A Common Copy Number Variation (CNV) Polymorphism in the CNTNAP4 Gene: Association with Aging in Females

Iakoubov, Leonid; Mossakowska, Małgorzata; Szwed, Małgorzata; Duan, Zhi-quan; Sesti, Federico; Puzianowska-Kuźnicka, Monika

doi:10.1371/journal.pone.0079790

Cited by 20 publications

(24 citation statements)

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“…In total, they identified three deletions and four duplications that were significantly enriched in the pediatric individuals and that primarily encompassed genes involved in RNA splicing, suggesting an impact of this biological mechanism on lifespan (Glessner et al ., 2013). Recently, an analysis of the association between 20 common CNVs not typically covered by commercial arrays and longevity in 222 senior American Caucasians with replication in 1283 community‐dwelling senior European Caucasians resulted in the identification of a deletion in the neurexin superfamily member CNTNAP4 on chromosome 16q23.1 that was inversely associated with survival to 80 years in women (Iakoubov et al ., 2013). Further investigation of CNVs in other gene members of the neurexin superfamily by the same group additionally led to the detection of a CNV in the CNTNAP2 gene on chromosome 7q35‐36.1 that negatively associated with healthy aging in octogenarian men (Iakoubov et al ., 2015).…”

Section: Introductionmentioning

confidence: 99%

Copy number variation associates with mortality in long‐lived individuals: a genome‐wide assessment

et al. 2015

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SummaryCopy number variants (CNVs) represent a significant source of genetic variation in the human genome and have been implicated in numerous diseases and complex traits. To date, only a few studies have investigated the role of CNVs in human lifespan. To investigate the impact of CNVs on prospective mortality at the extreme end of life, where the genetic component of lifespan appears most profound, we analyzed genomewide CNV data in 603 Danish nonagenarians and centenarians (mean age 96.9 years, range 90.0–102.5 years). Replication was performed in 500 long‐lived individuals from the Leiden Longevity Study (mean age 93.2 years, range 88.9–103.4 years). First, we assessed the association between the CNV burden of each individual (the number of CNVs, the average CNV length, and the total CNV length) and mortality and found a significant increase in mortality per 10 kb increase in the average CNV length, both for all CNVs (hazard ratio (HR) = 1.024, P = 0.002) and for duplications (HR = 1.011, P = 0.005), as well as per 100 kb increase in the total length of deletions (HR = 1.009, P = 0.0005). Next, we assessed the relation between specific deletions and duplications and mortality. Although no genome–wide significant associations were discovered, we identified six deletions and one duplication that showed consistent association with mortality in both or either of the sexes across both study populations. These results indicate that the genome–wide CNV burden, specifically the average CNV length and the total CNV length, associates with higher mortality in long‐lived individuals.

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Section: Introductionmentioning

confidence: 99%

Copy number variation associates with mortality in long‐lived individuals: a genome‐wide assessment

et al. 2015

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“…These age groups were selected for the study because they flank the age interval of 76-80 years, where current survival curves show the highest increase in the number of premature deaths [8]. In accordance with a demographic hypothesis by Perls et al [9], and as it was discussed previously [2], if the deaths are, at least partly, related to genetics, this could result in a substantial difference between the genetic profiles of the flanking age groups. However, no statistically significant difference was found between these age groups for any of the three CNVs studied.…”

Section: Resultsmentioning

confidence: 99%

“…In combination with the previously described CNV polymorphism in the CNTNAP4 gene and its female specificity [2], it is conceivable that the entire human population could be screened for a genetic predisposition to healthy aging, though independently for males and females.…”

Section: Discussionmentioning

confidence: 99%

A Common Copy Number Variation Polymorphism in the <b><i>CNTNAP2</i></b> Gene: Sexual Dimorphism in Association with Healthy Aging and Disease

Iakoubov

Mossakowska²,

Szwed³

et al. 2014

Gerontology

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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.

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“…Additionally, we correlated copy number alterations (CNAs) load with patient age. Several CNAs have been reported to be associated with aging and cancer . CNAs are defined as DNA segments larger than 1 kb in size that vary in copy number between individuals due to insertion, deletion or duplication .…”

Section: Introductionmentioning

confidence: 99%

“…Several CNAs have been reported to be associated with aging and cancer. 19,20 CNAs are defined as DNA segments larger than 1 kb in size that vary in copy number between individuals due to insertion, deletion or duplication. 21 The mechanisms through which CNAs can lead to phenotypic effects include among others gene interruption, gene fusion and changes in gene expression.…”

Section: Introductionmentioning

confidence: 99%

Somatic genome alterations in relation to age in lung adenocarcinoma

Meucci

Keilholz

Heim

et al. 2019

Intl Journal of Cancer

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Lung adenocarcinoma (LUAD) is the most common cause of global cancer‐related mortality and the major risk factor is smoking consumption. By analyzing 486 LUAD samples from The Cancer Genome Atlas, we detected a higher mutational burden among younger patients in the global cohort as well as in the TP53‐mutated subcohort. The interaction effect of patient age and TP53 mutations significantly affected the mutational rate of younger TP53‐mutated patients. Furthermore, we detected a significant enrichment of the smoking‐related signature SI4 (SI4) among younger TP53‐mutated patients, meanwhile the age‐related Signature 1 (SI1) significantly increased in proportion to patient age. Although present and past smoking is reported in the TP53 wild‐type patients, we observed a lower average number of somatic mutations, with no correlation with patient age. Overall, TP53 mutations were significantly higher in younger patients and mainly characterized by SI4 and Signature 24 (SI24). Therefore, TP53 seemed to acquire a particular sensitivity to smoking related C>A mutations in younger patients. We hypothesize that TP53 mutations at a younger age might be a crucial factor enhancing the sensitivity to smoking‐related mutations leading to a burst of somatic alterations. The mutational profile of cancer cell might reflect the mutational processes operative in aging in a given tissue. Therefore, TP53‐mutated and TP53 wild‐type patient groups might represent phenotypes which endure aging‐related mutational processes with different strength. Our study provides indications of age‐dependent differences in mutational backgrounds that might be relevant for cancer prevention and age‐adjusted treatment approaches.

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A Common Copy Number Variation (CNV) Polymorphism in the CNTNAP4 Gene: Association with Aging in Females

Cited by 20 publications

References 43 publications

Copy number variation associates with mortality in long‐lived individuals: a genome‐wide assessment

Copy number variation associates with mortality in long‐lived individuals: a genome‐wide assessment

A Common Copy Number Variation Polymorphism in the <b><i>CNTNAP2</i></b> Gene: Sexual Dimorphism in Association with Healthy Aging and Disease

Somatic genome alterations in relation to age in lung adenocarcinoma

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