Genetic variation in ORM1-like 3 (ORMDL3) and gasdermin-like (GSDML) and childhood asthma

Background:  A genome-wide association study identified ORM1-like 3 (orosomucoid 1-like 3, ORMDL3 ) as an asthma candidate gene. Single nucleotide polymorphisms (SNPs) in the region including ORMDL3 on chromosome 17q21 were related to childhood asthma risk and ORMDL3 expression levels in Europeans.
Objective:  We examined whether polymorphisms in ORMDL3 and the adjacent gasdermin-like ( GSDML ) gene associated with asthma in the genome-wide association study are related to childhood asthma and atopy in a Mexico City population.
Methods:  We genotyped rs4378650 in ORMDL3 and rs7216389 in GSDML in 615 nuclear families consisting of asthmatic children aged 4–17 years and their parents. Atopy was determined by skin prick tests to 25 aeroallergens.
Results:  Individuals carrying the C allele of rs4378650 or the T allele of rs7216389 had increased risk of asthma [relative risk (RR) = 1.73, 95% confidence interval (CI) 1.19–2.53, P  = 0.003 for one or two copies of rs4378650 C, and RR = 1.64, 95% CI 1.12–2.38, P  = 0.009 for one or two copies of rs7216389 T). Linkage disequilibrium between the two SNPs was high ( r ² = 0.92). Neither of the SNPs was associated with the degree of atopy. A meta-analysis of five published studies on rs7216389 in nine populations gave an odds ratio for asthma of 1.44 (95% CI, 1.35–1.54, P  < 0.00001).
Conclusions:  Our results and the meta-analysis provide evidence to confirm the finding from a recent genome-wide association study that polymorphisms in ORMDL3 and the adjacent GSDML may contribute to childhood asthma.     

Genetic polymorphisms in arginase I and II and childhood asthma and atopy

BACKGROUND: A recent microarray study implicated arginase I (ARG1) and arginase II (ARG2) in mouse allergic asthma models and human asthma. OBJECTIVES: To examine the association between genetic variation in ARG1 and ARG2 and childhood asthma and atopy risk. METHODS: We enrolled 433 case-parent triads, consisting of patients with asthma 4 to 17 years old and their biologic parents, from the allergy clinic of a public hospital in Mexico City between 1998 and 2003. Atopy to 24 aeroallergens was determined by skin prick tests. We genotyped 4 single nucleotide polymorphisms (SNPs) of ARG1 and 4 SNPs of ARG2 with minor allele frequencies higher than 10% by using the TaqMan assay (Roche Molecular Systems, Pleasanton, Calif). RESULTS: ARG1 SNPs and haplotypes were not associated with asthma, but all 4 ARG1 SNPs were associated with the number of positive skin tests (P = .007-.018). Carrying 2 copies of minor alleles for either of 2 highly associated ARG2 SNPs was associated with a statistically significant increased relative risk (RR) of asthma (1.5, 95% CI = 1.1-2.1 for arg2s1; RR = 1.6, 95% CI = 1.1-2.3 for arg2s2). The association was slightly stronger among children with a smoking parent (arg2s1 RR = 2.1, 95% CI = 1.2 - 3.9 with a smoking parent; RR = 1.2, 95% CI = 0.8-1.9 without; interaction P = .025). Haplotype analyses reduced the sample size but supported the single SNP results. One ARG2 SNP was related to the number of positive skin tests (P = .027). CONCLUSION: Variation in arginase genes may contribute to asthma and atopy in children.     

