Polymorphisms in interleukin-15 gene on chromosome 4q31.2 are associated with psoriasis vulgaris in Chinese population.

Through a series of linkage analyses in a large Chinese family cohort of psoriasis, we previously identified and confirmed a non-HLA psoriasis linkage locus PSORS9 within a small region at 4q31.2-32.1. Within the critical region of the PSORS9 locus, IL-15 has been long recognized as a strong candidate gene for psoriasis. In this study, we investigated the association between IL-15 genetic polymorphisms and psoriasis in a large Chinese sample. Highly significant evidence for association was identified at a single-nucleotide polymorphism (SNP) (g.96516A --> T) within the 3'-untranslated region (UTR) of the IL-15 gene (P=0.00006, after correction for multiple testing). Haplotype analysis using the SNPs within the 3'UTR region also provided strong supporting evidence for association (P=0.00005), where we identified a haplotype of the 3'UTR region of IL-15 associated with increased risk to psoriasis (odds ratio=1.65). This association was also supported by the results of our expression activity analyses, where we demonstrated that the identified risk haplotype is associated with an increased activity of IL-15. Therefore, we provided early evidence for the important role of IL-15 genetic variants in the pathogenesis of psoriasis, probably by increasing interleukin production and inflammation in the lesions of psoriasis.

Evidence for a novel psoriasis susceptibility locus at 9q33-9q34 in Chinese Hans.

Psoriasis is a heterogeneous disease for which nine linkage loci (PSORS loci 1-5 and PSORS7-10) have been accepted by the Human Genome Nomenclature Committee and an additional 16 potential susceptibility loci have been reported so far. Our previous genome-wide scan in 61 Chinese Han psoriasis vulgaris families found two susceptibility loci at 6p21.3 and 4q31 and additional suggestive linkage evidence at other regions, including 9q33. In this follow-up study, the linkage evidence at 9q33 was further investigated using an expanded sample of 160 families and improved marker coverage. Our follow-up linkage analysis of the 160 families demonstrated strong linkage evidence (P < or = 0.000022) throughout a region between 133.38 and 146.23 cM with a maximum nonparametric linkage (NPL) score of 4.64 (P = 0.00000023) and a heterogeneity LOD (HLOD) score of 5.03 (alpha = 46%) at 142.39 cM near the marker D9S290. By stratifying the 160 families into the subtypes of 130 early-onset and 30 late-onset families, we revealed stronger linkage evidence in the early-onset psoriasis families with a maximum multipoint HLOD score of 6.48 (alpha = 58%) and a maximum NPL score of 4.69 (P = 0.00000012) near marker D9S290. Our follow-up study has confirmed a novel susceptibility locus at 9q33-34 for early-onset psoriasis in the Chinese population.

Follow-up analysis of PSORS9 in 151 Chinese families confirmed the linkage to 4q31-32 and refined the evidence to the families of early-onset psoriasis.

Psoriasis linkage to 4q28-32 (PSORS9) was initially identified by our genome-wide scan in 61 Chinese families and subsequently supported by a meta-analysis of five genome-wide linkage scans of European populations. In this study, we performed a follow-up analysis of PSORS9 using an additional 90 families and improved marker coverage. Joint analysis of all 151 families obtained significant linkage evidence (HLOD=4.53, nonparametric linkage (NPL)=4.03 (P=0.000003)) at the marker interval D4S2997-D4S3033, and the same was obtained for the analysis of the independent new families (HLOD=4.33, NPL=3.15 (P=0.00004)). The linkage evidences from the whole families and the new families exceeded the genome-wide criteria for significant linkage. Furthermore, by performing an ordered subset analysis using mean age at onset as a covariate, we demonstrated that evidence for linkage to PSORS9 is concentrated in the early-onset families and suggested that further study of PSORS9 should focus on early-onset patients. This finding is contradictory to what was found in the Icelandic population and, together with other linkage results, suggests that Chinese and European populations are genetically different for linkage to PSORS9, which may partially explain the influence of ethnic factors on the varying prevalence of psoriasis.

Systematic evaluation of association between the microsomal glutathione S-transferase 2 common variation and psoriasis vulgaris in Chinese population.

