Objective monitoring tools for improved management of childhood asthma.

Asthma is a common chronic disease amongst children. Epidemiological studies showed that the mortality rate of asthma in children is still high worldwide. Asthma control is therefore essential to minimize asthma exacerbations, which can be fatal if the condition is poorly controlled. Frequent monitoring could help to detect asthma progression and ensure treatment effectiveness. Although subjective asthma monitoring tools are available, the results vary as they rely on patients' self-perception. Emerging evidence suggests several objective tools could have the potential for monitoring purposes. However, there is no consensus to standardise the use of objective monitoring tools. In this review, we start with the prevalence and severity of childhood asthma worldwide. Then, we detail the latest available objective monitoring tools, focusing on their effectiveness in paediatric asthma management. Publications of spirometry, fractional exhaled nitric oxide (FeNO), hyperresponsiveness tests and electronic monitoring devices (EMDs) between 2016 and 2023 were included. The potential advantages and limitations of each tool were also discussed. Overall, this review provides a summary for researchers dedicated to further improving objective paediatric asthma monitoring and provides insights for clinicians to incorporate different objective monitoring tools in clinical practices.

Bacteriophage endolysins against gram-positive bacteria, an overview on the clinical development and recent advances on the delivery and formulation strategies.

Facing the increasing threat of multi-drug antimicrobial resistance (AMR), humans strive to search for antibiotic drug candidates and antibacterial alternatives from all possible places, from soils in remote areas to deep in the sea. In this "gold rush for antibacterials," researchers turn to the natural enemy of bacterial cells, bacteriophage (phages), and find them a rich source of weapons for AMR bacteria. Endolysins (lysins), the enzymes phages use to break the bacterial cells from within, have been shown to be highly selective and efficient in killing their target bacteria from outside while maintaining a low occurrence of bacterial resistance. In this review, we start with the structures and mechanisms of action of lysins against Gram-positive (GM+) bacteria. The developmental history of lysins is also outlined. Then, we detail the latest preclinical and clinical research on their safety and efficacy against GM+ bacteria, focusing on the formulation strategies of these enzymes. Finally, the challenges and potential hurdles are discussed. Notwithstanding these limitations, the trends in development indicate that the first, approved lysin drugs will be available soon in the near future. Overall, this review presents a timely summary of the current progress on lysins as antibacterial enzymes for AMR GM+ bacteria, and provides a guidebook for biomaterial researchers who are dedicating themselves to the battle against bacterial infections.

Vulnerability and resilience in children during the COVID-19 pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is having a profound impact on the health and development of children worldwide. There is limited evidence on the impact of COVID-19 and its related school closures and disease-containment measures on the psychosocial wellbeing of children; little research has been done on the characteristics of vulnerable groups and factors that promote resilience. METHODS: We conducted a large-scale cross-sectional population study of Hong Kong families with children aged 2-12 years. Parents completed an online survey on family demographics, child psychosocial wellbeing, functioning and lifestyle habits, parent-child interactions, and parental stress during school closures due to COVID-19. We used simple and multiple linear regression analyses to explore factors associated with child psychosocial problems and parental stress during the pandemic. RESULTS: The study included 29,202 individual families; of which 12,163 had children aged 2-5 years and 17,029 had children aged 6-12 years. The risk of child psychosocial problems was higher in children with special educational needs, and/or acute or chronic disease, mothers with mental illness, single-parent families, and low-income families. Delayed bedtime and/or inadequate sleep or exercise duration, extended use of electronic devices were associated with significantly higher parental stress and more psychosocial problems among pre-schoolers. CONCLUSIONS: This study identifies vulnerable groups of children and highlights the importance of strengthening family coherence, adequate sleep and exercise, and responsible use of electronic devices in promoting psychosocial wellbeing during the COVID-19 pandemic.

Skin prick testing a better predictor than blood testing for the diagnosis of peanut allergy in Chinese children.