Association between genetic variations of vascular endothelial growth factor receptor 2 and atopy in the Korean population

BACKGROUND: Vascular endothelial growth factor (VEGF) has been suggested to be a key mediator in the development of atopy and T(H)2 inflammation. OBJECTIVE: We sought to evaluate the effects of variations in the gene coding VEGF receptor (VEGFR) 2 on intermediate phenotypes of asthma in the Korean population. METHODS: A cohort of 2055 children and adolescents responded to a questionnaire concerning asthma symptoms and risk factors and underwent methacholine bronchial challenge and skin tests. The VEGFR2 gene, including the promoter area, was sequenced on 24 healthy subjects to discover informative single nucleotide polymorphisms (SNPs; minor allele frequency >2%). After haplotype reconstruction, 4 tagging SNPs (IVS6+54A>G, +889G>A, +1416T>A, and IVS25-92G>A) were scored. These SNPs were also scored in 480 adult asthmatic patients to verify the above genetic association study. RESULTS: The prevalence of atopy was associated with a single SNP (+889G>A) of VEGFR2 with borderline significance (P = .048; relative risk, 1.13; 95% CI, 1.00-1.28). However, haplotype analysis showed that the atopy prevalence was strongly associated with a haplotype (AGAG) of VEGFR2 (P = .002; relative risk, 1.25; 95% CI, 1.09-1.42). As for airway hyperresponsiveness, neither individual SNPs nor haplotypes were found to be associated. Interestingly, the significant association was also found between atopy and the AGAG haplotype among adult asthmatic patients (P = .008; odds ratio, 1.66; 95% CI, 1.14-2.44). CONCLUSIONS: The present study demonstrated that genetic variations of VEGFR2 are significantly associated with atopy in the Korean population.     

Asthma Endophenotypes and Polymorphisms in the Histamine Receptor HRH4 Gene

Background: Histamine as an inflammatory mediator plays an important role in chronic allergic and asthmatic conditions. However, the role of genetic polymorphisms of the histamine receptor HRH4 (histamine receptor H4) gene in asthma susceptibility and endophenotypes has not been studied yet. Our aim was to investigate the possible association between single nucleotide polymorphisms (SNPs) in the HRH4 gene and asthma or some endophenotypes of asthma. Methods: Twenty-one SNPs of the HRH4 gene were genotyped in 313 asthmatic patients and 360 controls using Sequenom? iPLEX? Gold Genotyping Technology. Results: Genotype distribution of three HRH4 SNPs, namely rs17187619 [p = 0.002; odds ratio, OR (95% confidence interval, CI) = 2.4 (4.1-1.4)], rs527790 [p = 0.0002; OR (95% CI) = 3.3 (6.1-1.8)] and rs487202 [p = 0.00007; OR (95% CI) = 3.5 (6.6-1.9)] differed significantly between patients with or without infection-induced asthma. Haplotypes, which included the rs4800573-rs527790 CC allele combination, were found to be associated with infection-induced asthma [p = 0.0009, OR (95% CI) = 0.5 (0.4-0.8)]. The rs487202-rs574913 CA haplotype was more frequent among patients with infection-induced asthma [p = 0.0006, OR (95% CI) = 1.9 (1.3-2.6)]. None of the SNPs contributed directly to the risk of asthma. Conclusions: Our results suggest that genetic variation in the HRH4 gene might influence the pathogenesis of infection-induced asthma.     

Association of IL-13, RANTES, and leukotriene C4 synthase gene promoter polymorphisms with asthma and/or atopy in African Americans.

PURPOSE: IL-13, RANTES (Regulated on Activation, Normal T cells Expressed and Secreted), and cysteinyl leukotrienes are asthma and atopy mediators. Two RANTES -403(G to A) and -28(C to G), an -1055 IL-13(C to T), and a -444(A to C) leukotriene C4 synthase (LTC4S) single nucleotide polymorphisms (SNPs) have been shown in Caucasians and Asians as asthma and atopy risk factors. We studied these SNPs in African Americans with asthma and/or atopy. METHODS: We studied 61 patients with asthma and/or atopy and 129 to 157 newborn controls for the -403 RANTES, -28 RANTES, and -1055 IL-13 SNPs, as well as 47 patients and 60 newborn controls for the -444 LTC4S SNP. RESULTS: The two groups did not significantly differ at the genotypes of the -403 and -28 RANTES SNP. On the other hand, the mutant TT genotype for the -1055 IL-13 SNP was detected in 19.7% of patients versus 12.7% in controls (P < 0.04, OR 2.9, 95% CI 1.0-8.0), and the mutant T allele in 58.3% versus 36.6% in controls (P < 0.02, OR 2.4, 95% CI 1.1-5.2). In a similar fashion, for the -444 LTC4S SNP, the mutant AC genotype was detected in 19.1% versus 10.0% in controls (P > 0.28); mutant C allele had an OR of 2.1 (95% CI 0.7-6.3). CONCLUSION: African American asthmatics/atopics had higher frequency of the TT mutant gene for the -1055 IL-13 SNP and of its mutant T allele. Regarding the -444 LTC4S SNP, there was a definite difference, although not statistically significant, with an OR of 2.1 for the mutant AC genotype in patients. If these findings become reproduced by larger studies, it may suggest that IL-13 and LTC4S SNPs can be used as predictive markers for asthma/atopy in African Americans.     

