Baoqi Yang

Association analyses identify six new psoriasis susceptibility loci in the Chinese population

We extended our previous genome-wide association study for psoriasis with a multistage replication study including 8,312 individuals with psoriasis (cases) and 12,919 controls from China as well as 3,293 cases and 4,188 controls from Germany and the United States and 254 nuclear families from the United States. We identified six new susceptibility loci associated with psoriasis in the Chinese study containing the candidate genes ERAP1, PTTG1, CSMD1, GJB2, SERPINB8 and ZNF816A (combined P < 5 × 10−8) and replicated one locus, 5q33.1 (TNIP1-ANXA6), previously reported (combined P = 3.8 × 10−21) in the European studies. Two of these loci showed evidence for association in the German study at ZNF816A and GJB2 with P = 3.6 × 10−3 and P = 7.9 × 10−3, respectively. ERAP1 and ZNF816A were associated with type 1 (early onset) psoriasis in the Chinese Han population (test for heterogeneity P = 6.5 × 10−3 and P = 1.5 × 10−3, respectively). Comparisons with the results of previous GWAS of psoriasis highlight the heterogeneity of disease susceptibility between the Chinese and European populations. Our study identifies new genetic susceptibility factors and suggests new biological pathways in psoriasis.

A large-scale screen for coding variants predisposing to psoriasis.

To explore the contribution of functional coding variants to psoriasis, we analyzed nonsynonymous single-nucleotide variants (SNVs) across the genome by exome sequencing in 781 psoriasis cases and 676 controls and through follow-up validation in 1,326 candidate genes by targeted sequencing in 9,946 psoriasis cases and 9,906 controls from the Chinese population. We discovered two independent missense SNVs in IL23R and GJB2 of low frequency and five common missense SNVs in LCE3D, ERAP1, CARD14 and ZNF816A associated with psoriasis at genome-wide significance. Rare missense SNVs in FUT2 and TARBP1 were also observed with suggestive evidence of association. Single-variant and gene-based association analyses of nonsynonymous SNVs did not identify newly associated genes for psoriasis in the regions subjected to targeted resequencing. This suggests that coding variants in the 1,326 targeted genes contribute only a limited fraction of the overall genetic risk for psoriasis.

Genome-wide linkage, exome sequencing and functional analyses identify ABCB6 as the pathogenic gene of dyschromatosis universalis hereditaria

Background As a genetic disorder of abnormal pigmentation, the molecular basis of dyschromatosis universalis hereditaria (DUH) had remained unclear until recently when ABCB6 was reported as a causative gene of DUH. Methodology We performed genome-wide linkage scan using Illumina Human 660W-Quad BeadChip and exome sequencing analyses using Agilent SureSelect Human All Exon Kits in a multiplex Chinese DUH family to identify the pathogenic mutations and verified the candidate mutations using Sanger sequencing. Quantitative RT-PCR and Immunohistochemistry was performed to verify the expression of the pathogenic gene, Zebrafish was also used to confirm the functional role of ABCB6 in melanocytes and pigmentation. Results Genome-wide linkage (assuming autosomal dominant inheritance mode) and exome sequencing analyses identified ABCB6 as the disease candidate gene by discovering a coding mutation (c.1358C>T; p.Ala453Val) that co-segregates with the disease phenotype. Further mutation analysis of ABCB6 in four other DUH families and two sporadic cases by Sanger sequencing confirmed the mutation (c.1358C>T; p.Ala453Val) and discovered a second, co-segregating coding mutation (c.964A>C; p.Ser322Lys) in one of the four families. Both mutations were heterozygous in DUH patients and not present in the 1000 Genome Project and dbSNP database as well as 1,516 unrelated Chinese healthy controls. Expression analysis in human skin and mutagenesis interrogation in zebrafish confirmed the functional role of ABCB6 in melanocytes and pigmentation. Given the involvement of ABCB6 mutations in coloboma, we performed ophthalmological examination of the DUH carriers of ABCB6 mutations and found ocular abnormalities in them. Conclusion Our study has advanced our understanding of DUH pathogenesis and revealed the shared pathological mechanism between pigmentary DUH and ocular coloboma.

Dermatitis herpetiformis in China: a report of 22 cases.

Background  Although dermatitis herpetiformis (DH) is a relatively common disease in Caucasian populations, it is very rare in the Far East, including China.