Several recent studies have demonstrated the possible involvement of the microsomal glutathione S-transferase 2 (MGST2) gene in the pathogenesis of psoriasis. The objectives of this work are to determine whether the genetic polymorphisms of the MGST2 gene were associated with an increased risk of psoriasis in Chinese patients. We first characterized the linkage disequilibrium pattern within MGST2 and identified single-nucleotide polymorphisms (SNPs) for tagging common genetic variants. Genotype- and haplotype-based analyses were then performed by genotyping the Tag SNPs in a large-scale sample of cases and controls. We characterized the linkage disequilibrium pattern within MGST2 using 12 densely distributed SNPs and identified 6 SNPs for tagging common genetic variants. We then performed an association analysis by genotyping the six SNPs in 552 cases and 384 controls, but none of the genotype- and haplotype-based analyses revealed significant evidence for association. We also performed family-based association analysis by genotyping the six SNPs in 95 trios; no evidence for association was identified. Our comprehensive genetic analysis of MGST2 common variants in a large Chinese sample of psoriasis did not provide any supporting evidence for MGST2 to be the susceptibility gene within the PSORS9 locus.

Inversa acne (hidradenitis suppurativa): a case report and identification of the locus at chromosome 1p21.1-1q25.3.

Acne inversa (hidradenitis suppurativa) is a chronic relapsing inflammatory skin disease characterized by recurrent draining sinuses and abscesses, predominantly in skin folds that carry terminal hairs and apocrine glands. The genetic basis for this disease is unknown. In this study, we performed a genome-wide scan in a four-generation Chinese family to map the chromosome location of the responsible gene. We first identified a locus at chromosome 1p21.1-1q25.3 with the maximum logarithm of odds (LOD) score of 3.26 at the marker D1S2624 (at recombination fraction=0.00). The other two-point LOD scores >/=3 were observed at markers D1S2695, D1S2726, D1S252, and D1S2777. Haplotype analysis localized this locus to a 76 Mb region flanked by D1S248 and D1S2711. This is the first locus for the inversa acne and will be a starting point towards understanding the molecular mechanisms of this disease.

The epidemiology of childhood alopecia areata in China: a study of 226 patients.

To study the clinical and epidemiologic profile of childhood alopecia areata, we performed a survey in which a total of 226 childhood patients less than 16 years old were enrolled. Statistical analysis and heritability were performed using EPI INFO 6.0, SPSS10.0, and the Falconer method. The median age of onset was 10 years. The majority of patients (84.96%) presented with limited alopecia. The male : female ratio was 1.4:1. Boys appeared to have more severe involvement. The earlier the age of onset, the greater the severity of the disease. Sixty-seven patients (29.65%) had previous episodes of alopecia areata. Greater severity and longer duration were seen in the relapsing patients than in the primary patients. Six patients (2.65%) had an associated disease. A positive family history was reported in 25 patients (11.06%). The prevalence figures for alopecia areata in first-, second-, and third-degree relatives of the probands were 2.87%, 0.40%, and 0.13%, respectively. The heritabilities of AA in first-, second-, and third-degree relatives were 51.20%, 46.25%, and 25.65%, respectively. It can be speculated that the effect of genetic factors is important in the occurrence of this disease.

A novel MGST2 non-synonymous mutation in a Chinese pedigree with psoriasis vulgaris.

A balanced translocation was recently identified in a German psoriasis patient. One of the breakpoints was mapped immediately upstream of the microsomal glutathione S-transferase 2 (MGST2) gene, suggesting it as a candidate gene. Here, we report the identification of a novel non-synonymous mutation in MGST2 by a comprehensive sequence analysis of MGST2's coding region in Chinese psoriasis samples. We demonstrate that this mutation co-segregated with the disease phenotype within a Chinese family affected with psoriasis vulgaris and is predicted to have an impact on the normal function of MGST2 protein. However, the mutation was absent in 551 additional cases and 384 healthy Chinese controls. While requiring independent confirmation, our results suggest that this rare mutation could play a causal role in a small subset of psoriasis individuals.

Association of HLA class I alleles with aloplecia areata in Chinese Hans.