Atopy and new-onset asthma in young Danish farmers and CD14, TLR2, and TLR4 genetic polymorphisms: a nested case-control study

BACKGROUND: Evidence exists that exposure to high levels of microbial agents such as endotoxin in the farm environment decreases the risk of atopic sensitization. Genetic variation in innate immunity genes may modulate the response to microbial agents and thus influence susceptibility to asthma and atopy. OBJECTIVE: To study potential associations between single nucleotide polymorphisms (SNPs) in CD14, Toll-like receptor 2 (TLR2), and TLR4 genes, and atopy and new-onset asthma in young farmers. METHODS: A nested case-control study was conducted within a cohort of 1901 young Danish farmers. We genotyped 100 new-onset asthma cases and 88 control subjects for three CD14 SNPs, three TLR2 SNPs, and two TLR4 SNPs. Atopy at baseline (defined as a positive skin prick test to one or more common inhalant allergens) was found in 17 asthma cases (17.0%) and in 17 controls (19.3%). RESULTS: The CD14/-260T allele was significantly associated with less atopy [odds ratio (OR) 0.39; 95% confidence interval (CI) 0.21-0.72, additive genetic model], whereas the CD14/-651T allele was positively associated with atopy (OR 2.53; 95% CI 1.33-4.80). Similar results were obtained by haplotype analysis. Stratified analysis by farm childhood showed stronger effects of both CD14 SNPs on atopy among farmers who were born and raised on a farm, although no significant interaction was found. No associations between CD14, TLR2, or TLR4 genotypes and new-onset asthma were found. CONCLUSION: The CD14/-260 and CD14/-651 promoter polymorphisms are associated with atopy prevalence among young adults exposed to farm environments.     

Association between interleukin-1 receptor antagonist gene and asthma-related traits in a German adult population

Background:  A recent study in German and Italian families associated variants in the interleukin-1 receptor antagonist (IL1RA) gene with asthma. The aim of the present study was to further investigate the role of single nucleotide polymorphisms (SNPs) in the IL1RA gene in the development of atopy and lifelong asthma in a population-based study.
Methods:  DNA samples from the German centres of the European Community Respiratory Health Survey were analysed for genetic variants in the IL1RA gene and the development of asthma, atopy and bronchial hyperreactivity.
Results:  Carriers of the rare G allele of SNP rs447713 had a significantly increased risk of developing asthma ( P  = 0.0013) and allergic sensitization ( P  = 0.0119). Carriers of the rare C allele of SNP rs3087271 had an increased risk of asthma ( P  = 0.0227) and high immunoglobulin E (IgE) levels ( P  = 0.0232). A haplotype built from eight SNPs in the IL1RA gene (A-C-A-G-A-C-G-A) was associated with a higher prevalence of asthma ( P  = 0.007) and high total IgE ( P  = 0.02). Bronchial hyperreactivity was positively associated with the haplotype A-C-G-G-A-C-G-C ( P  = 0.02) and negatively with the A-C-G-G-A-C-T-C ( P  = 0.03).
Conclusion:  A previously described association between IL1RA and asthma in families could be reproduced in a population-based sample. The genetic variants of IL1RA gene do not to seem to affect asthma alone, but to act as modulators of asthma-related traits as well, where different haplotypes drive the development of different phenotypes.     