Lack of association between the single nucleotide polymorphism of ST18 and pemphigus in Chinese population

(5.9%) in the LAMB3 gene are reported as recurrent mutations in Caucasian people, but these are absent in Japanese. p.Arg972* in LAMB3, as in our case, has been previously reported as a recurrent mutation in the worldwide population, but represents only 1.8% of the mutation database. In conclusion, we experienced a Japanese patient with Herlitz junctional EB who initially showed a few blisters on the limited area and identified a novel deletion mutation (c.647delA) in the LAMB3 gene. From his initial clinical features, at first, we suspected him of having dystrophic EB, but it was not until we examined antigen mapping that diagnosis of Herlitz junctional EB was confirmed. Therefore, we would emphasize the importance of antigen mapping study in all cases of EB, even if the initial lesion is mild.

Investigation of the predisposing factor of pemphigus and its clinical subtype through a genome-wide association and next generation sequence analysis

Pemphigus is an autoimmune blistering disease with pemphigus vulgaris (PV) and foliaceus (PF) as the two major histological subtypes. Associations with HLA molecules have been suggested, but specific HLA risk variants as well as non‐HLA risk variants remain to be discovered.

Oxcarbazepine-induced Stevens-Johnson syndrome in a patient withHLA-B*1502genotype

A 10-year-old boy with a 9-year history of epilepsy was admitted to our hospital with rashes and oral ulcers. He had been on treatment with sodium valproate since 2005. Due to inadequate epilepsy control, oxcarbazepine was started at a dose of 150 mg twice daily. Nine days later he developed fever (maximum 40.3°C) and 2 days later an erythematous rash. A physical examination revealed numerous flat, atypical target-like lesions with central dusky discoloration on the face, neck, trunk, limbs and scrotum (Fig. 1). Ocular involvement included bilateral conjunctivitis with eyelid oedema and ocular discharge (Fig. 1). There were ulcers on his oral mucosa (Fig. 1). Total body surface area involvement at the time of presentation was 7%. Stevens–Johnson syndrome (SJS) was diagnosed on clinical features. Genotyping showed the presence of a HLAB*15:02 allele. Other laboratory results were normal. The patient was treated with methylprednisolone 64 mg and azithromycin 500 mg daily. Cream containing urea was applied on both lips to ease pain. Tobramycin-dexamethasone eyedrops thrice daily were added to the above treatment. Following 15 days of treatment he had completely recovered. SJS, characterised by high fever, target-like lesions, mucosal involvement and variable internal organ involvement, is a severe cutaneous adverse drug reaction (ADR) that are potentially life threatening. This condition is associated with a rate of death of approximately 5%. Antiepileptic drugs, especially those with an aromatic structure, such as carbamazepine, oxcarbazepine and lamotrigine, are among the more common causes of cutaneous ADR. Strong associations between carbamazepineinduced SJS and HLA-B*15: 02 allele have been identified in Han Chinese populations. Although oxcarbazepine, due to its different metabolic pathway, is thought to be safer than carbamazepine, there are reports of oxcarbazepineinduced cutaneous ADR. 3,4 One study has demonstrated an association between HLA-B*15:02 and oxcarbazepineinduced cutaneous ADR in Chinese patients. In summary, we describe a case of oxcarbazepine-induced SJS in a Chinese boy with HLA-B*15:02 allele. In both Taiwan and Singapore screening for HLA-B*15:02 is mandatory prior to the initiation of carbamazepine. Perhaps HLA-B*15:02 screening should also be considered before starting oxcarbazepine.

Glucocorticoid receptor polymorphisms: Lack of association with glucocorticoid resistance among Chinese bullous disease patients.

ciation of psoriasis. We diagnosed the bullae as BP with IgG autoantibodies mainly reactive to LAD-1. IgG autoantibodies to the BP180-NC16a domain were not considered to contribute to form tense bullae essentially, because immunoblotting studies of the BP180-NC16a domain RP showed no positive reactivity. Immunoglobulin G autoantibodies from patients with BP can react to the RP of the BP180-NC16a domain, LAD-1 and/or the BP180 C-terminal domain. In most cases of BP, the BP180-NC16a domain is recognized initially and then the other region as an intramolecular epitope-spreading phenomenon, and BP230 as an intermolecular epitopespreading phenomenon. However, there are cases of BP with autoantibodies only reactive with the outside of the BP180-NC16a domain. We speculated that LAD-1 was initially recognized and the BP180-NC16a domain was secondarily recognized as an unusual inverse direction in this case. Further case series should be accumulated to confirm occurrence of the inverse intramolecular epitope-spreading phenomenon. CONFLICT OF INTEREST: None.