982 Correspondence

of her relatives, cosegregation analysis showed perfect correlation between the mutation and ARCI status (Fig. 1a): her unaffected parents are heterozygous for the mutation, one of her unaffected sisters (IV.3 in Fig. 1c) does not carry it, and one of her affected brothers (IV.1) is homozygous for it. The mutation was not detected in a matching cohort of 338 unrelated Galicians without ARCI. Like the two ARCI-related PNPLA1 mutations identified by Grall et al.,4 the mutation c.100A>G affects the patatin domain (Ile16 to Thr185; Fig. 1d), which features the catalytic pair Asp172 and Ser53.6 It results in replacement of the hydrophobic residue alanine with hydrophilic threonine (p.Ala34Thr referred to as NP_001139189.2), a change that might well alter protein folding (Fig. 1e,f). Its pathogenic nature is supported by the predictions of the programs AlignGVGD, MAPP, PolyPhen-2.1 and SIFT, which are in general agreement with each other (Table 1). Using the same programs, we obtained very similar predictions for the variant c.176C>T, one of the two PNPLA1 mutations found by Grall et al.4 in two out of 10 families with a homozygous haplotype in the region 6p21 (Table 1). These latter mutations were shown by functional analyses to affect lamellar body function and to give rise to ultrastructural epidermal features similar to those associated with TGM1 deficiency.4 Hitherto, only two ARCI families with PNPLA1 mutations have been reported, both of North African origin. These two families had different PNPLA1 mutations, but both affected the patatin-like domain.4 The new missense mutation observed in this study in a family of European ancestry, c.100G>A (p.Ala34Thr), likewise affects the patatin-like domain. Although mutant PNPLA1 was found in about 6% of our Galician ARCI series, the small number of Galician ARCI families prevents us from generalizing this figure.

Acknowledgments The authors are grateful to the families for their cooperation and also thank Ian-Charles Coleman for helpful suggestions and English editing. L.F. is supported by the Isabel Barreto programme of the Xunta de Galicia and the European Social Fund. 1

Fundacion Publica Galega de Medicina Xenomica-SERGAS, Grupo de Medicina Xenomica-USC, CIBERER, IDIS, Santiago de Compostela, Spain 2 Dermatology Service, University Hospital Complex of Ferrol, SERGAS, Ferrol, Spain 3 Department of Dermatology, University Hospital Complex of Santiago de Compostela, SERGAS, Santiago de Compostela, Spain 4 Faculty of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain Correspondence: Ana Vega. E-mail: [email protected]

L. FACHAL1 L . R O D R IG U E Z - P A Z O S 2 M. GINARTE3,4 A. CARRACEDO1,4 J. TORIBIO3,4 A. VEGA1

British Journal of Dermatology (2014) 170, pp970–1001

References 1 Oji V, Tadini G, Akiyama M et al. Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Soreze 2009. J Am Acad Dermatol 2010; 63:607–41. 2 Rodrıguez-Pazos L, Ginarte M, Fachal L et al. Analysis of TGM1, ALOX12B, ALOXE3, NIPAL4 and CYP4F22 in autosomal recessive congenital ichthyosis from Galicia (NW Spain): evidence of founder effects. Br J Dermatol 2011; 165:906–11. 3 Fachal L, Rodrıguez-Pazos L, Ginarte M et al. Multiple local and recent founder effects of TGM1 in Spanish families. PLoS One 2012; 7:e33580. 4 Grall A, Guaguere E, Planchais S et al. PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans. Nat Genet 2012; 44:140–7. 5 Radner FPW, Marrakchi S, Kirchmeier P et al. Mutations in CERS3 cause autosomal recessive congenital ichthyosis in humans. PLoS Genet 2013; 9:e1003536. 6 Baulande S, Langlois C. Les proteines a domaine patatine. Med Sci 2010; 26:177–84. Funding sources: Ram on Areces Foundation project awarded to A.V. Conflicts of interest: None declared.

The oestrogen receptor 2 (ESR2) gene in female-pattern hair loss: replication of association with rs10137185 in German patients DOI: 10.1111/bjd.12756 DEAR EDITOR, The aetiopathogenesis of female pattern hair loss (FPHL) is poorly understood. Although research has strongly implicated genetic factors in familial occurrence,1,2 no association finding for FPHL has yet been replicated.3–5 Consequently, no causal biological pathways can be suggested on the basis of currently available genetic findings. A recent genome-wide association study of ESR2 (oestrogen receptor 2) investigated 32 tag single-nucleotide polymorphisms (SNPs) in an Australian FPHL sample and found nominal significance for three variants (rs10137185, rs17101774, rs2022748). The most significant SNP was rs10137185 (P = 0003 for genotype CC versus genotypes CT + TT).6 This effect was consistent across subgroups stratified for disease severity and age-at-onset. Although no finding withstood experiment-wide correction for multiple testing, the validity of the association with rs10137185 was supported by functional evidence from a public eQTL database, i.e. an association between the risk genotype CC and higher ESR2 expression levels in fibroblasts. This latter finding is consistent with reports that oestrogen has inhibitory effects on hair growth.7 In a previous study, we investigated four variants in the ESR2 gene in a U.K./German FPHL sample and found no association.5 However, this may have been attributable to the fact © 2013 British Association of Dermatologists