Polymorphisms in the 5' region of the CD14 gene are associated with eczema in young children

BACKGROUND: Variants in the CD14 gene (CD14) are hypothesized to be associated with atopic disorders. However, most studies have only investigated one polymorphism in this gene. OBJECTIVE: We sought to study the association of 5 single nucleotide polymorphisms (SNPs) in the 5' flanking region of CD14 with eczema and serum IgE levels in young children. METHODS: We genotyped 5 SNPs in an approximately 6.5-kb region in the 5' region of CD14 in 344 2-year-old white children from 2 birth cohorts in the northeastern United States. We examined the relation of both single SNPs and haplotypes in CD14 with the atopic outcomes. RESULTS: Two SNPs were significantly associated with eczema. In dominant models adjusted for potential confounders, SNP rs2569193 was associated with significantly decreased risk for eczema (odds ratio [OR] for CT/TT vs CC, 0.5; 95% CI, 0.3-0.8), whereas SNP rs2569190 (also reported as the C-159T) was associated with significantly increased risk for eczema (OR for CT/TT vs CC, 2.3; 95% CI, 1.4-3.8). The CT/TT genotypes of SNP rs2569190 also had higher geometric means of serum IgE than the CC genotype (24.6 vs 15 IU/mL, P = .025). Haplotype analyses provided results similar to those of the single SNP analyses. CONCLUSIONS: Our results contradict previous reports that have found a protective effect of the T allele of SNP rs2569190 (C-159T) against atopic disorders. Nevertheless, these results confirm the importance of polymorphisms in CD14 in the development of atopy, and future studies of this gene region will need to account for linkage disequilibrium and environmental exposures unique to the study population.     

Association and functional relevance of E237G, a polymorphism of the high-affinity immunoglobulin E-receptor β chain gene, to airway hyper-responsiveness

BACKGROUND: The hyper-sensitivity reaction of IgE, with its high-affinity receptors (FcepsilonRI), is central to the phenomenon of atopic diseases. OBJECTIVE: To evaluate the genetic effects of non-synonymous single-nucleotide polymorphisms (SNPs) of FcepsilonRI on intermediate phenotypes of asthma, i.e. atopy and airway hyper-responsiveness (AHR), in the Korean general population. SUBJECTS AND METHODS: Atopy and AHR were evaluated in a cohort of 2055 subjects, aged 10-18 years, using skin prick tests (SPTs) for common aeroallergens and total serum IgE and methacholine bronchial provocation tests. All FcepsilonRI-alpha, FcepsilonRI-beta, and FcepsilonRI-gamma gene exons of 24 healthy subjects were sequenced to locate informative non-synonymous SNPs (minor allele frequency>2%). Informative SNPs were then scored, using the high-throughput single base extension method. Relative risk (RR) was determined by multiple logistic regression analysis, after adjusting for confounding factors. The functional relevance of non-synonymous SNPs was analysed using the sorting intolerant from tolerant (SIFT) program. RESULTS: The SNP search found only one informative non-synonymous SNP in FcepsilonRI-beta: E237G (minor allele frequency=0.21). The positive rate of AHR was lower among subjects with the 237*E allele than among those with 237*G [RR (95% confidence interval)=0.41 (0.19-0.89); P=0.01]. However, the E237G substitution was not associated with either a positive SPT response or total serum IgE levels. Sequence evolution analysis predicted that the E237G variation is an intolerant amino acid substitution, with functional importance. CONCLUSION: In the Korean general population, AHR is significantly associated with the E237G polymorphism of FcepsilonRI-beta, which results in an intolerant amino acid substitution.     