BACKGROUND: Some studies suggested that human HLA status may potentiate development of the AA phenotype and exists ethic differences. No report has been published about HLA class I alleles associated with AA in Chinese Hans. OBJECTIVE: To study the distribution of HLA class I alleles and haplotypes in Chinese Hans AA patients and the relation of HLA class I profile with age of onset, severity, duration of current attack, past history and family history. METHODS: The polymerase chain reaction-sequence-specific primer (PCR-SSP) method was used to analyze the distribution of HLA class I alleles in 192 patients with AA and 252 healthy controls in Chinese Hans. RESULTS: The frequencies of HLA-A*02, -A*03, -B*18, -B*27, -B*52 and -Cw*0704 were significantly higher in patients than in controls. The A*2-B*18, A*2-B*27, A*2-B*52, A*2-Cw*0704, B*18-Cw*0704, B*27-Cw*0704, B*52-Cw*0704 were found as high-risk haplotypes in developing AA in this study. The HLA-A*02 and -A*03 were observed increased frequencies in patients less than 50% hair loss, and HLA-B*27 equally in patients of 50-99% hair loss, alopecia totalis and alopecia universalis. The frequencies of HLA-A*02 and -B*27 were significantly raised in recurrent patients, and ones of HLA-A*02, -A*03 and -B*27 similarly in patients without a positive family history. CONCLUSION: This study demonstrated the positive association of HLA class I alleles and haplotypes with AA. There may be differences in genetic background in patients with different age of onset, grade of scalp hair loss, duration of current attack, a past history and a family history.

Association of HLA-DQA1 and DQB1 alleles with alolpecia areata in Chinese Hans.

Accumulative evidences have shown that certain HLA loci are associated with alopecia areata (AA), but with existing differences in ethnic distribution. No report has ever been published about this in Chinese Hans. To investigate whether HLA-DQA1 and DQB1 alleles are associated with AA, and the correlation of the HLA profile with age of onset, severity, duration of current attack, recurrence and family history of AA in Chinese Hans. The polymerase chain reaction-sequence-specific primer (PCR-SSP) method was used to analyze the distribution of HLA-DQA1 and DQB1 alleles in 192 patients with AA and 273 healthy controls in Chinese Hans. The significant increased frequencies of HLA-DQA1*0104 (OR=3.38, P(c)<0.001), HLA-DQB1*0604 (OR=5.17, P(c)=0.006) and HLA-DQA1*0606 (OR=3.73, P(c)<0.001) were observed in patients compared with controls. The DQA1*0104-DQB1*0604, DQA1*0104-DQB1*0606, and DQA1*0302-DQB1*0606 were found as high-risk haplotypes in developing AA in this study. HLA-DQA1*0104 (OR=5.31, P(c)<0.001) and -DQB1*0604 (OR=5.56, P(c)=0.015) were more prevalent only in AA patients with long duration than controls. The frequencies of HLA-DQB1*0604 (OR=5.42, P(c)=0.009) and -DQB1*0606 (OR=4.11, P(c)<0.001) were obviously increased in patients less than 50% scalp hair loss. No locus was merely associated with early onset, severe involvement, recurrence and a positive family history of AA. This study demonstrated the positive association of HLA-DQA1 and DQB1 alleles and haplotypes with AA. There may be differences in genetic background in patients with different duration.

Identification of a novel locus for Marie Unna hereditary hypotrichosis to a 17.5 cM interval at 1p21.1-1q21.3.

Marie Unna hereditary hypotrichosis (MUHH) is a rare autosomal dominant disorder characterized by coarse, wiry, twisted hair developed in early childhood and followed by the development of alopecia. A locus for this disorder was localized to chromosome 8p, but no gene responsible for it has been identified. To map and determine whether MUHH is a genetically heterogeneous disorder and identify the disease gene locus in a four-generation Chinese family with MUHH. We performed a genome-wide scan in this family. Two-point linkage analysis was performed using Linkage programs version 5.10 software and haplotype was constructed with Cyrillic Version 2.02 software. We failed to confirm the previous locus for MUHH at chromosome 8p and obtained the conformed evidence for linkage at chromosome 1. Two-point logarithm of odds ratio scores > or =3 were observed at markers D1S2746 and D1S2881. Haplotype analysis localized this locus to a 42 Mb region. The previous results and this study have shown that MUHH is a genetically heterogeneous disorder. Our family was mapped to a 17.5 cM region between markers D1S248 and D1S2345.

A novel linkage to generalized vitiligo on 4q13-q21 identified in a genomewide linkage analysis of Chinese families.