Correspondence 983

that none of these four variants were in strong linkage disequilibrium with variants showing association in the Australian sample (max. r2 = 0149). We attempted to replicate the Australian findings with markers rs10137185, rs17101774 and rs2022748 in our German/U.K. FPHL case–control sample. The patients comprised 149 German and 145 U.K. hair clinic outpatients. The inclusion criterion was grade 2–3 FPHL according to the Ludwig scale8 in the German patients, and grade 2–5 according to the Sinclair et al. scale9 in the U.K. patients. Severe FPHL (Ludwig grade 3, Sinclair grade 4–5) was present in 25 German and 44 U.K. patients. An early age of onset (< 40 years) was reported in 63 German and 68 U.K. patients, a late age of onset (≥ 40 years) in 86 German and 77 U.K. patients. The controls comprised 230 healthy and unrelated female German blood donors and 179 U.K. super controls (women > 60 years without FPHL). Ethical approval was obtained from the respective Ethics Committees. Genotyping of rs10137185,

rs17101774 and rs2022748 was performed by KBioscience using the KASP SNP genotyping system (http://www.kbioscience.co.uk; last checked 12 January 2014). After applying SNP quality criteria (P < 005 of Hardy–Weinberg equilibrium in controls; SNP call rates < 95%), all three SNPs remained eligible for analysis. The Armitage trend test was used to detect allelic and genotypic effects. A specific attempt was made to replicate the previous association finding of rs10137185 by comparing the CC genotype of rs10137185, rs17101774 and rs2022748 with collapsed CT and TT genotypes. In a first step, analyses were performed in the overall German and U.K. samples. In a second step, analyses were performed in subgroups stratified according to disease severity and age of onset (Tables 1 and 2, Table S1). In the German sample, no significance was found for rs17101774 or rs2022748 (Tables 1 and 2, Table S1). However, significant association was found for rs10137185 in the overall sample [Puncorr. = 0012; odds ratio (OR) 191; 95%

Table 1 Association analysis for selected markers at the ESR2 gene locus and FPHL in the overall German and U.K. samples and subgroups

German controls (n = 230) All German cases (n = 149)

Severe cases (n = 25)

Mild cases (n = 124)

Early age of onset (n = 63)

Late age of onset (n = 86)

U.K. controls (n = 179) All U.K. cases (n = 145)

Severe cases (n = 44)

Mild cases (n = 101)

Early age of onset (n = 68)

Late age of onset (n = 77)

SNP Position (bp)a Allele A/Allele B

rs10137185 64775776 T/C

rs17101774 64793581 C/T

rs2022748 64825569 T/C

MAF MAF P-valuesb Allelic ORc MAF P-valuesb Allelic ORc MAF P-valuesb Allelic ORc MAF P-valuesb Allelic ORc MAF P-valuesb Allelic ORc MAF MAF P-valuesb Allelic ORc MAF P-valuesb Allelic ORc MAF P-valuesb Allelic ORc MAF P-valuesb Allelic ORc MAF P-valuesb Allelic ORc

0132 0074 0012 191 (112–325) 006 0131 238 (072–788) 0077 0082 183 (104–322) 0087 0162 159 (081–312) 0062 0010 231 (111–478) 008 0104 0318 075 (044–129) 0091 0735 087 (038–198) 011 0272 071 (039–128) 0097 055 08 (041–161) 0109 0303 071 (037–135)

0016 0018 0791 117 (037–372) 002 0817 129 (016–1072) 0018 0834 114 (033–394) 0008 0515 051 (006–415) 003 0375 173 (05–6) 0011 0011 0918 092 (021–417) 0011 0992 099 (011–896) 0011 0899 089 (016–494) 0015 0773 128 (023–709) 0007 0636 059 (007–535)

0018 0018 0976 102 (033–314) 002 0917 112 (014–912) 0018 099 099 (029–334) 0008 0422 044 (005–354) 003 0491 152 (045–513) 0011 0007 0585 063 (012–344) 0012 0983 102 (011–928) 0011 0464 045 (005–406) 0015 0749 132 (024–728) 0 0194 0 (0–654)

(95% CI)

(95% CI)

(95% CI)

(95% CI)

(95% CI)

(95% CI)

(95% CI)

(95% CI)

(95% CI)

(95% CI)

CI, confidence interval; FPHL, female-pattern hair loss; MAF, minor allele frequency; n, number of tested individuals; OR, odds ratio; SNP, single-nucleotide polymorphism. bold marks significant association. aNational Center for Biotechnology Information (NCBI) build 373. b P-values were calculated using the Armitage trend test. cORs are given with respect to the previously described risk alleles; for rs17101774 and rs2022748 this is the minor allele, while for rs10137185 it is the major allele.

