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Background: Acne vulgaris is classified based on the severity of skin lesions and post-healing scar types of these lesions. Numerous epidemiology studies have investigated the risk factors associated with acne presentation and severity, but studies for acne scarring are lacking. Objective: To investigate the prevalence of acne, severity, and scarring grades and their associated risk factors among Singapore Chinese. Methods: A total of 3,888 subjects (2,090 cases/1,798 controls; median age = 21 ± 4.589; range 17–71) completed an investigator-administered questionnaire as part of a cross-sectional study, which included sociodemographics, familial medical history, lifestyle factors, dietary habits, and acne history. Acne cases were further evaluated for their severity (n = 991) and scarring (n = 988) grades by a trained personnel. Results: The majority of the acne cases had mild acne/grade 1 scarring, while less than 1% had severe acne/grade 4 scarring. Parental acne was significantly associated with acne presentation and moderate/severe acne, while sibling acne was significantly associated with grade 3/4 scarring. Gender and age affected acne severity and scarring but not acne presentation, while tertiary maternal education level and the possession of ≥3 siblings were particularly associated with acne scarring. Underweight BMI was protective against acne presentation, while atopic diseases (asthma, allergic rhinitis, eczema) were its predisposing factors. Of the evaluated lifestyle factors, computer/TV usage had significant association with acne presentation, while alcohol consumption was significantly associated with acne severity. Frequent milk consumption was associated with a protective effect for moderate-severe acne, while frequent butter consumption had a detrimental effect on acne scarring extent. Conclusion: Positive familial history is a strong predisposing factor in determining acne presentation, severity, and scarring. Demographic factors (gender, age) and sedentary lifestyle (increased computer/TV usage) influence acne presentation, while dietary habits (milk and butter consumption) influence acne severity and scarring. The predisposing factors revealed in this study could help us to gain insights into acne pathophysiology and hence develop interventions especially targeting modifiable risk factors. [ABSTRACT FROM AUTHOR]

Background: Previous haplotype‐based association studies identified chromosome 4q21 as an allergic rhinitis (AR) susceptibility locus; however, the functional role of 4q21 single nucleotide polymorphisms (SNPs) on AR risk remains unclear. Objective: To investigate the functional effect of 4q21 SNPs on AR risk by conducting cohort‐based functional genomics and genetic association analyses. Methods: The associations between 4q21 SNPs and mRNA expression levels of three 4q21‐associated genes (SDAD1, NAAA and CXCL9) in peripheral blood mononuclear cells (PBMCs) were assessed in a Singapore/Malaysia Chinese cohort (n = 291). Exon expression levels of these genes in PBMCs were tested against the tag‐SNP genotypes in a Singapore Chinese cohort (n = 30). Serum protein levels of these genes were assessed with tag‐SNP genotypes in a Singapore Chinese cohort (n = 193). SNP functions were characterized through luciferase assay. In a Singapore Chinese cohort (n = 1794), we confirmed the associations between functional SNPs and AR. Results: Forty SNPs in 4q21 showed significant associations with NAAA (but not SDAD1 or CXCL9) mRNA expression in PBMCs, of which were tagged by two tag‐SNPs, rs17001237 and rs2242470. Both tag‐SNPs rs2242470 and rs12648687 (a proxy for rs17001237) were also significantly associated with the expression level of NAAA exon 1. Tag‐SNP rs12648687 was correlated with serum NAAA level. A four promoter SNPs‐haplotype tagged by rs17001237 influenced the NAAA promoter activity in HEK293T cells. Lastly, individuals carrying the risk allele A of rs12648687 exhibited significantly higher AR risk in the Singapore Chinese population. Conclusions & Clinical Relevance: The rs17001237 linkage set SNPs in the 4q21 locus are associated with NAAA expression at both gene and protein levels ex vivo, have functional consequences in vitro and contribute to AR susceptibility in our study population. Our findings provided a better understanding of the genetic mechanism that contributes to AR pathogenesis. [ABSTRACT FROM AUTHOR]

CTLA-4 polymorphisms in allergy and asthma and the TH1/ TH2 paradigm. Functional CTLA-4 variants associate to both allergic asthma and rhinitis potentially by modulating naïve regulatory T cells A genome-wide linkage study previously indicated the chromosome 2q region containing the cytotoxic T-lymphocyte protein 4 ( I CTLA-4 i ) gene might be a candidate asthma locus.1 However, prior reports of associations between I CTLA-4 i genetic variants and asthma are conflicting and inconclusive.2-4 This study aimed to determine the role of I CTLA-4 i single nucleotide polymorphisms (SNPs) on allergy risk by carrying out genetic association and functional analyses. [Extracted from the article]

