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. Author manuscript; available in PMC: 2011 Dec 1.
Published in final edited form as: J Invest Dermatol. 2011 Feb 17;131(6):1378–1380. doi: 10.1038/jid.2011.23

Filaggrin Null Mutations Are Not a Protective Factor for Acne Vulgaris

John EA Common 1,5, Sara J Brown 2,5, Rebecca L Haines 1, Christabelle SM Goh 1, Huijia Chen 1,2, Anita Balakrishnan 1, Colin S Munro 3, Audrey WH Tan 4, HH Tan 4, Mark BY Tang 4, E Birgitte Lane 1
PMCID: PMC3094589  EMSID: UKMS34419  PMID: 21326297

TO THE EDITOR

Acne vulgaris is a very common skin disorder, affecting to some degree 88–94% of Singaporean adolescents (Tan et al., 2007; Yosipovitch et al., 2007). Genetic predisposition is a significant risk factor, as illustrated by familial and twin studies (Bataille et al., 2002; Ghodsi et al., 2009). The clinical features of acne include sebor-rhea, comedone formation, inflammatory pustules, nodules, and cysts, with resultant scarring. Important pathogenic mechanisms in acne include increased sebum production, hyperkeratinization and occlusion of the follicular duct, proliferation of Propionibacterium acnes, and an inflammatory reaction (Purdy and de Berker, 2006). P. acnes produces lipases, which liberate proinflammatory fatty acids from sebum and also triggers a cytokine response.

Filaggrin is expressed in terminally differentiating keratinocytes and has a key role in epithelial barrier formation. Immunostaining demonstrates increased filaggrin expression in the sebaceous duct and infundibulum of acne vulgaris skin (Kurokawa et al., 1988), and P. acnes strains increase the expression of filaggrin and other differentiation-specific markers in normal human epidermal keratinocytes in vitro and in the suprabasal layers of human skin explants (Jarrousse et al., 2007). Similarly, inflammatory cytokines resulted in increased filaggrin expression in sebaceous gland explants (Guy and Kealey, 1998). However, it is not known whether differences in filaggrin expression represent a primary or secondary effect in the pathogenesis of acne.

Null mutations in the filaggrin gene (FLG) result in reduced filaggrin expression and cause ichthyosis vulgaris (Smith et al., 2006). Such mutations are common in the general population, being carried by ~10% of Europeans and 7.3% of Singaporean Chinese (Sandilands et al., 2007; Chen et al., personal communication). This high carrier rate in different populations suggests a heterozygote advantage, and it has been proposed that a more permeable skin barrier may have been beneficial in evolutionary history (Irvine and McLean, 2006). The co-existence of FLG null mutations with other gene mutations that disrupt epidermal differentiation may increase phenotype severity (Liao et al., 2007; Gruber et al., 2009). It is also possible that heterozygosity for null mutations has other effects on skin physiology. Studying a cohort of 284 European dermatology patients not selected for dry skin (Sergeant et al., 2009) raised the possibility that carriage of one FLG null mutation could provide a protective effect against acne vulgaris. In the Sergeant study, the odds ratio of acne in the carrier group was 0.3 (95% confidence interval 0.1–1.0), but the difference between these individuals and the group without FLG mutations did not reach statistical significance (P = 0.08). In addition, this study relied¼ on a recalled history of acne. We therefore aimed to test the hypothesis that FLG null mutations are protective against the development of acne vulgaris by studying a well-documented group of patients with acne, and comparing with a population control group.

A total of 287 Singaporean Chinese patients presenting with acne vulgaris to the National Skin Centre, a major dermatology outpatient facility in Singapore, were recruited: mean age 22 o years (SD 4.8), range 14–50 (27% <20 years of age and 95% were under 30 years), 76.3% were male. Acne vulgaris symptoms were reported for a mean o of 5.6 years (SD 4.2), range from <1 to 32 years. Patients with polycystic ovarian syndrome were excluded from this study. Acne severity was assessed using the Global Severity Assessment Score (Lehmann et al., 2002): 100 patients (34.8%) had mild acne, 129 (44.9%) had moderate acne, and 58 (20.3%) had severe acne. DNA samples from 440 unselected Singaporean Chinese population controls with a mean age of 44.6 years (SD 14.0), range 1–80, 44.1% male, for whom acne vulgaris status was unknown, were obtained from Singapore Bio-Bank, Singapore. This study was approved by the local domain specific ethical review board in accordance with the Declaration of Helsinki and all participants gave written, informed consent.

