Baurecht 2007
Baurecht 2007
Baurecht 2007
Background: With an impressive series of replication studies, Clinical implications: These results underline the importance of
filaggrin (FLG) has become the gene with the most widely a genetically determined epidermal barrier disruption in AE.
replicated association to atopic eczema (AE). However, studies (J Allergy Clin Immunol 2007;120:1406-12.)
published to date demonstrate differences concerning study
design and strength of associations. Key words: Atopic eczema, filaggrin, meta-analysis, atopic
Objectives: We sought to provide a general and overall estimate dermatitis
of FLG effect sizes and to estimate allele and carrier
frequencies.
Methods: We searched Medline and Institute for Scientific Atopic eczema (AE) is one of the most common
Information Web of Knowledge databases for relevant studies inflammatory skin disorders and affects up to 20% of
and abstracts from professional societies that were published children and up to 10% of adults in developed countries.1
through June 30, 2007. Initially, we accounted for different It is firmly established that AE is under strong genetic con-
study types and evaluated an overall estimate for case-control trol.2 Its frequent occurrence with other atopic pheno-
and family studies. In a second step, we combined those 2 study types, including asthma and allergic rhinitis, suggests
types and used a random-effects analysis approach to calculate
shared genetic risk variants.3 In addition, it is highly prob-
overall odds ratios (ORs). Tests of asymmetry were applied to
able that there are organ- and disease-specific factors, as
detect potential publication bias.
Results: Nine studies that met the inclusion criteria were indicated by genome-wide scans.2
included in the meta-analysis. For the combined genotype Despite considerable efforts that resulted in numerous
(R501X or 2282del4), we found an overall OR of 4.09 (95% CI, proposed or refuted associations with AE susceptibility
2.64-6.33) from the case-control studies and a summary OR of genes, until recently, no strong and reproducible genetic
2.06 (95% CI, 1.76-2.42) from the family studies. determinant could be identified. The detection of filaggrin
Conclusion: The powerful effect of FLG variation on AE risk (FLG) as major gene for AE in 2006 was an important
exceeds that of any other investigated candidate gene for AE breakthrough.4,5 Subsequent studies have shown FLG to
thus far and makes FLG one of the strongest genes known to be the gene with the most widely replicated association
date for complex diseases.
to AE.6-13
FLG is located within the epidermal differentiation
complex (EDC) in a region on chromosome 1q21, with a
significant linkage signal to AE and psoriasis.14,15 The
From athe Institute for Medical Statistics and Epidemiology (IMSE), Technical
dermatology, and drug allergy
TABLE I. Unadjusted ORs and 95% CIs of studies on the association of FLG variants with AE included in the meta-analysis
Combined
R501X 2282del4 genotype
Diagnosis of AE
Study Type Population n OR 95% CI OR 95% CI OR 95% CI based on:
Weidinger et al12 Fam Germany 476 3.82 2.02-7.68 2.43 1.60-3.76 2.73 1.89-4.01UK Working Party
Weidinger et al13 cc Germany 274/252 3.59 1.43-9.01 5.07 2.42-10.64 4.17 2.30-7.59UK Working Party
Marenholz et al7 Fam Europe 490* 1.73 1.16-2.61 2.13 1.61-2.84 2.13 1.68-2.72Hanifin and Rajka
cc Germany 188/319 6.65 2.43-18.22 2.42 1.09-5.38 3.73 1.98-7.03Hanifin and Rajka
Barker et al6 cc United Kingdom 163/1463 5.85 3.86-8.86 7.61 4.74-12.21 7.59 5.30-10.87
UK Working Party
Palmer et al4 cc Denmark 142/190 — — — — 2.49 1.26-4.93Hanifin and Rajka
cc Scotland 279/1008à — — — — 2.89à 2.04-4.11à
Questionnaire
Ruether et al9 Fam Germany 338 2.17 1.34-3.61 — — — — Hanifin and Rajka
cc Germany 272/276 3.59 1.80-7.05 7.1 3.41-14.78 — — Hanifin and Rajka
Morar et al8 cc§ Northern Europe# 426/564 2.55 1.50-4.34 1.93 1.23-3.03 2.03 1.46-2.81 —
Fam§ Northern Europe# 426 2.55 1.70-3.90 2.38 1.55-3.71 1.72 1.32-2.25Modified Hanifin
and Rajka
Famk Northern Europe# 148 2.40 1.15-5.02 3.00 1.60-5.62 1.94 1.27-2.95 —
Fam{ United Kingdom 278 2.62 1.58-4.33 1.88 1.02-3.44 1.58 1.12-2.24 —
Stemmler et al11 cc Germany 378/700 1.31 0.65-2.62 1.93 1.25-2.96 4.18 2.60-6.73 Hanifin and Rajka
Sandilands et al10 cc Ireland** 188/736 14.05 8.04-24.53 8.94 4.99-16.01 10.02àà 6.74-14.89 UK Working Party
Pooled estimate 1 95% CI cc 4.23 2.36-7.59 4.13 2.38-7.16 4.09 2.64-6.33 —
Fam 2.32 1.73-3.09 2.25 1.83-2.77 2.10 1.66-2.65 —
Total 3.51 2.24-5.50 3.62 2.43-5.41 3.58 2.43-5.26 —
Continental Europeans Total 2.61 1.81-3.78 2.82 1.99-4.00 2.97 2.28-3.87 —
Fam, Family study; cc, case-control study; Total, combined analysis of both study types.
