Background: New therapeutic targets are needed to fight aging-related diseases and increase life span. A new female-specific association with diseases and limited survival past 80 years was recently reported for a copy number variation (CNV) in the CNTNAP4 gene from the neurexin superfamily. Objective: We asked whether there are CNVs that are associated with aging phenotypes within other genes from the neurexin superfamily and whether this association is sex specific. Methods: Select CNV polymorphisms were genotyped with proprietary TaqMan qPCR assays. Results: A case/control study, in which a group of 81- to 90-year-old community-dwelling Caucasians with no chronic diseases (case) was compared to a similar control group of 65- to 75-year-olds, revealed a negative association with healthy aging for the ins allele of common esv11910 CNV in the CNTNAP2 gene (n = 388; OR = 0.29, 95% CI: 0.14-0.59, p = 0.0004 for males, and OR = 0.82, 95% CI: 0.42-1.57, p = 0.625 for females). This male-specific association was validated in a study of an independent group of 76- to 80-year-olds. To look for a corresponding positive association of the allele with aging-related diseases, two case subgroups of 81- to 90-year-olds, one composed of individuals with cognitive impairment and the other with various diseases not directly related to the nervous system, such as cardiovascular diseases, etc., were compared to a healthy control subgroup of the same age. A positive male-specific association was found for both cases (OR = 2.75, p = 0.008 for association with cognitive impairment, and OR = 3.18, p = 0.002 for other diseases combined). Conclusions: A new male-specific association with aging is reported for a CNV in the CNTNAP2 gene. The polymorphism might be useful for diagnosing individual genetic predispositions to healthy aging versus aging complicated by chronic diseases.

Keywords:
Healthy aging, Cognitive impairment, Copy number variation, CNTNAP2, CASPR2, CNTNAP4, Sexual dimorphism, Sex specificity, Aging-related diseases, Polymorphism
1.
Kuningas M, Estrada K, Hsu YH, Nandakumar K, Uitterlinden AG, Lunetta KL, van Duijn CM, Karasik D, Hofman A, Murabito J, Rivadeneira F, Kiel DP, Tiemeier H: Large common deletions associate with mortality at old age. Hum Mol Genet 2011;20:4290-4296.
2.
Iakoubov L, Mossakowska M, Szwed M, Duan Z, Sesti F, Puzianowska-Kuznicka M: A common copy number variation (CNV) polymorphism in the CNTNAP4 gene: association with aging in females. PLoS One 2013;8:e79790.
3.
Peñagarikano O, Abrahams BS, Herman EI, Winden KD, Gdalyahu A, Dong H, Sonnenblick LI, Gruver R, Almajano J, Bragin A, Golshani P, Trachtenberg JT, Peles E, Geschwind DH: Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell 2011;147:235-246.
4.
Girault JA, Oguievetskaia K, Carnaud M, Denisenko-Nehrbass N, Goutebroze L: Transmembrane scaffolding proteins in the formation and stability of nodes of Ranvier. Biol Cell 2003;95:447-452.
5.
Anderson GR, Galfin T, Xu W, Aoto J, Malenka RC, Südhof TC: Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development. Proc Natl Acad Sci USA 2012;109:18120-18125.
6.
Rodenas-Cuadrado P, Ho J, Vernes SC: Shining a light on CNTNAP2: complex functions to complex disorders. Eur J Hum Genet 2014;22:171-178.
7.
Bledowski P, Mossakowska M, Chudek J, Grodzicki T, Milewicz A, Szybalska A, Wieczorowska-Tobis K, Wiecek A, Bartoszek A, Dabrowski A, Zdrojewski T: Medical, psychological and socioeconomic aspects of aging in Poland: assumptions and objectives of the PolSenior project. Exp Gerontol 2011;46:1003-1009.
8.
Laslett P: One necessary knowledge: age and aging in the societies of the past; in Kertzer DI, Laslett P (eds): Aging in the Past: Demography, Society, and Old Age. Berkeley, University of California Press, 1995, pp 4-79.
9.
Perls T, Kunkel LM, Puca AA: The genetics of exceptional human longevity. J Mol Neurosci 2002;19:233-238.
10.
