Mitochondrial DNA genetic variants are associated with systemic lupus erythematosus susceptibility, glucocorticoids efficacy and prognosis.

OBJECTIVE: To investigate the associations of mitochondrial DNA (mtDNA) genetic variants with SLE susceptibility, glucocorticoid (GC) efficacy and prognosis. METHODS: Our study was done in two stages. First, we performed whole mitochondrial genome sequencing in 100 patients and 100 controls to initially screen potential mtDNA variants associated with disease and GC efficacy. Then, we validated the results in an independent set of samples. In total, 605 SLE patients and 604 normal controls were included in our two-stage study. A two-stage efficacy study was conducted in 512 patients treated with GCs for 12 weeks. We also explored the association between mtDNA variants and SLE prognosis. RESULTS: In the combined sample, four mtDNA variants (A4833G, T5108C, G14569A, CA514-515-) were associated with SLE susceptibility (all PBH < 0.05). We confirmed that T16362C was related to efficacy of GCs (PBH = 0.014). Significant associations were detected between T16362C and T16519C and the efficacy of GCs in females with SLE (PBH < 0.05). In the prognosis study, variants A4833G (PBH = 0.003) and G14569A (PBH = 9.744 × 10-4) substantially increased SLE relapse risk. Female patients harbouring variants T5108C and T16362C were more prone to relapse (PBH < 0.05). Haplotype analysis showed that haplogroup G was linked with SLE susceptibility (PBH = 0.001) and prognosis (PBH = 0.013). Moreover, mtDNA variant-environment interactions were observed. CONCLUSION: We identified novel mtDNA genetic variants that were associated with SLE susceptibility, GC efficacy, and prognosis. Interactions between mtDNA variants and environmental factors were related to SLE risk and GC efficacy. Our findings provide important information for future understanding of the occurrence and development of SLE.

Hsp70 Gene Polymorphisms Are Associated With Disease Susceptibility and HRQOL Improvement in Chinese Han Population With Systemic Lupus Erythematosus.

OBJECTIVES: The aim of this study is to investigate whether heat shock protein 70 (Hsp70) gene polymorphisms are implicated in systemic lupus erythematous (SLE) susceptibility, the efficacy of glucocorticoids (GCs) treatment, and improvement of health-related quality of life. METHODS: A total of 499 SLE patients and 499 controls were included in a case-control study, and 468 SLE patients treated with GCs for 12 weeks were involved in a follow-up study. Patients who completed the 12-week follow-up were divided into GCs-sensitive and GCs-insensitive group by using the SLE disease activity index. The SF-36 was used to evaluate the health-related quality of life of SLE patients, and genotyping was performed by improved multiplex ligation detection reaction. RESULTS: rs2075800 was associated with SLE susceptibility (adjusted odds ratio [ORadj], 1.437; 95% confidence interval [CI], 1.113-1.855; Padj = 0.005; PBH = 0.020 by dominant model; ORadj, 1.602; 95% CI, 1.072-2.395; Padj = 0.022; PBH = 0.029 by TT vs CC model; ORadj = 1.396; 95% CI = 1.067-1.826; Padj = 0.015; PBH = 0.029 by TC vs CC model). In the follow-up study, rs2075799 was associated with the improvement in mental health (p = 0.004, PBH = 0.044), but we failed to find any association between the efficacy of GCs and Hsp70 gene polymorphisms. CONCLUSIONS: Hsp70 gene polymorphisms may be associated with susceptibility to SLE and improvement of mental health in Chinese Han population.

Associations of FKBP4 and FKBP5 gene polymorphisms with disease susceptibility, glucocorticoid efficacy, anxiety, depression, and health-related quality of life in systemic lupus erythematosus patients.