© 2013 British Association of Dermatologists

British Journal of Dermatology (2014) 170, pp970–1001

British Journal of Dermatology (2014) 170, pp970–1001 215 (96) 8 (4) 0

8 (4) 215 (96)

Co-dominant model CC 132 (96) CT 5 (4) TT 0

Dominant model CT/TT 5 (4) CC 132 (96)

7 (3) 218 (97)

Dominant model CC/CT 5 (4) TT 133 (96)

0976

0976

0792

0791

0014

0012

102 (033–318)

102 (033–314)

117 (036–376)

117 (037–372)

051 (029–089)

191 (112–325)

OR (95% CI)

4 (5) 70 (95)

70 (95) 4 (5) 0

4 (5) 71 (95)

0 4 (5) 71 (95)

9 (12) 64 (88)

64 (88) 9 (12) 0

0505

0491

0394

0375

0014

0010

Late age of onset Cases n (%) P-valuesb

153 (045–525)

152 (045–513)

1. 75 (049–617)

173 (05–600)

041 (019–088)

231 (111–478)

OR (95% CI)

2 (1) 138 (99)

138 (99) 2 (1) 0

3 (2) 138 (98)

0 3 (2) 138 (98)

26 (19) 114 (81)

114 (81) 23 (16) 3 (2)

4 (2) 172 (98)

172 (98) 4 (2) 0

4 (2) 170 (98)

0 4 (02) 170 (98)

27 (15) 148 (85)

148 (85) 26 (15) 1 (< 1)

Overall U.K. sample Cases Controls n (%) n (%)

058

0585

0918

0918

0459

0318

P-valuesb

062 (011–345)

063 (012–344)

092 (02–42)

092 (021–417)

125 (069–226)

075 (044–129)

OR (95% CI)

0 73 (100)

73 (100) 0 0

1 (2) 72 (98)

0 1 (2) 72 (98)

14 (19) 59 (81)

59 (81) 14 (19) 0

0257

0194

0947

0636

0854

0303

Late age of onset Cases n (%) P-valuesb

/

0 (0–654)

059 (006–537)

059 (007–535)

13 (064–265)

071 (037–135)

OR (95% CI)

National Center for Biotechnology Information (NCBI) build 37; bP-values were calculated using the Armitage trend test, based on the minor allele while for rs10137185 calculation was based on the major allele according to Yip et al.;6 n, number of tested individuals. bold marks significant association.

a

rs2022748

0 7 (3) 218 (97)

Dominant model CT/TT 20 (15) CC 116 (85)

Co-dominant model CC 0 CT 5 (4) TT 133 (96)

57 (25) 167 (75)

Co-dominant model CC 116 (85) CT 20 (15) TT 0

rs10137185

rs17101774

167 (75) 55 (24) 2 (1)

Genotype

SNPa

Overall German sample Cases Controls n (%) n (%) P-valuesb

Table 2 Dominant and co-dominant model in the overall German and U.K. female-pattern hair loss samples and in the late-age-of-onset subgroup

984 Correspondence

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Correspondence 985

confidence interval (CI) 112–325]. The strongest association for rs10137185 was found in the late-onset FPHL subgroup (Puncorr. = 0010; OR 231, 95% CI 111–478) (Table 1). Comparison of the CC genotype of rs10137185 with collapsed CT and TT genotypes again generated significant results in the overall sample (Puncorr. = 0014; OR 051, 95% CI 029– 089), as well as in the late-onset FPHL subgroup (Puncorr. = 0014; OR 041, 95% CI 019–088) (Table 2). In the U.K. sample, none of the three variants showed significant association in either the overall sample or the subgroup analyses (Tables 1 and 2, Table S1). In summary, we replicated the association finding for rs101371856 in our German sample but not in our U.K. sample. One possible explanation for the nonreplication is limited power. Future studies should address this limitation by using larger samples. A second possible explanation is that the genetic effect might be less pronounced in mildly affected patients (Sinclair et al. grade 2, which is included in grade 1 of the Ludwig scale). Such patients were included in the U.K. sample but not in the Australian or the German sample. We were unable to replicate the previously reported association with rs17101774 and rs2022748,6 in either the German or in the U.K. sample. This may reflect a lack of power, as in the original report, the effect sizes for these two markers were smaller than for rs10137185. In conclusion, our results provide independent support for the hypothesis that ESR2 directly influences susceptibility to FPHL. Future studies are warranted to elucidate the genetic architecture and functional effects of this risk locus.