Asthma and atopy are associated with chromosome 17q21 markers in Chinese children

Background:  Single-nucleotide polymorphism (SNP)-based genome-wide association study revealed that markers on chromosome 17q21 were linked to childhood asthma but not atopy in Caucasians, with the strongest signal being detected for the SNP rs7216389 in the ORMDL3 gene. Such association was unknown in Chinese. This study delineated the allele and genotype frequencies of 10 SNPs at chromosome 17q21, and investigated the relationship between these SNPs and asthma and plasma IgE in southern Chinese children.
Methods:  Asthmatic children and non-allergic controls were recruited from pediatric clinics. Their plasma total and aeroallergen-specific IgE concentrations were measured by immunoassay. Ten SNPs on 17q21 region were genotyped by multiplex SNaPshot™, and their genotype associations with asthma traits analyzed using multivariate regression.
Results:  315 patients and 192 controls were enrolled. The allele frequency for C allele of rs7216389 varied significantly from 0.232 in our controls, 0.389 in Han Chinese to 0.536 in Caucasians. Asthma diagnosis was associated with rs11650680 and five other SNPs including rs7216389 ( P  =   0.019–0.034), whereas atopy was associated only with rs11650680 ( P  =   0.0004). Linear regression revealed the covariates for plasma total IgE to be significant for rs11650680 ( P  =   0.008–0.0002). Haplotypic associations were found with atopy and increased plasma total IgE, with the respective odds ratios and 95% confidence intervals for TTTCCGTT haplotype to be 0.21 and 0.09–0.52 ( P  =   0.0002) and 0.41 and 0.18–0.90 ( P  =   0.025).
Conclusion:  Childhood asthma and atopy are associated with chromosome 17q21 in Chinese, but such association may involve genes other than ORMDL3 in this region.     

Relation between tumour necrosis factor polymorphism TNFalpha-308 and risk of asthma

Tumour necrosis factor (TNF) alpha affects immune response and airway inflammation, which are characteristics of asthma. Genetic factors may impact TNFalpha levels, and several polymorphisms in the TNF gene cluster on chromosome 6p21 have been associated with TNFalpha production and potential increased risk of asthma. The present paper evaluates the relation between two single nucleotide polymorphisms (SNPs) in the TNF gene cluster and asthma risk. The SNPs investigated here are guanine (G) to adenosine (A) substitutions in the TNFalpha and lymphotoxin alpha (LTalpha) genes. The TNFalpha SNP is at position -308 in the promoter region (TNFalpha-308), while the LTalpha SNP is in the first intron NcoI recognition sequence (LTalpha-NcoI). (For both SNPs the G allele is denoted as 1, and the A allele 2.) We determined TNFalpha-308 and LTalpha-NcoI genotypes in 511 individuals: 236 asthma cases and 275 non-asthmatic controls. Data were analysed by logistic regression of asthma status on the genotypes and potential confounders. TNFalpha-308*2 was positively associated with asthma, and this relation was strengthened when restricting cases to individuals reporting acute asthma: the adjusted odds ratio (OR) comparing carriers of one or two TNFalpha-308*2 alleles versus none was 1.86 (95% confidence interval (CI)=1.03-3.34, P=0.04). Further restricting the subjects to those with a family history of asthma, and those of European-American ancestry strengthened the association even more: adjusted OR=3.16 (95% CI=1.04-9.66; P=0.04). LTalpha-NcoI*1 was weakly associated with asthma, and analysis of both genes suggests that only the TNFalpha-308*2 allele increases risk of asthma.     

Relationship between the 17q21 locus and adult asthma in a Czech population

Several whole-genome association studies have shown a significant link between childhood asthma and the 17q12 chromosome region. We selected tagging single nucleotide polymorphisms (SNPs) in the ORMDL3 gene (17q12) to investigate gene variability in relation to adult allergic asthma and asthma/atopy traits in a Czech Caucasian population of adults. We conducted a case-control association study comprising 668 unrelated subjects (337 asthmatic and 331 control subjects). Four selected SNPs (rs17608925, rs12603332, rs8076131, and rs3169572) were genotyped using the TaqMan SNP Genotyping Assays. The single locus analysis showed only a borderline association between rs3169572 variant and asthma (p = 0.030, p(corr) > 0.05). However, seven different haplotypes were identified; among them, the TTAA haplotype was marginally associated with asthma (p = 0.045, p(corr) > 0.05) and TCAG haplotype was significantly associated with asthma in males (p = 0.009, p(corr) < 0.05, odds ratio = 1.48, 95% confidence interval = 1.10-2.00). In addition, associations between the ORMDL3 genotypes and the total IgE level (p = 0.05, p(corr) > 0.05) and hypersensitivity to the pollen (p = 0.007, p(corr) < 0.05) were established. However, no relationship between ORMDL3 SNPs and the pulmonary functions was found (p > 0.05). These findings suggest that the genetic variability in the 17q21 region may be one of the risk factors also for adult asthma, especially in male individuals.     

