Evidence from case-control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity

Mette Soerensen; Serena Dato; Qihua Tan; Mikael Thinggaard; Rabea Kleindorp; Marian Beekman; H. Eka D. Suchiman; Rune Jacobsen; Matt McGue; Tinna Stevnsner; Vilhelm A. Bohr; Anton J.M. De Craen; Rudi G.J. Westendorp; Stefan Schreiber; P. Eline Slagboom; Almut Nebel; James W. Vaupel; Kaare Christensen; Lene Christiansen

doi:10.1007/s11357-011-9373-7

Evidence from case-control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity

Mette Soerensen, Serena Dato, Qihua Tan, Mikael Thinggaard, Rabea Kleindorp, Marian Beekman, H. Eka D. Suchiman, Rune Jacobsen, Matt McGue, Tinna Stevnsner, Vilhelm A. Bohr, Anton J.M. De Craen, Rudi G.J. Westendorp, Stefan Schreiber, P. Eline Slagboom, Almut Nebel, James W. Vaupel, Kaare Christensen, Lene Christiansen

Psychology (Twin Cities)

Research output: Contribution to journal › Article › peer-review

65 Scopus citations

Abstract

In this study, we investigated 102 single-nucleotide polymorphisms (SNPs) covering the common genetic variation in 16 genes recurrently regarded as candidates for human longevity: APOE; ACE; CETP; HFE; IL6; IL6R; MTHFR; TGFB1; APOA4; APOC3; SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. In a case-control study of 1,089 oldest-old (ages 92-93) and 736 middle-aged Danes, the minor allele frequency (MAF) of rs769449 (APOE) was significantly decreased in the oldest-old, while the MAF of rs9923854 (CETP) was significantly enriched. These effects were supported when investigating 1,613 oldest-old (ages 95-110) and 1,104 middle-aged Germans. rs769449 was in modest linkage equilibrium (R ² = 0.55) with rs429358 of the APOE-ε4 haplotype and adjusting for rs429358 eliminated the association of rs769449, indicating that the association likely reflects the well-known effect of rs429358. Gene-based analysis confirmed the effects of variation in APOE and CETP and furthermore pointed to HSPA14 as a longevity gene. In a longitudinal study with 11 years of follow-up on survival in the oldest-old Danes, only one SNP, rs2069827 (IL6), was borderline significantly associated with survival from age 92 (P-corrected = 0.064). This advantageous effect of the minor allele was supported when investigating a Dutch longitudinal cohort (N = 563) of oldest-old (age 85+). Since rs2069827 was located in a putative transcription factor binding site, quantitative RNA expression studies were conducted. However, no difference in IL6 expression was observed between rs2069827 genotype groups. In conclusion, we here support and expand the evidence suggesting that genetic variation in APOE, CETP, and IL6, and possible HSPA14, is associated with human longevity.

Original language	English (US)
Pages (from-to)	487-500
Number of pages	14
Journal	AGE
Volume	35
Issue number	2
DOIs	https://doi.org/10.1007/s11357-011-9373-7
State	Published - Apr 2013

Bibliographical note

Funding Information:
Acknowledgments This study was financially supported by the Max Planck Institute for Demographic Research (Rostock, Germany), the INTERREG 4 A programme Syddanmark- Schleswig-K.E.R.N. (by EU funds from the European Regional Development Fund), the National Institute on Aging (P01 AG08761), the Novo Nordisk Foundation, the Aase and Ejnar Danielsen Foundation, the Augustinus Foundation, the Brødrene Hartmann Foundation, the King Christian the 10th foundation, the Einer Willumsens Mindelegat Foundation, and by a Dutch grant from the Netherlands Consortium for Healthy Ageing (grant 050-060-810) in the framework of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO). The Danish Aging Research Center is supported by a grant from the VELUX Foundation. Susanne Knudsen, Steen Gregersen, Ulla Munk, Shuxia Li, Anne Mette Hedegaard Nielsen, Marlene Graff Sørensen, and Lene Elnegaard are thanked for excellent technical work.