*Four hundred ninety families including 903 children with eczema.
Children of mothers with asthma.
àPatients with asthma and eczema.
§Consists of individuals belonging to nuclear families of 2 panels.
kECZ1 panel of northern Europe (90% white, 1% Asian, and 4.3% mixed 1 others).
{MRCE panel (69% white, 14% South Asian, and 8% mixed 1 others).
#Inclusive United Kingdom.
**Irish study by Palmer et al4 is included in Sandilands et al.10
Morar (case-control) excluded.
ààOR includes 3 additional rare variants.
Sandilands et al,10 which we therefore used for the present sizes in Ireland/United Kingdom cohorts, the differences
analysis. remained nonsignificant (Table III).4-13,32-34
dermatology, and drug allergy
TABLE II. Minor allele frequencies of FLG variants (R501X, 2282del4, and combined genotype) and HWE test results
observed in studies on FLG published until April 2007
Weidinger et al12 Fam Germany 930 2.8% .371 952 5.5% .238 930 8.2% .319
Weidinger et al13 cc Germany 251 1.2% .848 250 1.8% .772 249 3.0% .624
Marenholz et al7 Fam Europe 970 2.8% NS 958 6.6% NS – 9.3% NS
cc Germany 319 0.8% .888 316 1.7% .753 314 2.5% .643
Barker et al6 cc United Kingdom 1463 2.9% .102 1463 1.7% .515 1463 4.6% .248
Palmer et al4 cc Ireland** 189 3.2% .652 186 1.1% .882 186 4.3% .540
cc Denmark – – – – – – 190 4.2% .233
cc Scotland 1008à 3.0% .026 1008 1.9% .542 1008à 4.9% .831
pop§ France 158 2.5% – 155 1.0% – – – –
pop§ Ireland/Scotland 242 2.8% – 257 1.0% – – – –
Ruether et al9 Famà Germany – – – – – – – – –
Ccà Germany – 2.2% – – 1.7% – – – –
Morar et al8 cc Northern Europe# – – NS – – NS – – NS
Fam Northern Europe# – – NS – – NS – – NS
Fam United Kingdom – – NS – – NS – – NS
Stemmler et al11 cc Germany 700à 1.6% 8.0 3 1026 678 3.5% .831 630c 2.2% .207
Sandilands et al10 cc Ireland 736 1.3% .723 736 1.3% .723 736 3.9% .918
Zhao et al32§ cc Ireland 654 1.5% .691 654 1.6% .676 654 3.1% .408
cc United Kingdom 1463 2.9% .102 1463 1.7% .515 1463 4.6% .248
Hüffmeier et al33§k cc Germany 369 1.8% NS 360 2.8% NS – – –
Smith et al5§ pop Ireland – 4.1% – – 0.5% – – – –
pop Scotland – 2.1% – – 1.2% – – – –
pop United States{ 124 2.4% – 133 1.1% – – – –
Gruber et al34§ pop Austria – 1.4% – – 1.4% – – 2.7% –
Pooled allele frequency (95% CI) 1.9% (0.3% to 3.5%) 1.9% (0.5% to 3.3%) 4.1% (1.4% to 6.8%)
Continental European 1.7% (0% to 4.0%) 2.8% (0.2% to 5.3%) 4.1% (0% to 8.5%)
MAF, Minor allele frequency; Fam, family study; cc, case-control study; NS, not significant; –, information not available; pop, population-based cohort.
*Number of control subjects in case-control–based studies, number of parents in family-based studies, and total number in population-based studies.