BACKGROUND: Peanut allergy is common in Chinese children, yet the most predictive diagnostic cut-offs for skin prick test (SPT) and blood testing in this population are unclear. OBJECTIVES: We aimed to determine the optimal cut-off values for whole-peanut SPT, specific IgE (sIgE) and component-resolved diagnostics (CRD) for Chinese children based on outcomes of open oral food challenges (OFC) to peanut. METHODS: We recruited ethnic-Chinese patients 1-18 years old who were suspected of having peanut allergy based on a history of reactions after exposure or sensitization although peanut naïve. Considering the AUC value of 0.8, 80% power and 5% level of significance with two tails, 26 patients were needed. Sensitivities, specificities, positive and negative predictive values, and receiver operating characteristic curves (ROCs) and their area-under-curves (AUCs) for SPT, peanut sIgE, and CRD were compared. RESULTS: Thirty-one subjects participated. Only SPT reached statistical significance (AUC 0.91, p = 0.0001), but not the other tests. Seven retrospective data were added to optimize the power. SPT remained to be the best predictor, followed by Ara h 2 sIgE (AUC 0.72, p = 0.02). An SPT wheal size of 3 mm and Ara h 2 sIgE of 0.14 kU(A)/L yielded the highest Youden's index. The specificity of SPT and Ara h 2 sIgE reached 94% at 6 mm and 0.74 kU(A)/L, respectively. Comparisons of ROCs revealed that SPT was significantly better than Ara h 2 sIgE (p = 0.03) and whole-peanut sIgE (AUC 0.61, p = 0.26). CONCLUSION: In Chinese children, SPT appeared to be the best predictor for peanut allergy, followed by Ara h 2 sIgE.

A Comparison Between Chinese Children Infected with Coronavirus Disease-2019 and with Severe Acute Respiratory Syndrome 2003.

OBJECTIVES: To compare the clinical and laboratory features of severe acute respiratory syndrome 2003 (SARS) and coronavirus disease 2019 (COVID-19) in 2 Chinese pediatric cohorts, given that the causative pathogens and are biologically similar. STUDY DESIGN: This is a cross-sectional study reviewing pediatric patients with SARS (n = 43) and COVID-19 (n = 244) who were admitted to the Princess Margaret Hospital in Hong Kong and Wuhan Children's Hospital in Wuhan, respectively. Demographics, hospital length of stay, and clinical and laboratory features were compared. RESULTS: Overall, 97.7% of patients with SARS and 85.2% of patients with COVID-19 had epidemiologic associations with known cases. Significantly more patients with SARS developed fever, chills, myalgia, malaise, coryza, sore throat, sputum production, nausea, headache, and dizziness than patients with COVID-19. No patients with SARS were asymptomatic at the time of admission, whereas 29.1% and 20.9% of patients with COVID-19 were asymptomatic on admission and throughout their hospital stay, respectively. More patients with SARS required oxygen supplementation than patients with COVID-19 (18.6 vs 4.7%; P = .004). Only 1.6% of patients with COVID-19 and 2.3% of patients with SARS required mechanical ventilation. Leukopenia (37.2% vs 18.6%; P = .008), lymphopenia (95.4% vs 32.6%; P < .01), and thrombocytopenia (41.9% vs 3.8%; P < .001) were significantly more common in patients with SARS than in patients with COVID-19. The duration between positive and negative nasopharyngeal aspirate and the length in hospital stay were similar in patients with COVID-19, regardless of whether they were asymptomatic or symptomatic, suggesting a similar duration of viral shedding. CONCLUSIONS: Children with COVID-19 were less symptomatic and had more favorable hematologic findings than children with SARS.

Risk factors for drug allergies in Chinese children.

BACKGROUND: Drug allergy, or drug hypersensitivity, is a potentially fatal disorder, and patients labeled with drug allergies have restricted access to first-line treatments. Full knowledge of the characteristics associated with drug allergies and severe reactions during allergy evaluation is beneficial for appropriate risk stratification. OBJECTIVE: We sought to determine whether certain clinical characteristics are associated with drug allergies in Chinese children. METHODS: Charts were reviewed for ethnic Chinese patients less than 18 years old referred to our tertiary allergy center for suspected drug allergies and completed skin and drug provocative testing between 2005 to 2017. Univariate and multivariate analyses were performed on the age of onset of drug allergies, gender, and other atopy versus drug allergies. RESULTS: Out of 75 children, 18 (24%) had IgE-mediated drug allergies, while 8 (10.7%) had delayed drug hypersensitivities, with a cumulative 26 subjects (34.7%) with any drug hypersensitivity. There were positive independent associations between drug hypersensitivities onset age vs IgE-mediated drug allergies (odds ratio (OR) = 14.9, 95% confidence intervals (CIs) = 1.5-148.3, P = 0.017) and between male gender and IgE-mediated drug allergies (OR = 4.4, CIs = 1.2-16.4, P = 0.019). Age 13 years was the best cut-off for IgE-mediated drug allergies according to the receiver operating characteristic curve (P = 0.026). Older age group (OR = 24.0, CIs = 1.4-417.8, P = 0.024) and atopic dermatitis (OR = 8.2, CIs = 1.4-49.8, P = 0.015) were correlated with delayed drug hypersensitivities. CONCLUSIONS: While several previous studies suggested a higher prevalence of IgE-mediated drug allergies in younger adult females, older boys were more likely to have drug allergies for Chinese children.