Background: The polymorphism Arg16 in β2‐adrenergic receptor (ADRB2) gene has been associated with an increased risk of exacerbations in asthmatic children treated with long‐acting β2‐agonists (LABA). However, it remains unclear whether this increased risk is mainly attributed to this single variant or the combined effect of the haplotypes of polymorphisms at codons 16 and 27. Objective: We assessed whether the haplotype analysis could explain the association between the polymorphisms at codons 16 (Arg16Gly) and 27 (Gln27Glu) in ADRB2 and risk of asthma exacerbations in patients treated with inhaled corticosteroids (ICS) plus LABA. Methods: The study was undertaken using data from 10 independent studies (n = 5903) participating in the multi‐ethnic Pharmacogenomics in Childhood Asthma (PiCA) consortium. Asthma exacerbations were defined as asthma‐related use of oral corticosteroids or hospitalizations/emergency department visits in the past 6 or 12 months prior to the study visit/enrolment. The association between the haplotypes and the risk of asthma exacerbations was performed per study using haplo.stats package adjusted for age and sex. Results were meta‐analysed using the inverse variance weighting method assuming random‐effects. Results: In subjects treated with ICS and LABA (n = 832, age: 3–21 years), Arg16/Gln27 versus Gly16/Glu27 (OR: 1.40, 95% CI: 1.05–1.87, I2 = 0.0%) and Arg16/Gln27 versus Gly16/Gln27 (OR: 1.43, 95% CI: 1.05–1.94, I2 = 0.0%), but not Gly16/Gln27 versus Gly16/Glu27 (OR: 0.99, 95% CI: 0.71–1.39, I2 = 0.0%), were significantly associated with an increased risk of asthma exacerbations. The sensitivity analyses indicated no significant association between the ADRB2 haplotypes and asthma exacerbations in the other treatment categories, namely as‐required short‐acting β2‐agonists (n = 973), ICS monotherapy (n = 2623), ICS plus leukotriene receptor antagonists (LTRA; n = 338), or ICS plus LABA plus LTRA (n = 686). Conclusion and clinical relevance: The ADRB2 Arg16 haplotype, presumably mainly driven by the Arg16, increased the risk of asthma exacerbations in patients treated with ICS plus LABA. This finding could be beneficial in ADRB2 genotype‐guided treatment which might improve clinical outcomes in asthmatic patients. [ABSTRACT FROM AUTHOR]

Abstract Background Recent genome-wide association studies (GWAS) for asthma have been successful in identifying novel associations which have been well replicated. The aim of this study is to identify the genetic variants that influence predisposition towards asthma in an ethnic Chinese population in Singapore using a GWAS approach. Methods A two-stage GWAS was performed in case samples with allergic asthma, and in control samples without asthma and atopy. In the discovery stage, 490 case and 490 control samples were analysed by pooled genotyping. Significant associations from the first stage were evaluated in a replication cohort of 521 case and 524 control samples in the second stage. The same 980 samples used in the discovery phase were also individually genotyped for purposes of a combined analysis. An additional 1445 non-asthmatic atopic control samples were also genotyped. Results 19 promising SNPs which passed our genome-wide P value threshold of 5.52 × 10-8 were individually genotyped. In the combined analysis of 1011 case and 1014 control samples, SNP rs2941504 in PERLD1 on chromosome 17q12 was found to be significantly associated with asthma at the genotypic level (P = 1.48 × 10-6, ORAG = 0.526 (0.369-0.700), ORAA = 0.480 (0.361-0.639)) and at the allelic level (P = 9.56 × 10-6, OR = 0.745 (0.654-0.848)). These findings were found to be replicated in 3 other asthma GWAS studies, thus validating our own results. Analysis against the atopy control samples suggested that the SNP was associated with allergic asthma and not to either the asthma or allergy components. Genotyping of additional SNPs in 100 kb flanking rs2941504 further confirmed that the association was indeed to PERLD1. PERLD1 is involved in the modification of the glycosylphosphatidylinositol anchors for cell surface markers such as CD48 and CD59 which are known to play multiple roles in T-cell activation and proliferation. Conclusions These findings reveal the association of a PERLD1 as a novel asthma candidate gene and reinforce the involvement of genes on the 17q12-21 chromosomal region in the etiology of asthma.