Calculated with stated genotyping rate of 0.99 and 0.977 for R501X and 2282del4, respectively.
àNot pooled because of violation of HWE or missing number of successfully genotyped control subjects.
§Control subjects from studies on related phenotypes.
kCalculated with stated genotyping rate of 0.981 and 0.957 for R501X and 2282del4, respectively.
{European Americans.
#Inclusive United Kingdom.
TABLE III. Carrier frequencies of FLG variants (R501X, 2282del4, and combined genotype) in cases and control subjects for
case-control studies or offspring and parents for family studies in studies on FLG published until April 2007
Weidinger et al12 Fam Germany 5.7% 8.8% 10.9% 15.8% 16.0% 22.8%
Weidinger et al13 cc Germany 2.4% 8.1% 3.6% 15.9% 6.0% 21.1%
Marenholz et al7 Fam Europe – – – – – 22.9%
cc Germany 1.6% 9.6% 3.5% 8.0% 5.1% 16.7%
Barker et al6 cc United Kingdom 5.6% 25.8% 3.4% 20.9% 8.8% 42.3%
Palmer et al4 cc Irelandk 6.4% 38.5% 2.2% 26.9% 8.6% 55.8%
cc Denmark – – – – 7.9% 17.6%
cc Scotland 5.8%* – 3.8% – 9.3%* 22.9%
pop France – – – – – –
pop Ireland/Scotland – – – – – –
Ruether et al9 Fam Germany – – – – – –
cc Germany – – – – – –
Morar et al8 cc Northern Europe§ – – – – – –
Fam Northern Europe§ – – – – – –
Fam United Kingdom – – – – – –
Stemmler et al11 cc Germany 2.9%* 3.7% 6.8% 12.3% 4.3%* 15.8%
Sandilands et al10 cc Ireland 2.6% 27.1% 2.6% 19.1% 7.6% 45.2%
Zhao et al32 cc Ireland 3.1% n.AE 3.2% n.AE 6.3% n.AE
cc United Kingdom 5.6% n.AE 3.4% n.AE 8.8% n.AE
Hüffmeier et al33 cc Germany – n.AE – n.AE – n.AE
Smith et al5 pop Ireland – n.AE – n.AE – n.AE
pop Scotland – n.AE – n.AE – n.AE
pop United Statesà – n.AE – n.AE – n.AE
Gruber et al34 pop Austria – n.AE – n.AE – n.AE
Pooled allele frequency (95% CI) 3.5% (0.9% 9.0% (3.1% 3.8% (1.5% 14.7% (8.0% 8.0% (4.3% 22.9% (16.4%
to 6.0%) to 15.0%) to 6.2%) to 21.4%) to 11.7%) to 29.3%)
Continental European 2.8% (0% 6.4% (0.7% 5.7% (0.9% 12.6% (5.0% 8.2% (0.2% 22.9% (15.1%
to 6.8%) to 12.1%) to 10.4%) to 20.3%) to 14.2%) to 30.7%)
Fam, family study; cc, case-control study; –, information not available; pop, population-based cohort; n.AE, other trait than AE.
*Not pooled because of distortion of the HWE.
Control subjects from studies on FLG with related phenotypes.
àEuropean American.
dermatology, and drug allergy
CI, 1.99-4.00) for 2282del4, and 2.97 (95% CI, 2.28-3.87) independently conferred by both null polymorphisms,
for the combined genotype. Between the studies, there was with an estimated overall OR of 3.51, 3.62, and 3.58 for
no evidence for significant heterogeneity (P 5 .074). R501X, 2282del4, and the combined genotype, respec-
tively. Thus the powerful effect of FLG variation on AE
risk exceeds that of any other investigated candidate
DISCUSSION gene for AE thus far.2 Comparison with effects observed
for candidate genes of other complex diseases (eg
In this study we have conducted the most comprehen- ADAM33 and asthma35 or TCF7L2 and diabetes36) shows
sive assessment of currently available data on the effect of that FLG is also one of the strongest known genes for com-
the 2 most common FLG polymorphisms in European plex diseases in general. With values of 57% and 49% for
populations on AE. Our comprehensive meta-analysis is breast cancer by age 75 years, BRCA1 and BRCA2 muta-
based on an impressive series of replication studies that tions show penetrance rates comparable with FLG and
have followed the initial publication from Palmer et al4 AE.37 However, in contrast to FLG, BRCA mutations
in early 2006. Although these studies exhibited a consid- account for less than 5% of all breast cancer cases.38
erable heterogeneity concerning study design and the Although frequencies of at least one of the null alleles
magnitude of the genetic effect, they have firmly estab- were comparable among control subjects, strikingly
lished FLG as major gene for AE. Our analysis demon- higher carrier frequencies were observed in British and
strates that across all studies there is a high risk Irish case collections (22.9% to 45.2%) along with a
J ALLERGY CLIN IMMUNOL Baurecht et al 1411
VOLUME 120, NUMBER 6
FIG 1. Association of FLG mutations R501X and 2282del4 (combined genotype) with increased AE risk. Forest
plots showing the ORs and respective 95% CIs for the different studies (given by first author, year, and ethnic-
ity of the study population) included in the meta-analysis are shown: A, case-control studies; B, family studies;
C, combined analysis. The rhombus designates the overall estimate of all studies. The consistently higher AE
risk conferred by FLG null alleles in all studies is reflected by a high overall estimated OR. GER, Germany;
UK, United Kingdom; DEN, Denmark; SCO, Scotland; IRL, Ireland; cc, case control study.