Polymorphisms in metalloproteinase-9 are associated with the risk for asthma in Mexican pediatric patients

Asthma is characterized by chronic airway inflammation, which induces airway remodelling of the extracellular matrix over time. Matrix metalloproteinases (MMPs) are involved in this process, and single-nucleotide polymorphisms (SNPs) in MMP genes may influence their mRNA expression levels or abilities to bind substrates and inhibitors, thereby contributing to asthma predisposition and severity. MMP-9 is highly expressed in airways and many studies support its involvement in asthma pathogenesis; however the contribution of MMP-9 SNPs is controversial. To investigate whether MMP-9 SNPs are associated with childhood-onset asthma in Mexican patients we conducted a case-control study including 403 children with clinical asthma diagnoses and 426 healthy controls from Mexico. The cases and controls were matched by ethnicity and gender. We found that the SNPs rs2274755, rs17577, and rs3918249 were associated with asthma risk. The most significant associations were with rs2274755 (OR = 2.10, 95% CI 1.31–3.39, P = 0.001) and rs17577 (OR = 2.07, 95% CI 1.29–3.30, P = 0.001); which were in strong linkage disequilibrium. Both SNPs were also associated with atopic asthma (OR = 2.38, 95% CI 1.44–3·96, P = 0.0005). The SNP rs3918249 exhibited a female gender-dependent association with asthma (OR = 1.66, 95% CI 1.14–2.43, P = 0.007). Our results suggest that MMP-9 polymorphisms could play a role in the susceptibility to childhood-onset asthma.     

Association of ALOX5AP gene single nucleotide polymorphisms and cerebral infarction in the Han population of northern China

ABSTRACT: BACKGROUND: To explore the association of ALOX5AP single nucleotide polymorphisms (SNPs) and haplotype with the occurrence of cerebral infarction in the Han population of northern China. METHODS: Blood samples were collected from 236 patients of Han ancestry with a history of cerebral infarction and 219 healthy subjects of Han ancestry with no history of cerebral infarction or cardiovascular disease. Applied Biosystems(R) TaqMan(R) SNP Genotyping Assays for SNP genotyping were used to determine the genotypes of 7 ALOX5AP SNP alleles (rs4073259, rs4769874, rs9315050, rs9551963, rs10507391, rs9579646, and rs4147064). RESULTS: One SNP allele (A) of rs4073259 was significantly associated with development of cerebral infarction (P = 0.049). In comparison to control groups, haplotype rs9315050&rs9551963 AAAC [OR (95 % CI) =1.53 (1.02-2.29)], and genotypes rs4147064 CT [OR (95 % CI) =1.872 (1.082-3.241)], and rs9551963 AC [OR (95 % CI) = 2.015 (1.165-3.484)] increased the risk of cerebral infarction in patients with hypertension. Genotype rs9579646 GG [OR (95 % CI) = 2.926 (1.18-7.251)] increased the risk of, while rs4073259 GG [OR (95 % CI) = 0.381 (0.157-0.922)] decreased the risk of cerebral infarction in patients with diabetes. CONCLUSION: These results suggest the ALOX5AP SNP A allele in rs4073259 and genotype rs9579646 GG, rs9551963 AC, and haplotype rs9315050 & rs9551963 AAAC were associated with an increased risk of ischemic stroke in the Han population, while rs4073259 GG was associated with a decreased risk.     