Abstract Background The use of pooled DNA on SNP microarrays (SNP-MaP) has been shown to be a cost effective and rapid manner to perform whole-genome association evaluations. While the accuracy of SNP-MaP was extensively evaluated on the early Affymetrix 10 k and 100 k platforms, there have not been as many similarly comprehensive studies on more recent platforms. In the present study, we used the data generated from the full Affymetrix 500 k SNP set together with the polynomial-based probe-specific correction (PPC) to derive allele frequency estimates. These estimates were compared to genotyping results of the same individuals on the same platform, as the basis to evaluate the reliability and accuracy of pooled genotyping on these high-throughput platforms. We subsequently extended this comparison to the new SNP6.0 platform capable of genotyping 1.8 million genetic variants. Results We showed that pooled genotyping on the 500 k platform performed as well as those previously shown on the relatively lower throughput 10 k and 100 k array sets, with high levels of accuracy (correlation coefficient: 0.988) and low median error (0.036) in allele frequency estimates. Similar results were also obtained from the SNP6.0 array set. A novel pooling strategy of overlapping sub-pools was attempted and comparison of estimated allele frequencies showed this strategy to be as reliable as replicate pools. The importance of an appropriate reference genotyping data set for the application of the PPC algorithm was also evaluated; reference samples with similar ethnic background to the pooled samples were found to improve estimation of allele frequencies. Conclusion We conclude that use of the PPC algorithm to estimate allele frequencies obtained from pooled genotyping on the high throughput 500 k and SNP6.0 platforms is highly accurate and reproducible especially when a suitable reference sample set is used to estimate the beta values for PPC.

Identifying the genetic architecture underlying phenotypic variation in natural populations and assessing the consequences of polymorphisms for individual fitness are fundamental goals in evolutionary and molecular ecology. Consistent between‐individual differences in behaviour have been documented for a variety of taxa. Dissecting the genetic basis of such behavioural differences is however a challenging endeavour. The molecular underpinnings of natural variation in aggression remain elusive. Here, we used comparative gene expression (transcriptome analysis and RT–PCR), genetic association analysis and pharmacological experiments to gain insight into the genetic basis of aggression in wild‐caught jumping spiders (Portia labiata). We show that spider aggression is associated with a putative viral infection response gene, BTB/POZ domain‐containing protein 17 (BTBDH), in addition to a putative serotonin receptor 1A (5‐HT1A) gene. Spider aggression varies with virus loads, and BTBDH is upregulated in docile spiders and exhibits a genetic variant associated with aggression. We also identify a putative serotonin receptor 5‐HT1A gene upregulated in docile P. labiata. Individuals that have been treated with serotonin become less aggressive, but individuals treated with a nonselective serotonin receptor antagonist (methiothepin) also reduce aggression. Further, we identify the genetic variants in the 5‐HT1A gene that are associated with individual variation in aggression. We therefore conclude that co‐evolution of the immune and nervous systems may have shaped the between‐individual variation in aggression in natural populations of jumping spiders. [ABSTRACT FROM AUTHOR]

Background: Skin desquamation is facilitated by serine proteases KLK5 and KLK7, which are tightly regulated by lympho‐epithelial Kazal‐type related inhibitor (LEKTI). LEKTI itself is controlled through degraded by mesotrypsin. Here, we sought to determine whether LEKTI exonic mutations associated with atopic dermatitis (AD) affect the protease inhibitory activity of LEKTI or its susceptibility to mesotrypsin degradation. Methods: The inhibitory activities of the LEKTI domain 4 (D4) and D6 WT and AD‐associated mutants on the enzyme activities of KLK5 and KLK7 were compared using fluorogenic substrates. A keratinocyte cell culture system using HaCat cells was established to assess the role of D6 WT and D386N on triggering inflammation via the induction of thymic stromal lymphopoietin (TSLP). A degradation assay was used to assess the susceptibility of D4 and D6 mutants to mesotrypsin degradation. Results: Enzymatic assays revealed that the D6 D386N mutation affected the inhibitory activity of LEKTI on KLK5 but not KLK7. Other exonic mutations on D6 (N368S, V395M, and E420K) and D4 (R267Q) did not alter LEKTI inhibition. The D386N mutation disrupted the role of D6 in suppressing TSLP induction by KLK5 in HaCat cells. Although WT D4 is more susceptible to mesotrypsin degradation than WT D6, the D4 R267Q mutant was more resistant to mesotrypsin degradation, whereas the D6 E420K mutant showed enhanced mesotrypsin‐mediated degradation. Conclusion: Exonic mutations in D6, which previously have been associated with AD, may cause a disruption of inhibitory activity on KLK5 or enhance the degradation by mesotrypsin. [ABSTRACT FROM AUTHOR]