FIG 2. Funnel plots showing the ORs and 95% CIs for the association between FLG mutations R501X and
2282del4 (combined genotype) and AE observed in case-control studies (A), family studies (B), and both study
types (combined analysis; C). Tests of asymmetry showed no significant deviation from the symmetry
assumption (Fig 2, A, P 5 .973; Fig 2, B, P 5 .953; Fig 2, C, P 5 .199), thus not indicating publication bias.
major methodological issues of the various studies, and 13. Weidinger S, Rodrı́guez E, Stahl C, Wagenpfeil S, Klopp N, Illig T, et al.
Filaggrin mutations strongly predispose to early-onset and extrinsic
significant results were observed in all of the studies per-
atopic dermatitis. J Invest Dermatol 2007;127:724-6.
formed thus far, as well as in the pooled analysis. Given 14. Cookson WO, Ubhi B, Lawrence R, Abecasis GR, Walley AJ, Cox HE,
that additional prevalent variants have recently been et al. Genetic linkage of childhood atopic dermatitis to psoriasis suscep-
described,10 the current estimate of overall contribution tibility loci. Nat Genet 2001;27:372-3.
of FLG to AE is likely an underestimate, with additional 15. Mischke D, Korge BP, Marenholz I, Volz A, Ziegler A. Genes encoding
structural proteins of epidermal cornification and s100 calcium-binding
recurrent polymorphisms likely to be revealed in specific proteins form a gene complex (‘‘epidermal differentiation complex’’)
populations. on human chromosome 1q21. J Invest Dermatol 1996;106:989-92.
Clearly, well-defined and large-scale, population-based 16. Candi E, Schmidt R, Melino G. The cornified envelope: a model of cell
and longitudinal studies are needed to more precisely death in the skin. Nat Rev Mol Cell Biol 2005;6:328-40.
17. Presland RB, Dale BA. Epithelial structural proteins of the skin and oral cav-
work out the contribution of FLG polymorphisms to AE
ity: function in health and disease. Crit Rev Oral Biol Med 2000;11:383-408.
risk, to evaluate their role in other atopic diseases, and to 18. Sandilands A, O’Regan GM, Liao H, Zhao Y, Terron-Kwiatkowski A,
determine their effect in the general population. In addi- Watson RM, et al. Prevalent and rare mutations in the gene encoding fil-
tion, because it has been shown that FLG polymorphisms aggrin cause ichthyosis vulgaris and predispose individuals to atopic der-
are not solely responsible for the significant genetic link- matitis. J Invest Dermatol 2006;126:1770-5.
19. Nomura T, Sandilands A, Akiyama M, Liao H, Evans AT, Sakai K, et al.
age signal to the EDC region on chromosome 1q21,8 fur- Unique mutations in the filaggrin gene in Japanese patients with ichthyosis
ther investigation of this complex locus is likely to identify vulgaris and atopic dermatitis. J Allergy Clin Immunol 2007;119:434-40.
additional genetic variants with effects on AE. 20. Hudson TJ. Skin barrier function and allergic risk. Nat Genet 2006;38:
399-400.
21. Irvine AD. Fleshing out filaggrin phenotypes. J Invest Dermatol 2007;
We thank Domenique Ludwig for correcting the manuscript. 127:504-7.
22. Irvine AD, McLean WHI. Breaking the (un)sound barrier: filaggrin is a
major gene for atopic dermatitis. J Invest Dermatol 2006;126:1200-2.
23. McGrath JA. Second cite. Clin Exp Dermatol 2006;31:826-8.
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