Myocardial oedema in an 8-year-old Chinese boy with Idiopathic systemic capillary leak syndrome.

BACKGROUND: Idiopathic systemic capillary leak syndrome (ISCLS) is rare, and there has been about 32 cases reported in children worldwide since this disorder was first described in 1960. Clinical guidelines on the management approach stemming from robust scientific evidence are lacking. This case report presents the first reported paediatric case of severe ISCLS with significant myocardial oedema and emphasizes this disease's impact on a child's cardiac function. CASE PRESENTATION: A Chinese boy had his first attack of severe hypovolaemic shock that responded to fluid resuscitation when he was 6 years of age. His second attack developed at 8 years of age. He was then transferred to our cardiac unit for refractory hypotensive shock. The patient's echocardiogram revealed ventricular wall thickening with significant cardiac dysfunction requiring extracorporeal membrane oxygenation support. Subsequently, he made a full recovery, including his myocardial wall thickness and function. The echocardiographic findings suggested myocardial oedema that was transient in nature. Clinical and laboratory investigation from both episodes were compatible with ISCLS. CONCLUSION: ISCLS is rare, and therefore there is only a limited understanding on the pathophysiology of this disorder. The current treatment approach is based on a few case reports and series. During the acute phase, optimal supportive management is paramount. Our case highlights the importance of early recognition and consideration for extracorporeal membrane oxygenation support in patients with a life-threatening presentation, as it was lifesaving for this child who suffered myocardial oedema and ventricular dysfunction.

Cross-reactivity pattern of a rare presentation of generalized delayed-type hypersensitivity to local anaesthetics.

A seven-year-old girl developed angioedema and a generalized, erythematous rash several hours after receiving lignocaine with adrenaline reproducible on provocative challenge, confirming the first known case of generalized delayed-type hypersensitivity to local anaesthetics with cross-reactivity to bupivacaine but not chloroprocaine.

The unmet provision of allergy services in Hong Kong impairs capability for allergy prevention-implications for the Asia Pacific region.

INTRODUCTION: There is a high and rising prevalence of many allergic diseases in the Asia Pacific, including Hong Kong (HK), which is unmatched by a commensurate provision of clinical allergy services. METHOD: This review highlights progress and deficiencies in allergy service and training in HK. The allergy work force was estimated from the numbers of doctors practicing allergy registered with the HK Medical Council Specialist Register in Immunology and Allergy; Paediatric Immunology and Infectious Diseases (includes allergy); Paediatrics; and Immunology (as a discipline of Pathology). The numbers of trainees were estimated from the trainee lists of the Hong Kong Colleges of Physicians, Paediatrics and Pathology. The numbers of allergy clinics were estimated from existing services in Hospital Authority public hospitals in HK. RESULTS: In the last 3 years, two new drug allergy clinics have been established in public hospitals, and for the first time in 20 years, Hong Kong has a trainee in adult allergy. The current ratio of allergists per head of population has improved slightly from 1:1.46 million in 2014 to 1:1.17 million, but it is still low compared to many countries. There are 5-fold more paediatric allergists than adult allergists per head of population in HK. DISCUSSION: Hong Kong is not equipped to take advantage of major public health advances in allergy prevention. If the unbalance of adult to paediatric allergists remains uncorrected, continuing care for allergic children as they grow into adulthood will be an increasing problem. CONCLUSION: Hong Kong still has an unmet need for allergy specialists and is ill equipped to exploit recently discovered public health opportunities to prevent allergy. This review provides recommendations to improve allergy service provision and training, including the creation of Centres of Excellence in allergy to drive the growth of the specialty.