OBJECTIVES: To explore the associations of FKBP4 and FKBP5 gene polymorphisms with disease susceptibility, glucocorticoid (GC) efficacy, anxiety, depression, and health-related quality of life (HRQOL) in systemic lupus erythematosus (SLE) patients. METHODS: All subjects were collected from the First and the Second Affiliated Hospital of Anhui Medical University in Hefei, China, during 2011 to 2015. In the case-control study, 541 SLE patients and 543 controls were recruited. In the follow-up study, 466 patients completed the 12-week follow-up and then were divided into GC-sensitive and GC-insensitive groups. Genotyping was determined using Multiplex SNaPshot technique. Data were analyzed using chi-square test and univariate and multivariate logistic regression analyses. RESULTS: rs4713904, rs9368878, and rs7757037 of FKBP5 were associated with depression in SLE patients (rs4713904, PBH = 0.037; rs9368878, PBH = 0.001; rs7757037, PBH = 0.003). Moreover, rs4713904 was associated with GC efficacy in males with SLE (PBH = 0.011). The rs755658 of FKBP5 was associated with improvement in social function (PBH = 0.022) and mental component summary (PBH = 0.028). The rs4713907 of FKBP5 was related to improvement in total score of SF-36, bodily pain, and mental component summary score (all PBH = 0.018). Furthermore, the rs12582595 of FKBP4 was correlated with general health improvement (PBH = 0.033). No associations were seen between FKBP4/FKBP5 gene polymorphisms and SLE susceptibility and anxiety. CONCLUSIONS: FKBP5 gene polymorphisms may be associated with depression and GC efficacy of SLE patients. Meanwhile, the genetic polymorphisms of FKBP4 and FKBP5 genes may be associated with HRQOL improvement in SLE patients. Key Points • FKBP5 gene polymorphisms were associated with depression of SLE patients. • FKBP5 gene polymorphisms were associated with GC efficacy of SLE patients. • FKBP5 gene polymorphisms were associated with HRQOL improvement in SLE patients. • FKBP4 gene polymorphisms were associated with HRQOL improvement in SLE patients.

Photodynamic therapy for port-wine stains in extremities: Report of 4 cases.

OBJECTIVES: To observe the clinical efficacy of photodynamic therapy mediated by hemoporfin (HMME-PDT) for port-wine stains (PWS) on extremities and explore its possible influencing factors. METHODS: Four patients with PWS in extremities were treated by HMME-PDT, and patients with negative results in the skin test were given an intravenous injection of 5 mg/kg of HMME. The patients were irradiated with 532 nm LED green light, and immediately applied cold compress after treatment. These patients were informed to stay away from light for two weeks. A follow-up every 2 weeks was conducted with treatment for 2 or 3 times in total. After the end of treatment, a follow-up was carried out for 6-12 months and the efficacy and safety were evaluated. RESULT: Three of the four patients were considered cured, and the treatment was ineffective for one patient. During the follow-up observation, all patients had different degrees of edema, and there were no signs of chromatosis or scarring. CONCLUSION: PDT treatment for patients with extremity PWS demonstrate high efficiency and safety, without obvious adverse reactions and recurrence.

Associations of HSP90AA2 gene polymorphisms with disease susceptibility, glucocorticoids efficacy and health-related quality of life in Chinese systemic lupus erythematosus patients.

Although the current glucocorticoids (GCs) treatment for systemic lupus erythematosus (SLE) is effective to a certain extent, the difference in therapeutic effect between patients is still a widespread problem. Some patients can have repeated attacks that greatly diminish their quality of life. This study was conducted to investigate the relationship between HSP90AA2 polymorphisms and disease susceptibility, GCs efficacy and health-related quality of life (HRQoL) in Chinese SLE patients. A case-control study was performed in 470 SLE patients and 470 normal controls. Then, 444 patients in the case group were followed up for 12 weeks to observe efficacy of GCs and improvement of HRQoL. Two single nucleotide polymorphisms (SNPs) of HSP90AA2 were selected for genotyping: rs1826330 and rs6484340. HRQoL was assessed using the SF-36 questionnaire. The minor T allele of rs1826330 and the TT haplotype formed by rs1826330 and rs6484340 showed associations with decreased SLE risk (T allele: PBH = 0.022; TT haplotype: PBH = 0.033). A significant association between rs6484340 and improvement of HRQoL was revealed in the follow-up study. Five subscales of SF-36 were appeared to be influenced by rs6484340: total score of SF-36 (additive model: PBH = 0.026), physical function (additive model: PBH = 0.026), role-physical (recessive model: PBH = 0.041), mental health (dominant model: PBH = 0.047), and physical component summary (additive model: PBH = 0.026). No statistical significance was found between HSP90AA2 gene polymorphisms and GCs efficacy. These results revealed a genetic association between HSP90AA2 and SLE. Remarkably, HSP90AA2 has an impact on the improvement of HRQoL in Chinese population with SLE.

Association of HSP90B1 genetic polymorphisms with efficacy of glucocorticoids and improvement of HRQoL in systemic lupus erythematosus patients from Anhui Province.