Poliak S, Gollan L, Martinez R, Custer A, Einheber S, Salzer JL, Trimmer JS, Shrager P, Peles E: Caspr2, a new member of the neurexin superfamily, is localized at the juxtaparanodes of myelinated axons and associates with K+ channels. Neuron 1999;24:1037-1047.
11.
Nicolini P, Ciulla MM, De Asmundis C, Magrini F, Brugada P: The prognostic value of heart rate variability in the elderly, changing the perspective: from sympathovagal balance to chaos theory. Pacing Clin Electrophysiol 2012;35:622-638.
12.
Poliak S, Salomon D, Elhanany H, Sabanay H, Kiernan B, Pevny L, Stewart CL, Xu X, Chiu SY, Shrager P, Furley AJ, Peles E: Juxtaparanodal clustering of shaker-like K+ channels in myelinated axons depends on Caspr2 and TAG-1. J Cell Biol 2003;162:1149-1160.
13.
Brown AA, Xu T, Arroyo EJ, Levinson SR, Brophy PJ, Peles E, Scherer SS: Molecular organization of the nodal region is not altered in spontaneously diabetic BB-Wistar rats. J Neurosci Res 2001;65:139-149.
14.
Sesti F, Liu S, Cai SQ: Oxidation of potassium channels by ROS: a general mechanism of aging and neurodegeneration? Trends Cell Biol 2010;20:45-51.
15.
Cotella D, Hernandez-Enriquez B, Wu X, Li R, Pan Z, Leveille J, Link CD, Oddo S, Sesti F: Toxic role of K+ channel oxidation in mammalian brain. J Neurosci 2012;32:4133-4144.
16.
Mattison JA, Roth GS, Beasley TM, Tilmont EM, Handy AM, Herbert RL, Longo DL, Allison DB, Young JE, Bryant M, Barnard D, Ward WF, Qi W, Ingram DK, de Cabo R: Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 2012;489:318-321.
17.
Fallin MD, Matteini A: Genetic epidemiology in aging research. J Gerontol A Biol Sci Med Sci 2009;64:47-60.
18.
Corbo RM, Pinto A, Scacchi R: Gender-specific association between FSHR and PPARG common variants and human longevity. Rejuvenation Res 2013;16:21-27.
19.
Panaitof SC, Abrahams BS, Dong H, Geschwind DH, White SA: Language-related Cntnap2 gene is differentially expressed in sexually dimorphic song nuclei essential for vocal learning in songbirds. J Comp Neurol 2010;518:1995-2018.
20.
Liu Y, Rutlin M, Huang S, Barrick CA, Wang F, Jones KR, Tessarollo L, Ginty DD: Sexually dimorphic BDNF signaling directs sensory innervation of the mammary gland. Science 2012;338:1357-1360.
21.
Won H, Mah W, Kim E: Autism spectrum disorder causes, mechanisms, and treatments: focus on neuronal synapses. Front Mol Neurosci 2013;5:6-19.
22.
Ashrafi S, Betley JN, Comer JD, Brenner-Morton S, Bar V, Shimoda Y, Watanabe K, Peles E, Jessell TM, Kaltschmidt JA: Neuronal Ig/Caspr recognition promotes the formation of axoaxonic synapses in mouse spinal cord. Neuron 2014;81:120-129.
23.
Alarcón M, Abrahams BS, Stone JL, Duvall JA, Perederiy JV, Bomar JM, Sebat J, Wigler M, Martin CL, Ledbetter DH, Nelson SF, Cantor RM, Geschwind DH: Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet 2008;82:150-159.
24.
Kulminski AM, Arbeev KG, Culminskaya I, Arbeeva L, Ukraintseva SV, Stallard E, Christensen K, Schupf N, Province MA, Yashin AI: Age, gender, and cancer but not neurodegenerative and cardiovascular diseases strongly modulate systemic effect of the apolipoprotein E4 allele on lifespan. PLoS Genet 2014;10:e1004141.
25.
Gems D: Evolution of sexually dimorphic longevity in humans. Aging (Albany NY) 2014;6:84-91.
26.
Altmann A, Tian L, Henderson VW, Greicius MD; Alzheimer's Disease Neuroimaging Initiative Investigators: Sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol 2014;75:563-573.
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2014
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