro.

In: BMC Genomics, Vol. 18, 803, 14.11.2017.

Research output: Contribution to journalArticle

Fuku, N, Díaz-Peña, R, Arai, Y, Abe, Y, Zempo, H, Naito, H, Murakami, H, Miyachi, M, Spuch, C, Serra-Rexach, JA, Emanuele, E, Hirose, N & Lucia, A 2017, 'Epistasis, physical capacity-related genes and exceptional longevity: FNDC5 gene interactions with candidate genes FOXOA3 and APOE', BMC Genomics, vol. 18, 803. https://doi.org/10.1186/s12864-017-4194-4
Fuku, Noriyuki ; Díaz-Peña, Roberto ; Arai, Yasumichi ; Abe, Yukiko ; Zempo, Hirofumi ; Naito, Hisashi ; Murakami, Haruka ; Miyachi, Motohiko ; Spuch, Carlos ; Serra-Rexach, José A. ; Emanuele, Enzo ; Hirose, Nobuyoshi ; Lucia, Alejandro. / Epistasis, physical capacity-related genes and exceptional longevity : FNDC5 gene interactions with candidate genes FOXOA3 and APOE. In: BMC Genomics. 2017 ; Vol. 18.
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abstract = "Background: Forkhead box O3A (FOXOA3) and apolipoprotein E (APOE) are arguably the strongest gene candidates to influence human exceptional longevity (EL, i.e., being a centenarian), but inconsistency exists among cohorts. Epistasis, defined as the effect of one locus being dependent on the presence of 'modifier genes', may contribute to explain the missing heritability of complex phenotypes such as EL. We assessed the potential association of epistasis among candidate polymorphisms related to physical capacity, as well as antioxidant defense and cardiometabolic traits, and EL in the Japanese population. A total of 1565 individuals were studied, subdivided into 822 middle-aged controls and 743 centenarians. Results: We found a FOXOA3 rs2802292 T-allele-dependent association of fibronectin type III domain-containing 5 (FDNC5) rs16835198 with EL: the frequency of carriers of the FOXOA3 rs2802292 T-allele among individuals with the rs16835198 GG genotype was significantly higher in cases than in controls (P<0.05). On the other hand, among non-carriers of the APOE 'risk' ε4-allele, the frequency of the FDNC5 rs16835198 G-allele was higher in cases than in controls (48.4{\%} vs. 43.6{\%}, P<0.05). Among carriers of the 'non-risk' APOE ε2-allele, the frequency of the rs16835198 G-allele was higher in cases than in controls (49{\%} vs. 37.3{\%}, P<0.05). Conclusions: The association of FDNC5 rs16835198 with EL seems to depend on the presence of the FOXOA3 rs2802292 T-allele and we report a novel association between FNDC5 rs16835198 stratified by the presence of the APOE ε2/ε4-allele and EL. More research on 'gene*gene' and 'gene*environment' effects is needed in the field of EL.",
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AU - Arai, Yasumichi

AU - Abe, Yukiko

AU - Zempo, Hirofumi

AU - Naito, Hisashi

AU - Murakami, Haruka

AU - Miyachi, Motohiko

AU - Spuch, Carlos

AU - Serra-Rexach, José A.

AU - Emanuele, Enzo

AU - Hirose, Nobuyoshi

AU - Lucia, Alejandro

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N2 - Background: Forkhead box O3A (FOXOA3) and apolipoprotein E (APOE) are arguably the strongest gene candidates to influence human exceptional longevity (EL, i.e., being a centenarian), but inconsistency exists among cohorts. Epistasis, defined as the effect of one locus being dependent on the presence of 'modifier genes', may contribute to explain the missing heritability of complex phenotypes such as EL. We assessed the potential association of epistasis among candidate polymorphisms related to physical capacity, as well as antioxidant defense and cardiometabolic traits, and EL in the Japanese population. A total of 1565 individuals were studied, subdivided into 822 middle-aged controls and 743 centenarians. Results: We found a FOXOA3 rs2802292 T-allele-dependent association of fibronectin type III domain-containing 5 (FDNC5) rs16835198 with EL: the frequency of carriers of the FOXOA3 rs2802292 T-allele among individuals with the rs16835198 GG genotype was significantly higher in cases than in controls (P<0.05). On the other hand, among non-carriers of the APOE 'risk' ε4-allele, the frequency of the FDNC5 rs16835198 G-allele was higher in cases than in controls (48.4% vs. 43.6%, P<0.05). Among carriers of the 'non-risk' APOE ε2-allele, the frequency of the rs16835198 G-allele was higher in cases than in controls (49% vs. 37.3%, P<0.05). Conclusions: The association of FDNC5 rs16835198 with EL seems to depend on the presence of the FOXOA3 rs2802292 T-allele and we report a novel association between FNDC5 rs16835198 stratified by the presence of the APOE ε2/ε4-allele and EL. More research on 'gene*gene' and 'gene*environment' effects is needed in the field of EL.

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