Association between the three functional miR-146a single-nucleotide polymorphisms,rs2910164, rs57095329, and rs2431697, and autoimmune disease susceptibility: A meta-analysis

Studies suggest associations between the miR-146a single nucleotide polymorphisms (SNPs) and susceptibility to autoimmune diseases. However, the results are inconsistent and inconclusive. Therefore, the aim of this study was to arrive at a conclusion about the association between the three functional miR-146a SNPs and autoimmune disease risk. Studies were identified through PubMed/MEDLINE searches for studies published up to January 2016 using as keywords rs2910164, rs57095329, rs2431697, and miR-146a polymorphisms. Thirty studies were included in the meta-analysis. The SNP rs2910164?G?>?C was found to be associated with increased risk of multiple sclerosis (CC?+?CG versus GG, OR = 1.25, 95% CI: 1.01–1.55), with decreased risks of psoriasis (C versus G, OR = 0.81, 95% CI: 0.69–0.96; CC versus GC?+?GG, OR = 0.73, 95% CI: 0.56–0.94), Behcet’s disease (CC versus GC?+?GG, OR = 0.60, 95% CI: 0.50–0.73), asthma (C versus G, OR = 0.80, 95% CI: 0.69–0.93; CC versus GC?+?GG, OR = 0.65, 95% CI: 0.48–0.86), and uveitis (CC?+?CG versus GG, OR = 0.61, 95% CI: 0.49–0.77). The SNP rs2431697 C?>?T was found to be associated with an increased risk of SLE (T versus C, OR = 1.26, 95% CI: 1.15–1.38; TC?+?TT versus CC, OR = 1.28, 95% CI: 1.03–1.58; TT versus TC?+?CC, OR = 1.40, 95% CI: 1.21–1.62). The SNP rs57095329 A?>?G was found to be associated with an increased risk of SLE (G versus C, OR = 1.25, 95% CI: 1.17–1.35). The miR-146a SNPs rs2910164, rs57095329, rs2431697 are associated with susceptibility to certain autoimmune diseases. However, for other autoimmune diseases, they may be protective or insignificant.     

Polymorphisms in IL13, total IgE, eosinophilia, and asthma exacerbations in childhood

BACKGROUND: It is unclear whether single nucleotide polymorphisms (SNPs) in the gene for IL-13 (IL13) influence asthma severity and/or asthma morbidity. OBJECTIVES: To examine the relation between IL13 SNPs and asthma-related phenotypes in 2 independent populations. METHODS: We used family-based methods to test for association between SNPs in IL13 and asthma-related phenotypes in Costa Rican children with asthma. We attempted to reproduce significant findings in white (non-Hispanic) children with asthma in the Childhood Asthma Management Program (CAMP). RESULTS: In Costa Rica and in CAMP, the A allele (Gln) of IL13 coding SNP (rs20541) was significantly associated with increased eosinophil count (P < .011 in both studies) and increased serum total IgE (P < .054 in both studies). The T allele of IL13 promoter SNP (rs1800925) was inversely associated with asthma exacerbations in Costa Rica (P = .069). Although this SNP (rs1800925) was not associated with asthma exacerbations among all white children in CAMP, it was associated with increased risk of asthma exacerbations among children on inhaled corticosteroids (P = .02). CONCLUSION: Polymorphisms in IL13 were significantly associated with serum total IgE and eosinophil count in 2 populations. IL13 polymorphisms may also be associated with asthma exacerbations, and this effect may be dependent on medication use. Our study is the first to report a potential negative interaction between a genetic polymorphism and response to inhaled corticosteroids. CLINICAL IMPLICATIONS: Polymorphisms in IL13 are associated with serum total IgE and eosinophil count and may be associated with asthma exacerbations.     

