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Acne and Telomere Length: A New Spectrum between Senescence and Apoptosis Pathways

Open ArchivePublished:September 27, 2016DOI:https://doi.org/10.1016/j.jid.2016.09.014

      Abbreviations:

      kb (kilobase pair), LTL (leukocyte telomere length), SNP (single-nucleotide polymorphism)
      To the Editor
      Acne is a multifactorial disease with many factors thought to play a role, including skin microflora and nutrition as well as hormonal influences and stress (
      • Suh D.H.
      • Kwon H.H.
      What’s new in the physiopathology of acne?.
      ). Acne patients have increased sebum secretion, and both acne and activity of the sebaceous glands are under significant genetic control (
      • Bataille V.
      • Snieder H.
      • MacGregor A.J.
      • Sasieni P.
      • Spector T.D.
      The influence of genetics and environmental factors in the pathogenesis of acne: a twin study of acne in women.
      ,
      • Mourelatos K.
      • Eady E.A.
      • Cunliffe W.J.
      • Clark S.M.
      • Cove J.H.
      Temporal changes in sebum excretion and propionibacterial colonization in preadolescent children with and without acne.
      ). Recent genome-wide association studies have identified several variants linked to acne susceptibility (
      • He L.
      • Wu W.J.
      • Yang J.K.
      • Cheng H.
      • Zuo X.B.
      • Lai W.
      • et al.
      Two new susceptibility loci 1q24.2 and 11p11.2 confer risk to severe acne.
      ,
      • Navarini A.A.
      • Simpson M.A.
      • Weale M.
      • Knight J.
      • Carlavan I.
      • Reiniche P.
      • et al.
      Genome-wide association study identifies three novel susceptibility loci for severe Acne vulgaris.
      ,
      • Wang H.
      • Guo M.
      • Shen S.
      • He L.
      • Zhang X.
      • Zuo X.
      • et al.
      Variants in SELL, MRPS36P2, TP63, DDB2, CACNA1H, ADAM19, GNAI1, CDH13 and GABRG2 interact to confer risk of acne in Chinese population.
      ,
      • Zhang M.
      • Qureshi A.A.
      • Hunter D.J.
      • Han J.
      A genome-wide association study of severe teenage acne in European Americans.
      ).
      It has long been noticed by dermatologists that acne patients have reduced skin aging, often observed many years after the acne has recovered. Signs of aging, such as wrinkling and skin thinning, appear later in acne patients compared with nonaffected individuals. This was speculated to be due to increased sebum secretion during the lifetime, but other factors are likely involved (
      • Downing D.T.
      • Wertz P.W.
      • Stewart M.E.
      The role of sebum and epidermal lipids in the cosmetic properties of skin.
      ).
      In this study, we investigated leucocyte telomere length (LTL) in subjects with acne compared with control subjects using data from the TwinsUK registry (http://www.twinsuk.ac.uk/).
      Telomeres are repeat TTAGGG sequences at the end of linear chromosomes guarding against loss of genetic material during cellular replication. Repeated cell cycles eventually lead to a critically shortened LTL, signaling cellular senescence and triggering apoptosis. Hence, LTL has been shown to be predictive of biological aging (
      • Hewitt G.
      • Jurk D.
      • Marques F.D.
      • Correia-Melo C.
      • Hardy T.
      • Gackowska A.
      • et al.
      Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence.
      ).
      Volunteers in the TwinsUK cohort were not recruited on the basis of any specific trait or disease and have been shown to have diseases and lifestyle characteristics similar to those of the general population (
      • Andrew T.
      • Hart D.J.
      • Snieder H.
      • de Lange M.
      • Spector T.D.
      • MacGregor A.J.
      Are twins and singletons comparable? A study of disease-related and lifestyle characteristics in adult women.
      ). Guy’s and St. Thomas’ Hospital NHS Trust Research Ethics Committee approved the study, and all twins provided informed written consent. For historical reasons the TwinsUK registry involves mainly women, and men were therefore excluded from this study. The history of acne was self-reported during a nurse-administered questionnaire, and the female twins were asked if they had ever suffered from acne and whether their acne was self-treated, treated by a general physician or treated by a dermatologist (