Objective: The aim of this study was to investigate the associations between HSP90B1 gene polymorphisms and the efficacy of glucocorticoids (GCs) and the improvement of health-related quality of life (HRQoL) in Anhui patients with systemic lupus erythematosus (SLE). Method: A total of 305 patients with SLE were recruited to the study. These patients were treated with GCs for 12 weeks and classified into two groups (sensitivity and insensitivity) according to the response to GCs measured by the scores on SLE disease activity index (SLEDAI). The HRQoL of SLE patients were evaluated by 36-item Short Form Health Survey (SF-36) at baseline and 12 weeks respectively. HapMap database and Haploview software were used to select HSP90B1 gene tag single nucleotide polymorphisms (SNPs). Benjamini & Hochberg (BH) method based on false discovery rate (FDR) was used for multiple testing correction. Results: A total of 291 patients were included in final data analysis with 14 patients excluded due to loss to follow-up. Among these patients, 160 patients were sensitive to GCs and 131 patients were insensitive to GCs. Twelve tag SNPs of HSP90B1 gene were selected. The rs12426382 polymorphism was associated with the efficacy of GCs (dominant model: crude OR=0.514, 95% CI=0.321-0.824, P=0.006; adjusted OR=0.513, 95% CI=0.317-0.831, P=0.007). After BH correction, there was no association between rs12426382 polymorphism and efficacy of GCs (PBH =0.084). In haplotype analysis, the haplotype CCCGAACATCCC (OR=2.273, 95% CI=1.248-4.139, P=0.006) and CTGGGACGTTC (OR=0.436, 95% CI=0.208-0.916, P=0.025) showed significant associations with the efficacy of GCs. After corrected by BH method, CCCGAACATCCC was still associated with the efficacy of GCs (PBH =0.048). The rs3794241, rs1165681, rs2722188, rs3794240 and rs10861147 polymorphisms were associated with the improvement of HRQoL among SLE patients (P < 0.05). But no association existed after the correction of BH method (P > 0.05). Conclusions: The results of this study demonstrated that HSP90B1 genetic polymorphisms might be associated with the efficacy of GCs, but not associated with the improvement of HRQoL in Anhui population with SLE.

Single nucleotide polymorphisms of HSP90AA1 gene influence response of SLE patients to glucocorticoids treatment.

Heat shock protein 90 (HSP90) is an important glucocorticoid receptor (GR) chaperone protein, and is supposed to be the key factor in regulating glucocorticoids (GCs) effects. The aim of the present study was to explore whether single nucleotide polymorphisms (SNPs) within HSP90AA1 gene affect the response of systemic lupus erythematosus (SLE) patients to GCs treatment. Two hundred and forty-five SLE patients were treated with GCs (prednisone) for 12 weeks. SLE disease activity index (SLEDAI) was used to assess the response of SLE patients to GCs treatment, and patients were classified into sensitive group and insensitive group. HapMap database and Haploview software were used to select tag SNPs. Tag SNPs were genotyped by using multiplex SNaPshot method. Univariate and multivariate logistic regression analyses were used to discriminate the impact of SNPs of HSP90AA1 gene on the response of SLE patients to GCs treatment. Two hundred and thirty three SLE patients finished the 12-week follow-up. Of these patients, 128 patients were included in sensitive group, and 105 patients were included in insensitive group. Seven tag SNPs were selected within HSP90AA1 gene. We detected significant associations for rs7160651 (dominant model: crude OR 0.514, 95 % CI 0.297-0.890, P = 0.018; adjusted OR 0.518, 95 % CI 0.293-0.916, P = 0.024), rs10873531 (dominant model: crude OR 0.516, 95 % CI 0.305-0.876, P = 0.014; adjusted OR 0.522, 95 % CI 0.304-0.898, P = 0.019) and rs2298877 (dominant model: crude OR 0.543, 95 % CI 0.317-0.928, P = 0.026, adjusted OR 0.558, 95 % CI 0.323-0.967, P = 0.037) polymorphisms, but not for other polymorphisms (P > 0.05). The present study demonstrates that HSP90AA1 gene SNPs may affect the response of SLE patients to GCs treatment.

Glucocorticoid receptor genetic polymorphisms is associated with improvement of health-related quality of life in Chinese population with systemic lupus erythematosus.