Cases and controls were screened for all 22 population-specific FLG null mutations as recently reported (Chen et al., personal communication). In this group a total of 12 known FLG null mutations were detected: p.S406X, c.1249insG, c.2284del4, c.3321delA, p.S1302X, p.S15 15X, c.6950del8, p.Q2417X, p.E2422X, c.7945delA, p.S2706X, and p.R4307X, plus two mutations: c.6834del5 and c.8157delC, which to our knowledge are previously unreported. Fisher's exact test and logistic regression analyses were used to compare the prevalence of FLG null mutations between cases and controls, using the statistical analysis package Stata (Version 9, Stata for Linux, StataCorp LP, College Station, TX). Power calculations were performed using Quanto version 1.2.4 (University of Southern California, http://hydra.usc.edu/gxe/).

In this study, 8.2% of Singaporean Chinese acne vulgaris cases carried one or more FLG null mutations compared with 7.3% of the control population, a non-significant difference (Fisher's exact test P = 0.783, odds ratio 1.2, 95% confidence interval 0.7–2.1), shown in Table 1. It is unlikely that our failure to demonstrate an association has occurred because of lack of power, as analysis of 256 acne vulgaris patients and 434 controls, assuming a population prevalence of 88% for acne vulgaris of comparable severity (Tan et al., 2007) would give a power of 99% to detect an odds ratio of 0.3 (Sergeant et al., 2009) for the combined FLG null genotype, with two-sided P = 0.05. The equivalent calculation using a population prevalence of 23% (based on Singaporean teenagers reporting treatment for their acne (Yosipovitch et al., 2007)) gives an estimated power of 90% for this study. Furthermore, the comprehensive screening of all 22 reported FLG null mutations from this carefully characterized Singaporean Chinese population means that the lack of association is unlikely to have occurred because of incomplete ascertainment of the FLG genotype.

Table 1.

Genotyping results and Fisher's exact test to investigate the association between FLG null mutations and acne vulgaris in a case–control study

Genotype1
FLG null mutation Acne vulgaris cases and
unselected population controls		 AA Aa aa Total2 Fisher's
exact test P-value
p.S406X Cases 279 0 0 279 0.524
Controls 438 2 0 440
c.1249insG Cases 276 4 0 280 0.023
Controls 440 0 0 440
c.2282del4 Cases 275 0 0 275 1.000
Controls 436 1 0 437
c.3321delA Cases 277 4 0 281 0.582
Controls 439 10 0 440
p.S1302X Cases 272 0 0 272 0.304
Controls 434 4 0 438
p.S1515X Cases 275 1 0 276 1.000
Controls 438 2 0 440
c.6834del53 Cases 280 1 0 281 0.390
Controls 440 0 0 440
c.6950del8 Cases 278 3 0 281 1.000
Controls 436 4 0 440
p.Q2417X Cases 278 2 0 280 0.151
Controls 440 0 0 440
p.E2422X Cases 278 2 0 280 0.151
Controls 440 0 0 440
c.7945delA Cases 274 2 0 276 0.562
Controls 439 1 0 440
p.S2706X Cases 276 1 0 280 0.160
Controls 431 7 0 438
c.8157delC3 Cases 278 1 0 279 0.388
Controls 440 0 0 440
p.R4307X Cases 278 1 0 279 0.488
Controls 438 1 0 439
Combined FLG null genotype Cases 235 21 0 256 0.783
Controls 402 31 1 434
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1

AA, homozygous wild type for FLG null mutation; Aa, heterozygous for the stated FLG null mutation or, in the combined null genotype, any one of the screened mutations; aa, compound heterozygous (i.e., an individual having two different FLG null mutations). The rationale for generating this combined null genotype is based on the fact that each mutation results in premature termination of the profilaggrin molecule and hence absence of processed filaggrin (Sandilands et al., 2007).

2

The figures in the total column vary because of incomplete genotyping results; all available data have been used for optimal analysis of each individual variant, but the combined FLG null genotype data include only those individuals for whom all 14 genotype results are available.

3

Previously unreported FLG mutations.

Our finding, that in this Singaporean Chinese population the frequency of FLG null mutations in acne vulgaris patients is not statistically different from the ethnically matched controls, indicates that filaggrin haploinsufficiency is unlikely to have a generic protective effect in acne. It is likely that the overexpression of filaggrin in the pilosebaceous units reported in the disorder is a bystander effect, reflecting other alterations in keratinocyte differentiation, but not itself critical for acne pathogenesis.

ACKNOWLEDGMENTS

We would like to thank the affected individuals for their participation in this study. Work completed at the Institute of Medical Biology was funded by the Agency of Science, Technology and Research (A*STAR), S.J.B. is the recipient of a Wellcome Trust Intermediate Fellowship (ref 086398/Z/08/ Z), and clinical research at the National Skin Centre is funded by an Enabling Grant from the National Medical Research Council, Singapore.

Abbreviation

FLG

filaggrin gene

Footnotes

CONFLICT OF INTEREST

The authors state no conflict of interest.

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