Meta-analysis of GWAS on two Chinese populations followed by replication identifies novel genetic variants on the X chromosome associated with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that affects mainly females. What role the X chromosome plays in the disease has always been an intriguing question. In this study, we examined the genetic variants on the X chromosome through meta-analysis of two genome-wide association studies (GWAS) on SLE on Chinese Han populations. Prominent association signals from the meta-analysis were replicated in 4 additional Asian cohorts, with a total of 5373 cases and 9166 matched controls. We identified a novel variant in PRPS2 on Xp22.3 as associated with SLE with genome-wide significance (rs7062536, OR = 0.84, P = 1.00E-08). Association of the L1CAM-MECP2 region with SLE was reported previously. In this study, we identified independent contributors in this region in NAA10 (rs2071128, OR = 0.81, P = 2.19E-13) and TMEM187 (rs17422, OR = 0.75, P = 1.47E-15), in addition to replicating the association from IRAK1-MECP2 region (rs1059702, OR = 0.71, P = 2.40E-18) in Asian cohorts. The X-linked susceptibility variants showed higher effect size in males than that in females, similar to results from a genome-wide survey of associated SNPs on the autosomes. These results suggest that susceptibility genes identified on the X chromosome, while contributing to disease predisposition, might not contribute significantly to the female predominance of this prototype autoimmune disease.

Three SNPs in chromosome 11q23.3 are independently associated with systemic lupus erythematosus in Asians.

Systemic lupus erythematosus (SLE) has a complex etiology and is affected by both genetic and environmental factors. Although more than 40 loci have shown robust association with SLE, the details of these loci, such as the independent contributors and the genes involved, are still unclear. In this study, we performed meta-analysis of two existing genome-wide association studies (GWASs) on Chinese Han populations from Hong Kong and Anhui, China, and followed the findings by further replication on three additional Chinese and Thailand cohorts with a total of 4254 cases and 6262 controls matched geographically and ethnically. We discovered multiple susceptibility variants for SLE in the 11q23.3 region, including variants in/near PHLDB1 (rs11603023, P(_combined) = 1.25E-08, OR = 1.20), DDX6 (rs638893, P(_combined) = 5.19E-07, OR = 1.22) and CXCR5 (rs10892301, P(_combined) = 2.51E-08, OR = 0.85). Genetic contributions from the newly identified variants were all independent of SNP rs4639966, whose association was reported from the previous GWAS. In addition, the three newly identified variants all showed independent association with the disease through modeling by both stepwise and conditional logistic regression. The presence of multiple independent variants in this region emphasizes its role in SLE susceptibility, and also hints the possibility that distinct biological mechanisms might be involved in the disease involving this genomic region.

Meta-analysis followed by replication identifies loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with systemic lupus erythematosus in Asians.

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic involvement and ethnic differences. Susceptibility genes identified so far only explain a small portion of the genetic heritability of SLE, suggesting that many more loci are yet to be uncovered for this disease. In this study, we performed a meta-analysis of genome-wide association studies on SLE in Chinese Han populations and followed up the findings by replication in four additional Asian cohorts with a total of 5,365 cases and 10,054 corresponding controls. We identified genetic variants in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with the disease. These findings point to potential roles of cell-cycle regulation, autophagy, and DNA demethylation in SLE pathogenesis. For the region involving TET3 and that involving CDKN1B, multiple independent SNPs were identified, highlighting a phenomenon that might partially explain the missing heritability of complex diseases.

Genome-wide search followed by replication reveals genetic interaction of CD80 and ALOX5AP associated with systemic lupus erythematosus in Asian populations.

OBJECTIVES: Genetic interaction has been considered as a hallmark of the genetic architecture of systemic lupus erythematosus (SLE). Based on two independent genome-wide association studies (GWAS) on Chinese populations, we performed a genome-wide search for genetic interactions contributing to SLE susceptibility. METHODS: The study involved a total of 1 659 cases and 3 398 controls in the discovery stage and 2 612 cases and 3 441 controls in three cohorts for replication. Logistic regression and multifactor dimensionality reduction were used to search for genetic interaction. RESULTS: Interaction of CD80 (rs2222631) and ALOX5AP (rs12876893) was found to be significantly associated with SLE (OR_int=1.16, P_int_all=7.7E-04 at false discovery rate<0.05). Single nuclear polymorphism rs2222631 was found associated with SLE with genome-wide significance (P_all=4.5E-08, OR=0.86) and is independent of rs6804441 in CD80, whose association was reported previously. Significant correlation was observed between expression of these two genes in healthy controls and SLE cases, together with differential expression of these genes between cases and controls, observed from individuals from the Hong Kong cohort. Genetic interactions between BLK (rs13277113) and DDX6 (rs4639966), and between TNFSF4 (rs844648) and PXK (rs6445975) were also observed in both GWAS data sets. CONCLUSIONS: Our study represents the first genome-wide evaluation of epistasis interactions on SLE and the findings suggest interactions and independent variants may help partially explain missing heritability for complex diseases.