In our previous study, we found that glucocorticoid receptor (GR) gene genetic polymorphisms may play a major role in the efficacy of glucocorticoids (GCs) in Chinese systemic lupus erythematosus (SLE) patients. The aim of this study is to explore the association of GR gene genetic polymorphisms and improvement of health-related quality of life (HRQOL) in Chinese SLE patients treated with GCs. A total of 195 Chinese SLE patients were treated with GCs for 12 weeks. The HRQOL of patients was measured with the Medical Outcomes Study Short Form-36 (SF-36) at baseline and 12 weeks. Polymorphisms of GR gene were genotyped by using multiplex SNaPshot method. One hundred eighty-four patients (94.36 %) completed the 12-week follow-up. Twenty-three single-nucleotide polymorphisms of GR gene were genotyped. There was a significant association between rs10482672 polymorphism and improvement in physical function (P = 0.043), general health (P = 0.024), and social function (P = 0.013). The rs12656106 polymorphism was associated with improvement in the total score of SF-36 (P = 0.014), physical function (P = 0.013), general health (P = 0.010), vitality (P = 0.015), social function (P = 0.004), physical component summary (P = 0.016), and mental component summary (P = 0.014). The rs4912905 polymorphism was associated with improvement in bodily pain (P = 0.040) and general health (P = 0.038). The rs4912911 polymorphism was associated with improvement in general health (P = 0.026) and vitality (P = 0.027). The rs4986593 polymorphism was associated with improvement in bodily pain (P = 0.034). The rs7719514 polymorphism was associated with improvement in vitality (P = 0.002) and mental component summary (P = 0.041). We also found a significant association between rs9324924 polymorphism and improvement in physical function (P = 0.040), bodily pain (P = 0.007), and general health (P = 0.019). These results indicate that there may be an association of GR gene rs10482672, rs12656106, rs4912905, rs4912911, rs4986593, rs7719514, and rs9324924 polymorphisms with improvement of HRQOL in Chinese SLE patients treated with GCs.

Impact of environmental factors on efficacy of glucocorticoids in Chinese population with systemic lupus erythematosus.

Although glucocorticoids (GCs) are effective in inducing remission in systemic lupus erythematosus (SLE) patients, there is a significant variation in response to therapeutic GCs, and some patients do not achieve full remission. The aim of this study was to explore the impact of environmental factors on the efficacy of GCs in a Chinese population with SLE. This was a prospective cohort study, and a total of 260 SLE patients treated with GCs (prednisone) were followed up for 12 weeks. The efficacy of GCs was measured with the scores on SLE disease activity index. Environmental factors were collected using a questionnaire. Single-variable analysis and multivariate logistic regression analysis were used to discriminate the impact of environmental factors on the efficacy of GCs. Two hundred forty-seven patients (95.00 %) completed the 12-week follow-up. Among these patients, 131 (53.04 %) were classified into sensitive group and 116 (46.96 %) were classified into insensitive group. Results from logistic analysis showed that the following environmental factors were significantly associated with decreased efficacy of GCs: high salt intake (OR = 3.464, 95%CI = 1.481-8.102, P = 0.004), introverted personality (OR = 3.550, 95%CI = 1.901-6.628, P < 0.0001), experience with negative life events (OR = 5.526, 95%CI = 1.612-18.946, P = 0.007), and history of allergy (OR = 2.966, 95%CI = 1.312-6.704, P = 0.009). These results indicate that environmental factors, including salt intake, personality, experience with negative life events, and history of allergy, may play an important role in the efficacy of GCs in the Chinese population with SLE.

Association study of glucocorticoid receptor genetic polymorphisms with efficacy of glucocorticoids in systemic lupus erythematosus: a prospective cohort study.

The response to glucocorticoids (GCs) for patients with systemic lupus erythematosus (SLE) is characterized by wide interindividual variability, with a significant number of patients who have no response. We analyzed whether genetic polymorphisms within glucocorticoid receptor (GR) gene are related to variability in the efficacy of GCs in Chinese population with SLE. A cohort of 220 patients with SLE was studied. These patients were treated with GCs (prednisone) for 12 weeks. The efficacy of GCs was measured with the scores on SLE disease activity index (SLEDAI). Patients were classified into two groups (sensitive and insensitive) according to their response to GCs. Polymorphisms of GR gene were genotyped by using multiplex SNaPshot method. A total of 212 patients (96.4%) were included in the final data analyses. Of these patients, 110 patients were considered sensitive to GCs, and 102 patients were considered insensitive to GCs. Eighteen tag single nucleotide polymorphisms (SNPs) of GR gene were selected. Significant associations were seen for rs4912905 (dominant model: crude OR = 0.410, 95%CI = 0.233-0.722, p = 0.002; adjusted OR = 0.419, 95%CI = 0.233-0.754, p = 0.004), rs17100234 (dominant model: crude OR = 0.521, 95%CI = 0.282-0.963, p = 0.038; adjusted OR = 0.520, 95%CI = 0.279-0.970, p = 0.040) and rs7701443 (recessive model: crude OR = 2.736, 95%CI = 1.183-6.331, p = 0.019; adjusted OR = 2.639, 95%CI = 1.116-6.239, p = 0.027) in GR gene, but not for other polymorphisms (p > 0.05). The results of the present study suggest that GR genetic polymorphisms may play a major role in the efficacy of GCs in Chinese population with SLE.

Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis.

Disseminated superficial actinic porokeratosis (DSAP) is an autosomal dominantly inherited epidermal keratinization disorder whose etiology remains unclear. We performed exome sequencing in one unaffected and two affected individuals from a DSAP family. The mevalonate kinase gene (MVK) emerged as the only candidate gene located in previously defined linkage regions after filtering against existing SNP databases, eight HapMap exomes and 1000 Genomes Project data and taking into consideration the functional implications of the mutations. Sanger sequencing in 57 individuals with familial DSAP and 25 individuals with sporadic DSAP identified MVK mutations in 33% and 16% of these individuals (cases), respectively. All 14 MVK mutations identified in our study were absent in 676 individuals without DSAP. Our functional studies in cultured primary keratinocytes suggest that MVK has a role in regulating calcium-induced keratinocyte differentiation and could protect keratinocytes from apoptosis induced by type A ultraviolet radiation. Our results should help advance the understanding of DSAP pathogenesis.

Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus.

We performed a genome-wide association study (GWAS) of systemic lupus erythematosus (SLE) in a Chinese Han population by genotyping 1,047 cases and 1,205 controls using Illumina Human610-Quad BeadChips and replicating 78 SNPs in two additional cohorts (3,152 cases and 7,050 controls). We identified nine new susceptibility loci (ETS1, IKZF1, RASGRP3, SLC15A4, TNIP1, 7q11.23, 10q11.22, 11q23.3 and 16p11.2; 1.77 x 10(-25) < or = P(combined) < or = 2.77 x 10(-8)) and confirmed seven previously reported loci (BLK, IRF5, STAT4, TNFAIP3, TNFSF4, 6q21 and 22q11.21; 5.17 x 10(-42) < or = P(combined) < or = 5.18 x 10(-12)). Comparison with previous GWAS findings highlighted the genetic heterogeneity of SLE susceptibility between Chinese Han and European populations. This study not only advances our understanding of the genetic basis of SLE but also highlights the value of performing GWAS in diverse ancestral populations.

Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21.

We report the first large genome-wide association study (GWAS) in a Chinese population to identify susceptibility variants for psoriasis using a two-stage case-control design. In the first stage, we carried out a genome-wide association analysis in 1,139 cases and 1,132 controls of Chinese Han ancestry using Illumina Human 610-Quad BeadChips. In the second stage, we took top SNPs forward for replication in two independent samples of 5,182 cases and 6,516 controls of Chinese Han ancestry, and 539 cases and 824 controls of Chinese Uygur ancestry. In addition to the strong replication for two known susceptibility loci MHC (rs1265181, P = 1.93 x 10(-208), OR = 22.62) and IL12B (rs3213094, P(combined) = 2.58 x 10(-26), OR = 0.78), we identified a new susceptibility locus within the LCE gene cluster on 1q21 (rs4085613, P(combined) = 6.69 x 10(-30), OR = 0.76).

Holmium laser treatment of genital warts: an observational study of 1500 cases.

The treatment and relapse rate of genital warts are significant problems. The aim of this observational study was to assess the efficacy of holmium laser treatment of genital warts. A total of 1500 outpatients with genital human papillomavirus-induced lesions presenting from August 2002 to June 2005 were treated with holmium laser. The effects and side-effects of treatment were observed and analysed. Of this large cohort, lesions were excised at the first visit in 1488 cases. Twelve cases were treated a second or third time in the event that the lesions were too large to be removed at the first visit. The incidence of side-effects and complications after treatment with holmium laser was found to be low. Almost all warts can be excised at first treatment by holmium laser therapy with little bleeding during the treatment.