      • Bataille V.
      • Snieder H.
      • MacGregor A.J.
      • Sasieni P.
      • Spector T.D.
      The influence of genetics and environmental factors in the pathogenesis of acne: a twin study of acne in women.
      ). A total of 293 out of 1,205 twin volunteers (24.3%) had experienced acne in their lifetimes.
      LTL was measured using Southern blot analysis and was available for all subjects included in this study (
      • Valdes A.M.
      • Richards J.B.
      • Gardner J.P.
      • Swaminathan R.
      • Kimura M.
      • Xiaobin L.
      • et al.
      Telomere length in leukocytes correlates with bone mineral density and is shorter in women with osteoporosis.
      ) (see Supplementary Materials online for details). Mean LTL in the 1,205 subjects was 7.08 kilobase pairs (kb) (median = 7.06 kb, range = 5.70–8.67 kb). Mean weight was 67 kg (median = 65 kg, range = 40–115 kg), and mean height was 162 cm (median = 162 cm, range = 144–182 cm). The mean age of the twins at the time of DNA extraction was 48 ± 12 years.
      Linear regression (see Supplementary Materials for details) showed that samples from acne patients had longer LTL (mean = 7.17 ± 0.64 kb) compared with those from control subjects (mean = 6.92 ± 0.02 kb) after adjustment for age, twin relatedness, weight, and height (β = 0.11; standard error = 0.05; P = 0.01). Using score tests under a logistic regression model, we further investigated the association between acne and a set of single-nucleotide polymorphisms (SNPs) previously reported to be associated with LTL in a sample of 1,893 patients with severe acne and 5,132 population controls from the UK Acne Genetic study (
      • Codd V.
      • Nelson C.P.
      • Albrecht E.
      • Mangino M.
      • Deelen J.
      • Buxton J.L.
      • et al.
      Identification of seven loci affecting mean telomere length and their association with disease.
      ,
      • Mangino M.
      • Christiansen L.
      • Stone R.
      • Hunt S.C.
      • Horvath K.
      • Eisenberg D.T.
      • et al.
      DCAF4, a novel gene associated with leucocyte telomere length.
      ,
      • Navarini A.A.
      • Simpson M.A.
      • Weale M.
      • Knight J.
      • Carlavan I.
      • Reiniche P.
      • et al.
      Genome-wide association study identifies three novel susceptibility loci for severe Acne vulgaris.
      ). No LTL SNPs were significantly associated with acne after correction for multiple testing. However, rs3027234 in the CTC1 gene was nominally significant (see Supplementary Table S1 online). Finally, we performed a mixed-effect logistic regression analysis in whole-genome data from healthy skin samples comparing acne patients and control subjects. The expression data was measured in 705 women from the TwinsUK registry (http://www.muther.ac.uk/), of whom 346 had data on acne history. We selected 195 control twins who were perfectly age-matched to 39 twins with acne and gene expression data (see Supplementary Materials for details). Only the ZNF420 gene (probe ILMN_1720431) was significantly associated with acne history at a false discovery rate of 5%, showing a higher expression in control subjects (P = 7.73 × 10–7) (Table 1 and Figure 1). ZNF420 is one of the 30% most expressed genes in skin.
      Table 1Whole-genome differential expression between acne patients and control subjects using a mixed linear model to control for intrapair phenotypic correlation
      The table reports the top 20 hits from the mixed-effect logistic regression analysis. P-values, Storey Q-value, effect sizes (β), and standard errors are reported. Only the ZNF420 gene remained significant after multiple testing at 5% false discovery rate (Q < 0.05).
      GeneβSEPQ
      ZNF420–36.527.397.73 × 10-70.02
      KRTAP13-116.034.241.54 × 10-40.85
      TP53INP1–4.111.249.01 × 10-40.85
      PTPN98.322.531.01 × 10-30.85
      GOLGA4–4.701.441.14 × 10-30.85
      BCLAF1–2.870.891.17 × 10-30.85
      ZC3H104.881.511.23 × 10-30.85
      VGLL1–6.351.981.35 × 10-30.85
      GOLGA5–3.681.151.42 × 10-30.85
      C20orf1066.882.161.45 × 10-30.85
      FAM3A3.221.021.66 × 10-30.85
      ALDH3A12.030.651.78 × 10-30.85
      SUV420H1–8.682.801.93 × 10-30.85
      TNFAIP3–2.910.952.10 × 10-30.85
      PREB4.271.392.18 × 10-30.85
      HCFC1R12.740.902.22 × 10-30.85
