Gerhard Lutz

Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci

Alopecia areata (AA) is a prevalent autoimmune disease with ten known susceptibility loci. Here we perform the first meta-analysis in AA by combining data from two genome-wide association studies (GWAS), and replication with supplemented ImmunoChip data for a total of 3,253 cases and 7,543 controls. The strongest region of association is the MHC, where we fine-map 4 independent effects, all implicating HLA-DR as a key etiologic driver. Outside the MHC, we identify two novel loci that exceed statistical significance, containing ACOXL/BCL2L11(BIM) (2q13); GARP (LRRC32) (11q13.5), as well as a third nominally significant region SH2B3(LNK)/ATXN2 (12q24.12). Candidate susceptibility gene expression analysis in these regions demonstrates expression in relevant immune cells and the hair follicle. We integrate our results with data from seven other autoimmune diseases and provide insight into the alignment of AA within these disorders. Our findings uncover new molecular pathways disrupted in AA, including autophagy/apoptosis, TGFß/Tregs and JAK kinase signaling, and support the causal role of aberrant immune processes in AA.

Follow-Up Study of the First Genome-Wide Association Scan in Alopecia Areata: IL13 and KIAA0350 as Susceptibility Loci Supported with Genome-Wide Significance

Recently, the first genome-wide association study (GWAS) of alopecia areata (AA) was conducted in a North-American sample, and this identified eight susceptibility loci surpassing genome-wide significance. The aim of the present follow-up association analysis was to confirm five of these eight loci (single-nucleotide polymorphisms (SNPs) from the CTLA4, IL-2RA, and HLA regions were not included due to previous own findings) and test 12 other loci from the GWAS, which did not surpass the threshold for genome-wide significance. Twenty-three SNPs from the 17 loci were investigated using a sample of 1,702 Central European AA patients and 1,723 controls. Of the five loci with previously reported genome-wide significance, association was confirmed for all of these: ULBP3/ULBP6, PRDX5, IL-2/IL-21, STX17, and IKZF4/ERBB3 (P-value <0.05). To detect robust evidence for association among the 12 other loci, a meta-analysis of the present association data and the data of the recent GWAS was performed. Genome-wide significant association was found for rs20541 (P(comb)=7.52 × 10(-10); odds ratio (OR)=1.30 (1.23-1.38)) and rs998592 (P(comb)=1.11 × 10(-11); OR=1.28 (1.21-1.36)), thus establishing IL-13 and KIAA0350/CLEC16A as susceptibility loci for AA. Interestingly, IL-13 and KIAA0350/CLEC16A are susceptibility loci for other autoimmune diseases, supporting the hypothesis of shared pathways of autoimmune susceptibility.

The R620W polymorphism in PTPN22 confers general susceptibility for the development of alopecia areata

Background  The functional R620W (c.1858C>T) variant of the protein tyrosine phosphatase nonreceptor 22 gene (PTPN22) has been associated with a variety of autoimmune disorders. A recent study has suggested that R620W also contributes to the severe form of alopecia areata (AA).

Genome-wide pooling approach identifies SPATA5 as a new susceptibility locus for alopecia areata

Alopecia areata (AA) is a common hair loss disorder, which is thought to be a tissue-specific autoimmune disease. Previous research has identified a few AA susceptibility genes, most of which are implicated in autoimmunity. To identify new genetic variants and further elucidate the genetic basis of AA, we performed a genome-wide association study using the strategy of pooled DNA genotyping (729 cases, 656 controls). The strongest association was for variants in the HLA region, which confirms the validity of the pooling strategy. The selected top 61 single-nucleotide polymorphisms (SNPs) were analyzed in an independent replication sample (454 cases, 1364 controls). Only one SNP outside of the HLA region (rs304650) showed significant association. This SNP was then analyzed in a second independent replication sample (537 cases, 657 controls). The finding was not replicated on a significant level, but showed the same tendency. A combined analysis of the two replication samples was then performed, and the SNP rs304650 showed significant association with P=3.43 × 10−4 (OR=1.24 (1.10–1.39)). This SNP maps to an intronic region of the SPATA5 (spermatogenesis-associated protein 5) gene on chromosome 4. The results therefore suggest the SPATA5 locus is a new susceptibility locus for AA.

Investigation of the male pattern baldness major genetic susceptibility loci AR/EDA2R and 20p11 in female pattern hair loss

Background  The aetiology of female pattern hair loss (FPHL) is largely unknown. However, it is hypothesized that FPHL and male pattern baldness (AGA) share common susceptibility alleles. The two major susceptibility loci for AGA are the androgen receptor (AR)/ectodysplasin A2 receptor (EDA2R) locus on the X‐chromosome, and a locus on chromosome 20p11, for which no candidate gene has yet been identified.