Keywords

Candidate gene association study
Case-control data
Human longevity
Longitudinal data

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10.1007/s11357-011-9373-7

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Soerensen, M., Dato, S., Tan, Q., Thinggaard, M., Kleindorp, R., Beekman, M., Suchiman, H. E. D., Jacobsen, R., McGue, M., Stevnsner, T., Bohr, V. A., De Craen, A. J. M., Westendorp, R. G. J., Schreiber, S., Slagboom, P. E., Nebel, A., Vaupel, J. W., Christensen, K., & Christiansen, L. (2013). Evidence from case-control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity. AGE, 35(2), 487-500. https://doi.org/10.1007/s11357-011-9373-7

Soerensen, M, Dato, S, Tan, Q, Thinggaard, M, Kleindorp, R, Beekman, M, Suchiman, HED, Jacobsen, R, McGue, M, Stevnsner, T, Bohr, VA, De Craen, AJM, Westendorp, RGJ, Schreiber, S, Slagboom, PE, Nebel, A, Vaupel, JW, Christensen, K & Christiansen, L 2013, 'Evidence from case-control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity', AGE, vol. 35, no. 2, pp. 487-500. https://doi.org/10.1007/s11357-011-9373-7

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title = "Evidence from case-control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity",

abstract = "In this study, we investigated 102 single-nucleotide polymorphisms (SNPs) covering the common genetic variation in 16 genes recurrently regarded as candidates for human longevity: APOE; ACE; CETP; HFE; IL6; IL6R; MTHFR; TGFB1; APOA4; APOC3; SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. In a case-control study of 1,089 oldest-old (ages 92-93) and 736 middle-aged Danes, the minor allele frequency (MAF) of rs769449 (APOE) was significantly decreased in the oldest-old, while the MAF of rs9923854 (CETP) was significantly enriched. These effects were supported when investigating 1,613 oldest-old (ages 95-110) and 1,104 middle-aged Germans. rs769449 was in modest linkage equilibrium (R 2 = 0.55) with rs429358 of the APOE-ε4 haplotype and adjusting for rs429358 eliminated the association of rs769449, indicating that the association likely reflects the well-known effect of rs429358. Gene-based analysis confirmed the effects of variation in APOE and CETP and furthermore pointed to HSPA14 as a longevity gene. In a longitudinal study with 11 years of follow-up on survival in the oldest-old Danes, only one SNP, rs2069827 (IL6), was borderline significantly associated with survival from age 92 (P-corrected = 0.064). This advantageous effect of the minor allele was supported when investigating a Dutch longitudinal cohort (N = 563) of oldest-old (age 85+). Since rs2069827 was located in a putative transcription factor binding site, quantitative RNA expression studies were conducted. However, no difference in IL6 expression was observed between rs2069827 genotype groups. In conclusion, we here support and expand the evidence suggesting that genetic variation in APOE, CETP, and IL6, and possible HSPA14, is associated with human longevity.",

keywords = "Candidate gene association study, Case-control data, Human longevity, Longitudinal data",

author = "Mette Soerensen and Serena Dato and Qihua Tan and Mikael Thinggaard and Rabea Kleindorp and Marian Beekman and Suchiman, {H. Eka D.} and Rune Jacobsen and Matt McGue and Tinna Stevnsner and Bohr, {Vilhelm A.} and {De Craen}, {Anton J.M.} and Westendorp, {Rudi G.J.} and Stefan Schreiber and Slagboom, {P. Eline} and Almut Nebel and Vaupel, {James W.} and Kaare Christensen and Lene Christiansen",

note = "Funding Information: Acknowledgments This study was financially supported by the Max Planck Institute for Demographic Research (Rostock, Germany), the INTERREG 4 A programme Syddanmark- Schleswig-K.E.R.N. (by EU funds from the European Regional Development Fund), the National Institute on Aging (P01 AG08761), the Novo Nordisk Foundation, the Aase and Ejnar Danielsen Foundation, the Augustinus Foundation, the Br{\o}drene Hartmann Foundation, the King Christian the 10th foundation, the Einer Willumsens Mindelegat Foundation, and by a Dutch grant from the Netherlands Consortium for Healthy Ageing (grant 050-060-810) in the framework of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO). The Danish Aging Research Center is supported by a grant from the VELUX Foundation. Susanne Knudsen, Steen Gregersen, Ulla Munk, Shuxia Li, Anne Mette Hedegaard Nielsen, Marlene Graff S{\o}rensen, and Lene Elnegaard are thanked for excellent technical work.",

year = "2013",

month = apr,

doi = "10.1007/s11357-011-9373-7",

language = "English (US)",

volume = "35",

pages = "487--500",

journal = "AGE",

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T1 - Evidence from case-control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity

AU - Soerensen, Mette

AU - Dato, Serena

AU - Tan, Qihua

AU - Thinggaard, Mikael

AU - Kleindorp, Rabea

AU - Beekman, Marian

AU - Suchiman, H. Eka D.

AU - Jacobsen, Rune

AU - McGue, Matt

AU - Stevnsner, Tinna

AU - Bohr, Vilhelm A.

AU - De Craen, Anton J.M.

AU - Westendorp, Rudi G.J.