      ING1–3.881.272.22 × 10-30.85
      WDR17–8.952.932.22 × 10-30.85
      CXorf1–7.072.312.22 × 10-30.85
      RAPH1–2.960.972.37 × 10-30.85
      Abbreviation: SE, standard error.
      1 The table reports the top 20 hits from the mixed-effect logistic regression analysis. P-values, Storey Q-value, effect sizes (β), and standard errors are reported. Only the ZNF420 gene remained significant after multiple testing at 5% false discovery rate (Q < 0.05).
      Figure 1
      Figure 1Gene expression levels for ZNF420 (probe ILMN_1720431) in acne patients and control subjects. Gene expression levels are adjusted by age and twin relatedness and have been scaled between 0 and 1. Main plot: ZNF420 expression levels in control subjects (n = 195) and patients (n = 39). Inset plot: ZNF420 expression levels in patients with moderate acne, who treated only by the general practitioner (n = 31), and patients with severe acne cases, who were treated by a dermatologist (n = 8). Reported P-values are from logistic regression.
      This study investigated reduced skin aging observed in acne by assessing telomere length in circulating white blood cells and gene expression in the skin. Acne patients had longer telomeres after adjusting for age, height, and twin relatedness, suggesting that the delayed skin aging may be due to reduced senescence. Only one SNP predicting LTL was found to be associated with acne at nominal significance. This SNP is located within the CTC1 gene, which is a component of the CST complex and plays an important role in protecting telomeres against degradation (
      • Sarek G.
      • Marzec P.
      • Margalef P.
      • Boulton S.J.
      Molecular basis of telomere dysfunction in human genetic diseases.
      ). The reduced expression of the gene ZNF420, which encodes the protein Apak, in the normal skin of acne patients suggests that p53 is up-regulated in acne patients, because the ZNF420 gene is a negative regulator of p53-mediated apoptosis.
      Considering longer telomeres and the up-regulation of the p53 pathway in acne patients, it could be speculated that acne susceptibility may be linked to the biology of cancer. A recent study from the Nurses; Health study II, a large US cohort involving more than 99,000 female nurses (
      • Zhang M.
      • Qureshi A.A.
      • Fortner R.T.
      • Hankinson S.E.
      • Wei Q.
      • Wang L.E.
      • et al.
      Teenage acne and cancer risk in US women: A prospective cohort study.
      ), found an increased risk of cancer in acne patients (
      • Zhang M.
      • Qureshi A.A.
      • Fortner R.T.
      • Hankinson S.E.
      • Wei Q.
      • Wang L.E.
      • et al.
      Teenage acne and cancer risk in US women: A prospective cohort study.
      ). Additionally, recent genome-wide association studies have reported significant associations between acne and genes involved in cancer susceptibility, including the MYC gene and genes linked to the transforming growth factor-β cell signaling pathway (
      • Navarini A.A.
      • Simpson M.A.
      • Weale M.
      • Knight J.
      • Carlavan I.
      • Reiniche P.
      • et al.
      Genome-wide association study identifies three novel susceptibility loci for severe Acne vulgaris.
      ,
      • Zhang M.
      • Qureshi A.A.
      • Hunter D.J.
      • Han J.
      A genome-wide association study of severe teenage acne in European Americans.
      ). Further work is needed to investigate the associations between cell senescence, acne, and cancer susceptibility, but this work sheds light on this very common and often debilitating skin disease.

      Conflict of Interest

      The authors state no conflict of interest.

      Acknowledgments

      We wish to express our appreciation to all study participants of TwinsUK. MS, AV, and MF wish to acknowledge S. Burbidge of the Imperial College High-Performance Computing service for his assistance.
      TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, and the National Institute for Health Research-funded BioResource, Clinical Research Facility, and Biomedical Research Centre based at Guy’s and St. Thomas’ NHS Foundation Trust in partnership with King’s College London. MF, VB, and AV are supported by BSF grant no. 5044i.

      Supplementary Material

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