Acknowledgments The authors thank all patients and controls for their participation. We also thank the British Skin Foundation (A.G.M. and R.T.-A., 2005) for their support in the collection of the U.K. FPHL sample. S.R. is a past recipient of a BONFOR Gerok fellowship from the Medical Faculty of the University of Bonn. R.C.B. is the recipient of a Heisenberg Professorship from the German Research Foundation (DFG). 1

Institute of Human Genetics, University of Bonn, Sigmund-Freud-Street 25, D-53127 Bonn, Germany 2 Department of Dermatology, Royal Hallamshire Hospital, Sheffield, U.K. 3 German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany 4 Department of Genomics, Life & Brain Center, University of Bonn, Sigmund-FreudStreet 25, D-53127 Bonn, Germany 5 Department of Dermatology, University of Munich, Munich, Germany 6 Department of Infection and Immunity, University of Sheffield, Sheffield, U.K. 7 Dermatological Practice, Paderborn, Germany

S. REDLER1 P. BIRCH2 D. DRICHEL3 P. HOFMANN1,4 K. DOBSON2 A . C . B O€ H M E R 1 , 4 J. BECKER1,4 K.A. GIEHL5 R. TAZI-AHNINI6 R. KRUSE7 H. WOLFF5 A. MIESEL8 T. FISCHER8 M . B O€ H M 9 R. NUWAYHID10 N. GARCIA BARTELS10

© 2013 British Association of Dermatologists

8

Department of Dermatology, University of L€ubeck, L€ubeck, Germany 9 Department of Dermatology, Laboratory for Neuroendocrinology of the Skin and Interdisciplinary Endocrinology, University of M€unster, M€unster, Germany 10 Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charite-Universit€atsmedizin Berlin, Berlin, Germany 11 Dermatological Practice, Hair & Nail, Wesseling, Germany 12 Institute for Medical Biometry Informatics and Epidemiology, University of BonnSigmund-Freud-Street 25, D-53127 Bonn, Germany E-mail: [email protected]

G. LUTZ11 T. BECKER3,12 U. BLUME-PEYTAVI10 M . M . N O€ T H E N 1 , 4 A.G. MESSENGER2 R.C. BETZ1

References 1 Nyholt DR, Gillespie NA, Heath AC, Martin NG. Genetic basis of male pattern baldness. J Invest Dermatol 2003; 121:1561–4. 2 Smith MA, Wells RS. Male-type alopecia, alopecia areata, and normal hair in women; family histories. Arch Dermatol 1964; 89:95–8. 3 Redler S, Birch MP, Drichel D et al. Investigation of variants of the aromatase gene (CYP19A1) in female pattern hair loss. Br J Dermatol 2011; 165:703–5. 4 Redler S, Brockschmidt FF, Tazi-Ahnini R et al. Investigation of the male pattern baldness major genetic susceptibility loci AR/EDA2R and 20p11 in female pattern hair loss. Br J Dermatol 2012; 166:1314–18. 5 Redler S, Tazi-Ahnini R, Drichel D et al. Selected variants of the steroid-5-alpha-reductase isoforms SRD5A1 and SRD5A2 and the sex steroid hormone receptors ESR1, ESR2 and PGR: no association with female pattern hair loss identified. Exp Dermatol 2012; 21:390–3. 6 Yip L, Zaloumis S, Irwin D et al. Association analysis of oestrogen receptor beta gene (ESR2) polymorphisms with female pattern hair loss. Br J Dermatol 2012; 166:1131–4. 7 Ohnemus U, Uenalan M, Conrad F et al. Hair cycle control by estrogens: catagen induction via estrogen receptor (ER)-alpha is checked by ER beta signaling. Endocrinology 2005; 146:1214–25. 8 Ludwig E. Classification of the types of androgenetic alopecia (common baldness) occurring in the female sex. Br J Dermatol 1977; 97:247–54. 9 Sinclair R, Jolley D, Mallari R, Magee J. The reliability of horizontally sectioned scalp biopsies in the diagnosis of chronic diffuse telogen hair loss in women. J Am Acad Dermatol 2004; 51:189–99.

Supporting Information Additional Supporting Information may be found in the online version of this article at the publisher’s website: Table S1. Dominant and co-dominant model in the German and U.K. subgroups of mild, early and late affected FPHL samples. Funding sources: German Research Foundation DFG, BONFOR programme of the Medical faculty of the University of Bonn. Conflicts of interest: None declared

British Journal of Dermatology (2014) 170, pp970–1001

The oestrogen receptor 2 (ESR2) gene in female-pattern hair loss: replication of association with rs10137185 in German patients.

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