Association of vitamin D-binding protein polymorphisms and serum 25(OH)D concentration varies among Chinese healthy infants of different VDR-FokI genotypes: A multi-centre cross-sectional study.

Hypovitaminosis D during infancy is associated with the development of chronic diseases and poor health later in life. While the effect of environmental factors on vitamin D concentration has been extensively explored, this study aimed to explore the effect of genetic factors on vitamin D concentration among Chinese infants. We conducted a multi-centre cross-sectional study in Hong Kong from July 2019 to May 2021. A candidate genetic approach was adopted to study four selected genetic variants of the vitamin D-binding protein (DBP) and vitamin D receptor (VDR) (rs4588, rs7041, rs2282679 and rs2228570) to examine their associations with measured serum 25(OH)D concentration. A total of 378 Chinese infants aged 2-12 months were recruited in this study. Peripheral blood samples were collected from the infants to measure serum 25(OH)D concentration and extract DNA. Results showed that rs7041T and rs2282679C were significantly associated with lower serum 25(OH)D concentration. Further analysis of the DBP variants revealed that the GC1F allele was significantly associated with lower 25(OH)D concentration and identified as the risk DBP isoform in infants. While our results revealed that there is no direct association between VDR-FokI genotype and serum 25(OH)D concentration, a VDR-FokI genotype-specific pattern was observed in the association between DBP isoforms and serum 25(OH)D concentration. Specifically, significant associations were observed in the DBP genotypes GC1F/F, GC1F/2 and GC1S/2 among VDR-FokI TT/TC carriers, but not in VDR-FokI CC carriers. Our findings lay down the basis for the potential of genetic screening to identify high risk of hypovitaminosis D in Chinese infants.

Real-World Sensitization and Tolerance Pattern to Seafood in Fish-Allergic Individuals.

BACKGROUND: Seafood is a common cause of food allergy and anaphylaxis, but there are limited published real-world data describing the clinical presentation of fish and shellfish allergies. OBJECTIVE: This study aimed to examine the clinical characteristics, immunological profile, and tolerance pattern to fish, crustaceans, and mollusks in fish-allergic individuals. METHODS: Patients presenting with IgE-mediated fish allergy between 2016 and 2021 were recruited. A comprehensive sensitization profile including specific IgE and skin prick test to various fish and shellfish species and a detailed clinical history including individuals' recent seafood consumption were evaluated. RESULTS: A total of 249 fish-allergic individuals (aged 4.2 ± 5.8 years) were recruited from 6 allergy clinics in Hong Kong, and they had experienced their fish-allergic reaction 2.2 ± 3.4 years before enrollment. Seventy-five subjects (30%) reacted to either grass carp, salmon, grouper, or cod in oral food challenges. We identified an IgE sensitization gradient that corresponded to the level of ß-parvalbumin in fish. In total, 40% of fish-allergic individuals reported tolerance to 1 or more types of fish, more commonly to fish with a lower ß-parvalbumin level such as tuna and salmon, compared with ß-parvalbumin-rich fish such as catfish and grass carp. Despite fish and shellfish cosensitization, 41% of individuals reported tolerance to crustaceans, mollusks, or both, whereas shellfish avoidance occurred in half of the fish-allergic individuals, of whom 33% lacked shellfish sensitization. CONCLUSIONS: Fish allergy commonly presents in early childhood. A considerable proportion of fish-allergic patients are selectively tolerant to certain fish, typically those with lower levels of ß-parvalbumin. There is an unmet need to promote precision medicine for seafood allergies.

ELF1 is associated with systemic lupus erythematosus in Asian populations.

Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong genetic involvement. The susceptibility genes identified so far can only explain a small proportion of disease heritability. Through a genome-wide association in a Hong Kong Chinese cohort and subsequent replication in two other Asian populations, with a total of 3164 patients and 4482 matched controls, we identified association of ELF1 (E74-like factor 1) with SLE (rs7329174, OR = 1.26, joint P= 1.47 × 10(-8)). ELF1 belongs to the ETS family of transcription factors and is known to be involved in T cell development and function. Database analysis revealed transcripts making use of three alternative exon1s for this gene. Near equivalent expression levels of distinct transcripts initiated from alternative exon1s were detected in peripheral blood mononuclear cells from both SLE patients and healthy controls. Although a direct association of rs7329174 with the three forms of transcripts for this gene was not detected, these findings support an important role of ELF1 in SLE susceptibility and suggest a potentially tight regulation for the expression of this gene.