AU - Schreiber, Stefan

AU - Slagboom, P. Eline

AU - Nebel, Almut

AU - Vaupel, James W.

AU - Christensen, Kaare

AU - Christiansen, Lene

N1 - Funding Information: Acknowledgments This study was financially supported by the Max Planck Institute for Demographic Research (Rostock, Germany), the INTERREG 4 A programme Syddanmark- Schleswig-K.E.R.N. (by EU funds from the European Regional Development Fund), the National Institute on Aging (P01 AG08761), the Novo Nordisk Foundation, the Aase and Ejnar Danielsen Foundation, the Augustinus Foundation, the Brødrene Hartmann Foundation, the King Christian the 10th foundation, the Einer Willumsens Mindelegat Foundation, and by a Dutch grant from the Netherlands Consortium for Healthy Ageing (grant 050-060-810) in the framework of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO). The Danish Aging Research Center is supported by a grant from the VELUX Foundation. Susanne Knudsen, Steen Gregersen, Ulla Munk, Shuxia Li, Anne Mette Hedegaard Nielsen, Marlene Graff Sørensen, and Lene Elnegaard are thanked for excellent technical work.

PY - 2013/4

Y1 - 2013/4

N2 - In this study, we investigated 102 single-nucleotide polymorphisms (SNPs) covering the common genetic variation in 16 genes recurrently regarded as candidates for human longevity: APOE; ACE; CETP; HFE; IL6; IL6R; MTHFR; TGFB1; APOA4; APOC3; SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. In a case-control study of 1,089 oldest-old (ages 92-93) and 736 middle-aged Danes, the minor allele frequency (MAF) of rs769449 (APOE) was significantly decreased in the oldest-old, while the MAF of rs9923854 (CETP) was significantly enriched. These effects were supported when investigating 1,613 oldest-old (ages 95-110) and 1,104 middle-aged Germans. rs769449 was in modest linkage equilibrium (R 2 = 0.55) with rs429358 of the APOE-ε4 haplotype and adjusting for rs429358 eliminated the association of rs769449, indicating that the association likely reflects the well-known effect of rs429358. Gene-based analysis confirmed the effects of variation in APOE and CETP and furthermore pointed to HSPA14 as a longevity gene. In a longitudinal study with 11 years of follow-up on survival in the oldest-old Danes, only one SNP, rs2069827 (IL6), was borderline significantly associated with survival from age 92 (P-corrected = 0.064). This advantageous effect of the minor allele was supported when investigating a Dutch longitudinal cohort (N = 563) of oldest-old (age 85+). Since rs2069827 was located in a putative transcription factor binding site, quantitative RNA expression studies were conducted. However, no difference in IL6 expression was observed between rs2069827 genotype groups. In conclusion, we here support and expand the evidence suggesting that genetic variation in APOE, CETP, and IL6, and possible HSPA14, is associated with human longevity.

AB - In this study, we investigated 102 single-nucleotide polymorphisms (SNPs) covering the common genetic variation in 16 genes recurrently regarded as candidates for human longevity: APOE; ACE; CETP; HFE; IL6; IL6R; MTHFR; TGFB1; APOA4; APOC3; SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. In a case-control study of 1,089 oldest-old (ages 92-93) and 736 middle-aged Danes, the minor allele frequency (MAF) of rs769449 (APOE) was significantly decreased in the oldest-old, while the MAF of rs9923854 (CETP) was significantly enriched. These effects were supported when investigating 1,613 oldest-old (ages 95-110) and 1,104 middle-aged Germans. rs769449 was in modest linkage equilibrium (R 2 = 0.55) with rs429358 of the APOE-ε4 haplotype and adjusting for rs429358 eliminated the association of rs769449, indicating that the association likely reflects the well-known effect of rs429358. Gene-based analysis confirmed the effects of variation in APOE and CETP and furthermore pointed to HSPA14 as a longevity gene. In a longitudinal study with 11 years of follow-up on survival in the oldest-old Danes, only one SNP, rs2069827 (IL6), was borderline significantly associated with survival from age 92 (P-corrected = 0.064). This advantageous effect of the minor allele was supported when investigating a Dutch longitudinal cohort (N = 563) of oldest-old (age 85+). Since rs2069827 was located in a putative transcription factor binding site, quantitative RNA expression studies were conducted. However, no difference in IL6 expression was observed between rs2069827 genotype groups. In conclusion, we here support and expand the evidence suggesting that genetic variation in APOE, CETP, and IL6, and possible HSPA14, is associated with human longevity.

KW - Candidate gene association study

KW - Case-control data

KW - Human longevity

KW - Longitudinal data

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Evidence from case-control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity

Abstract

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