Generalized vitiligo is a common, autoimmune, familial-clustering depigmentary disorder of the skin and hair that results from selective destruction of melanocytes. Generalized vitiligo is likely a heterogeneous disease, with five susceptibility loci reported so far--on chromosomes 1p31, 6p21, 7q, 8p, and 17p13--in white populations. To investigate vitiligo susceptibility loci in the Chinese population, we performed a genomewide linkage analysis in 57 multiplex Chinese families, each with at least two affected siblings, and we identified interesting linkage evidence on 1p36, 4q13-q21, 6p21-p22, 6q24-q25, 14q12-q13, and 22q12. Subsequently, to extract more linkage information, we investigated our initial genomewide linkage findings in a follow-up analysis of 49 new families and additional markers. Our initial genomewide linkage analysis and our subsequent follow-up analysis have identified a novel linkage to vitiligo on 4q13-q21, with highly significant linkage evidence (a nonparametic LOD score of 4.62 [P=.000003] and a heterogeneity LOD score of 4.01, under a recessive inheritance model), suggesting that 4q13-q21 likely harbors a major susceptibility locus for vitiligo in the Chinese population. We observed a minimal overlap between the linkage results of our current genomewide analysis in the Chinese population and the results of previous analyses in white populations, and we thus hypothesize that, as a polygenic disorder, vitiligo may be associated with great genetic heterogeneity and a substantial difference in its genetic basis between ethnic populations.

Identification of a novel mutation in the DSRAD gene in a Chinese pedigree with dyschromatosis symmetrica hereditaria.

Dyschromatosis symmetrica hereditaria (DSH) is an autosomal dominant skin disorder characterized by a mixture of hyperpigmented and hypopigmented macules distributed on the face and dorsal aspects of the extremities that appear in infancy or early childhood. The DSH locus has recently been mapped to chromosome 1q21 and then pathogenic mutations have been identified in the DSRAD gene. In the study reported here we examined the DSRAD gene mutations of a three-generation Chinese pedigree with DSH by direct sequencing. We identified a novel heterozygous nucleotide T-->C transition at position 3388 in exon 14 of the DSRAD gene which induces a C1130R change in the putative deaminase domain of DSRAD. Our study expands the database on the DSRAD gene mutations in DSH and enriches the knowledge about the function of the DSRAD gene.

Two frameshift mutations in the RNA-specific adenosine deaminase gene associated with dyschromatosis symmetrica hereditaria.

OBJECTIVE: To report and analyze the mutations of the double-stranded RNA-specific adenosine deaminase (DSRAD) gene in 2 Chinese pedigrees with dyschromatosis symmetrica hereditaria (DSH). DESIGN: Pedigree study. SETTING: Anhui province of China. PATIENTS: Two Chinese families, consisting of 19 individuals (family 1) and 5 individuals (family 2). INTERVENTIONS: We directly performed mutation detection of the DSRAD gene in 2 Chinese families with DSH by sequencing. The whole coding region of DSRAD was amplified by polymerase chain reaction, and products were analyzed by direct sequencing. MAIN OUTCOME MEASURES: Frameshift DSRAD gene mutations. RESULTS: The c.3513insC (Arg1171fs) mutation was found in all patients but not in the healthy individuals from family 1, and the c.3220_3224delGCATC (Gly1073fs) mutation was found in 2 patients but not in the healthy members of family 2. These 2 mutations were not found in 96 unrelated control individuals. CONCLUSION: Our data suggest that these 2 novel frameshift mutations in the DSRAD gene could cause DSH in the Chinese Han population and add new variants to the repertoire of DSRAD mutations in DSH.

Seven novel mutations of the ADAR gene in Chinese families and sporadic patients with dyschromatosis symmetrica hereditaria (DSH).

Dyschromatosis symmetrica hereditaria (DSH) is an autosomal dominant pigmentary genodermatosis characterized by hyperpigmented and hypopigmented macules of on the extremities and caused by the mutations in the ADAR gene(also called DSRAD) encoding for RNA-specific adenosine deaminase. Here we reported clinical and molecular findings of 6 Chinese multi-generation families and 2 sporadic patients with DSH. We found that the same mutation could lead to different phenotypes even in the same family and we did not establish a clear correlation between genotypes and phenotypes. Seven novel heterozygous mutations of ADAR were identified, which were c.2433_2434delAG (p.T811fs), c.2197G>T (p.E733X), c.3286C>T (p.R1096X), c.2897G>T (p.C966F), c.2797C>T (p.Q933X), c.2375delT (p.L792fs) and c.3203-2A>G respectively. Our data add new variants to the repertoire of ADAR mutations in DSH.