Epistatic interaction between genetic variants in susceptibility gene ETS1 correlates with IL-17 levels in SLE patients.

T-helper cells that produce IL-17 (Th17 cells) are a subset of CD4(+) T-cells with pathological roles in autoimmune diseases including systemic lupus erythematosus (SLE), and ETS1 is a negative regulator of Th17 cell differentiation. Our previous work on genome-wide association study (GWAS) identified two variants in the ETS1 gene (rs10893872 and rs1128334) as being associated with SLE. However, like many other risk alleles for complex diseases, little is known on how these genetic variants might affect disease pathogenesis. In this study, we examined serum IL-17 levels from 283 SLE cases and observed a significant correlation between risk variants in ETS1 and serum IL-17 concentration in patients, which suggests a potential mechanistic link between these variants and the disease. Furthermore, we found that the two variants act synergistically in influencing IL-17 production, with evidence of significant genetic interaction between them as well as higher correlation between the haplotype formed by the risk alleles and IL-17 level in patient serum. In addition, the correlation between ETS1 variants and IL-17 level seems to be more significant in SLE patients manifesting renal involvement, dsDNA autoantibody production or early-onset.

Relationship between autoantibody clustering and clinical subsets in SLE: cluster and association analyses in Hong Kong Chinese.

OBJECTIVE: This study aims to identify the existence of, and relationship between autoantibody clusters and clinical subsets in Chinese SLE patients. METHODS: Data from 1928 SLE patients from Hong Kong were analysed. Using cluster analysis, patients were grouped by autoantibodies into clusters. The frequencies of various clinical manifestations were then compared between each cluster. Separate association analyses between individual autoantibodies and clinical manifestations as well as between clinical manifestations were also performed without any prior clustering. RESULTS: Three separate autoantibody clusters were identified, each with significantly different clinical manifestations. Cluster 1 was characterized by anti-dsDNA and the greatest prevalence of renal disorder but the lowest frequencies of other clinical manifestations. Cluster 2 was represented by the predominance of anti-Smith, anti-RNP and aPL, with greater prevalence of malar rash, oral ulcers, arthritis and serositis. Cluster 3 was characterized by anti-Ro and anti-La with greater prevalence of discoid rash, photosensitivity and haematological involvement. Individual association analysis also revealed similar findings. Patients of clusters 2 and 3 were more closely related, while cluster 1 was more distinct, associated with renal disorder only and negatively associated or not associated with other manifestations. CONCLUSION: We conclude that autoantibody clustering and clinical subsets exist in SLE patients of our locality. These clusters may be viewed as a bipolar spectrum of related autoantibody and clinical manifestations. At one end are patients with over-representation of anti-dsDNA and renal disorder, while at the other end are two distinct autoantibody clusters (anti-Sm/anti-RNP/aPL and anti-Ro/anti-La) with overlapping of other clinical manifestations.

Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus.

Systemic lupus erythematosus is a complex and potentially fatal autoimmune disease, characterized by autoantibody production and multi-organ damage. By a genome-wide association study (320 patients and 1,500 controls) and subsequent replication altogether involving a total of 3,300 Asian SLE patients from Hong Kong, Mainland China, and Thailand, as well as 4,200 ethnically and geographically matched controls, genetic variants in ETS1 and WDFY4 were found to be associated with SLE (ETS1: rs1128334, P = 2.33x10(-11), OR = 1.29; WDFY4: rs7097397, P = 8.15x10(-12), OR = 1.30). ETS1 encodes for a transcription factor known to be involved in a wide range of immune functions, including Th17 cell development and terminal differentiation of B lymphocytes. SNP rs1128334 is located in the 3'-UTR of ETS1, and allelic expression analysis from peripheral blood mononuclear cells showed significantly lower expression level from the risk allele. WDFY4 is a conserved protein with unknown function, but is predominantly expressed in primary and secondary immune tissues, and rs7097397 in WDFY4 changes an arginine residue to glutamine (R1816Q) in this protein. Our study also confirmed association of the HLA locus, STAT4, TNFSF4, BLK, BANK1, IRF5, and TNFAIP3 with SLE in Asians. These new genetic findings may help us to gain a better understanding of the disease and the functions of the genes involved.