title: IL7R gene expression network associates with human healthy ageing.
abstract: BACKGROUND
  The level of expression of the interleukin 7 receptor (IL7R) gene in blood has recently been found to be associated with familial longevity and healthy ageing. IL7R is crucial for T cell development and important for immune competence. To further investigate the IL7R pathway in ageing, we identified the closest interacting genes to construct an IL7R gene network that consisted of IL7R and six interacting genes: IL2RG, IL7, TSLP, CRLF2, JAK1 and JAK3. This network was explored for association with chronological age, familial longevity and immune-related diseases (type 2 diabetes, chronic obstructive pulmonary disease and rheumatoid arthritis) in 87 nonagenarians, 337 of their middle-aged offspring and 321 middle-aged controls from the Leiden Longevity Study (LLS).
  
  
  RESULTS
  We observed that expression levels within the IL7R gene network were significantly different between the nonagenarians and middle-aged controls (P = 4.6 × 10(-4)), being driven by significantly lower levels of expression in the elderly of IL7, IL2RG and IL7R. After adjustment for multiple testing and white blood cell composition and in comparison with similarly aged controls, middle-aged offspring of nonagenarian siblings exhibit a lower expression level of IL7R only (P = 0.006). Higher IL7R gene expression in the combined group of middle-aged offspring and controls is associated with a higher prevalence of immune-related disease (P = 0.001). On the one hand, our results indicate that lower IL7R expression levels, as exhibited by the members of long-lived families that can be considered as 'healthy agers', are beneficial in middle age. This is augmented by the observation that higher IL7R gene expression associates with immune-related disease. On the other hand, IL7R gene expression in blood is lower in older individuals, indicating that low IL7R gene expression might associate with reduced health. Interestingly, this contradictory result is supported by the observation that a higher IL7R gene expression level is associated with better prospective survival, both in the nonagenarians (Hazard ratio (HR) = 0.63, P = 0.037) and the middle-aged individuals (HR = 0.33, P = 1.9 × 10(-4)).
  
  
  CONCLUSIONS
  Overall, we conclude that the IL7R network reflected by gene expression levels in blood may be involved in the rate of ageing and health status of elderly individuals.
authors.affiliation: Section of Molecular Epidemiology, Leiden University Medical Center, Zone S5-P, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Willemijn M
authors.initials: WM
authors.lastname: Passtoors
authors.affiliation: Section of Molecular Epidemiology, Leiden University Medical Center, Zone S5-P, P.O. Box 9600, 2300 RC Leiden, The Netherlands ; The Delft Bioinformatics Lab, Delft University of Technology, 2600 GA Delft, The Netherlands.
authors.forename: Erik B
authors.initials: EB
authors.lastname: van den Akker
authors.affiliation: Section of Molecular Epidemiology, Leiden University Medical Center, Zone S5-P, P.O. Box 9600, 2300 RC Leiden, The Netherlands ; Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Joris
authors.initials: J
authors.lastname: Deelen
authors.affiliation: Section of Gerontology and Geriatrics, Department of Internal Medicine, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Andrea B
authors.initials: AB
authors.lastname: Maier
authors.affiliation: Section of Molecular Epidemiology, Leiden University Medical Center, Zone S5-P, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Ruud
authors.initials: R
authors.lastname: van der Breggen
authors.affiliation: Department of Psychiatry, VU University Medical Center, Neuroscience Campus Amsterdam, 1081 BT Amsterdam, The Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Jansen
authors.affiliation: Department of Cardiology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands ; Department of Gerontology and Geriatrics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Stella
authors.initials: S
authors.lastname: Trompet
authors.affiliation: Department of Gerontology and Geriatrics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Diana
authors.initials: D
authors.lastname: van Heemst
authors.affiliation: Center for Medical Research, University of Tübingen, 72072 Tübingen, Germany.
authors.forename: Evelyna
authors.initials: E
authors.lastname: Derhovanessian
authors.affiliation: Center for Medical Research, University of Tübingen, 72072 Tübingen, Germany.
authors.forename: Graham
authors.initials: G
authors.lastname: Pawelec
authors.affiliation: Center for Human and Clinical Genetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands ; The Netherlands Center for Medical Systems Biology, Leiden, The Netherlands.
authors.forename: Gert-Jan B
authors.initials: GJ
authors.lastname: van Ommen
authors.affiliation: Section of Molecular Epidemiology, Leiden University Medical Center, Zone S5-P, P.O. Box 9600, 2300 RC Leiden, The Netherlands ; Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.affiliation: Section of Molecular Epidemiology, Leiden University Medical Center, Zone S5-P, P.O. Box 9600, 2300 RC Leiden, The Netherlands ; Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Marian
authors.initials: M
authors.lastname: Beekman
keywords: Gene expression; Healthy ageing; IL7R