Genetic Variants in CTLA4 Are Strongly Associated with Alopecia Areata

K. Bhattacharya, Richard A. Smith, Patti L. Johnson, Jianjun Chen, Kathleen E. Nelson, Robert C. Tuckey, Duane Miller, Yan Jiao, Weikuan Gu and Arnold E. Postlethwaite Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee, USA; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, USA; Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA; Orthopedic Surgery, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA; Department of Biology, Christian Brothers University, Memphis, Tennessee, USA; School of Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, Crawley, Western Australia, Australia; Division of Connective Tissue Diseases, University of Tennessee Health Science Center, Memphis, Tennessee, USA and Department of Veterans Affairs Medical Center, Christian Brothers University, Memphis, Tennessee, USA E-mail: aslominski@uthsc.edu

Investigation of selected cytokine genes suggests that IL2RA and the TNF/LTA locus are risk factors for severe alopecia areata.

Background  Alopecia areata (AA) is the second most common cause of hair loss in humans, and has a genetically complex inheritance. The hypothesis that AA is autoimmune in nature is supported by previous studies. These report an association with specific HLA alleles, as well as genetic variants of other genes implicated in autoimmunity, such as various cytokine genes. However, these cannot yet be considered proven susceptibility loci, as many of these association findings were derived from small patient samples.

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.

Abstract:  Female pattern hair loss (FPHL) is a common disorder with a complex mode of inheritance. Although understanding of its etiopathogenesis is incomplete, an interaction between genetic and hormonal factors is assumed to be important. The involvement of an androgen‐dependent pathway and sex steroid hormones is the most likely hypothesis. We therefore selected a total of 21 variants from the steroid‐5‐alpha‐reductase isoforms SRD5A1 and SRD5A2, the sex steroid hormone receptors ESR1, ESR2 (oestrogen receptor) and PGR (progesterone receptor) and genotyped these in a case–control sample of 198 patients (145 UK; 53 German patients) and 329 controls (179 UK; 150 German). None of these variants showed any significant association, either in the overall UK and German samples or in the subgroup analyses. In summary, the present results, while based on a limited selection of gene variants, do not point to the involvement of SRD5A1, SRD5A2, ESR1, ESR2 or PGR in FPHL.

Investigation of six novel susceptibility loci for male androgenetic alopecia in women with female pattern hair loss

Androgenetic alopecia is the most frequent hair loss disorder in both sexes, termed male-pattern baldness (AGA) in men, and female pattern hair loss (FPHL) in women. The aetiopathogenesis of FPHL is poorly understood; however, reports of familial cases and the occurrence of both FPHL and AGA in some families point to genetic factors and a shared genetic background [1,2]. The likely hypothesis of shared common disease-causing mechanisms is further supported by the presence of elevated androgen levels and male pattern hair loss in some affected women, and the identical histology of FPHL and AGA [3,4]. Our own recent findings could not demonstrate involvement of the well-established AGA susceptibility locus on chromosome 20p11 in FPHL, but suggested that the major AGA locus, the X-chromosomal locus containing the androgen receptor (AR) and the ectodysplasin A2 receptor (EDA2R) genes, may be specifically involved in the pathogenesis of earlyonset FPHL [5]. This finding underpins the assumption of shared susceptibility loci in FPHL and AGA. Recently, a large-scale meta-analysis of seven genome-wide association studies (GWAS) of males with early-onset AGA was published [6]. Genome-wide significance was obtained for six

Investigation of variants of the aromatase gene (CYP19A1) in female pattern hair loss

alterations in melanoma. N Engl J Med 2005; 353:2135–47. 4 Husain EA, Mein C, Pozo L et al. Heterogeneous topographic profiles of kinetic and cell cycle regulator microsatellites in atypical (dysplastic) melanocytic nevi. Mod Pathol 2011; 24:471–86. 5 Lee JH, Choi JW, Kim YS. Frequencies of BRAF and NRAS mutations are different in histological types and sites of origin of cutaneous melanoma: a meta-analysis. Br J Dermatol 2011; 164:776–84. 6 Guo Y, Feng Y, Trivedi NS, Huang S. Medusa structure of the gene regulatory network: dominance of transcription factors in cancer subtype classification. Exp Biol Med (Maywood) 2011; 236:628–36. 7 Diaz-Cano SJ. General morphological and biological features of neoplasms: integration of molecular findings. Histopathology 2008; 53:1–19. 8 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144:646–74.