Analysis of mutations and the association between polymorphisms in the cerebral dopamine neurotrophic factor (CDNF) gene and Parkinson disease

Neurotrophic factors support the survival of dopaminergic neurons. The cerebral dopamine neurotrophic factor (CDNF) is a novel neurotrophic factor with strong trophic activity on dopaminergic neurons comparable to that of glial cell line-derived neurotrophic factor (GDNF). To investigate whether rare or common variants in CDNF are associated with Parkinson disease (PD), we performed mutation analysis of CDNF and a genetic association study between CDNF polymorphisms and PD. We screened 110 early-onset Parkinson disease (EOPD) patients for CDNF mutations. Allelic and genotype frequencies of 3 CDNF single nucleotide polymorphisms (SNPs) (rs1901650, rs7094179, and rs11259365) were compared in 215 PD patients and age- and sex-matched controls. We failed to identify any mutations in CDNF among the EOPD patient sample population. We observed a trend towards increased risk for PD in patients carrying the C allele of SNP rs7094179 (odds ratio (OR)=1.27, 95% confidence interval (CI) 0.96-1.67). Patients carrying the C allele were susceptible to PD in both dominant (CC+CA vs. AA; OR=7.20, 95% CI 0.88-59.1) and recessive (CA+AA vs. CC; OR=0.64, 95% CI 0.41-0.99) models. Genotype and allele frequencies of SNPs rs1901650 and rs11259365 did not differ between PD patients and controls. Our study suggests that the C allele of an intronic CDNF SNP (rs7094179) might be an allele for susceptibility to PD. Further studies with larger sample size are required to confirm our results.     

Variant in promoter region of platelet-derived growth factor receptor-alpha (PDGFRalpha) gene is associated with the severity and allergic status of childhood asthma

BACKGROUND: Upregulation of the platelet-derived growth factor receptor-alpha (PDGFRalpha) in airway myofibroblast cells is one of the mechanisms of airway remodeling. The genetic association between PDGFRalpha promoter polymorphism and severity of childhood asthma was examined. METHODS: Five single nucleotide polymorphisms (SNPs) at the promoter regions of the PDGFRalpha gene were genotyped in 277 unrelated allergic and nonallergic asthmatic children and 93 age-matched controls. Promoter haplotypes were constructed using SNP genotyping data. The serum level of PDGF-AA, the ligand for PDGFRalpha, was assayed by ELISA kits. RESULTS: The genotype distribution of SNP rs1800810 (-1171G/C) in nonallergic asthma was significantly different from controls (p=0.038), as well as its allele distribution (p=0.028). Using haplotype analysis, the combination frequency of the low expression of H1 homozygous and heterozygous genotype (H1/H1+H1/H2) was significantly higher in nonallergic asthma as compared to controls (OR=1.94, CI=1.11-3.39, p<0.02). The frequency of H2/H2 homozygous was higher in persistent asthma than in intermittent asthma (p=0.008, OR=2.625). In addition, the PDGF-AA serum level in H2/H2 homozygous haplotype was significantly lower as compared to non-H2/H2 homozygous haplotype both in asthmatic (138.1+/-62.9 vs. 249.7+/-97.1 ng/ml, p<0.05) and nonallergic asthmatic children (113.8+/-38.0 vs. 256.6+/-58.3 ng/ml, p<0.05). CONCLUSIONS: The developmental deficiency due to the low expression of PDGFRalpha may be one of the susceptible factors for nonallergic asthmatic children. There was also an autocrine effect of lower PDGF-AA and higher PDGFRalpha expression that might lead to airway remodeling causing the severity of asthma.     

Variation in the TEK gene is not associated with asthma but with allergic conjunctivitis

The Tie2 receptor is an important player in angiogenesis. The Tie2 mRNA and protein are abundantly expressed in the lungs and the associated pathway also has an important role in the development and function of the eye. Tie2 is encoded by the TEK gene in humans. Recently, variations in the TEK gene have been found associated with asthma. The objective of the present study was to investigate whether variations in the TEK gene influenced the susceptibility to pediatric asthma and/or associated phenotypes like GINA status, viral‐ or exercise‐induced asthma, allergic asthma, indoor, outdoor, inhalative allergies, IgE and eosonophil levels, allergic rhinitis and allergic conjunctivitis. Three single nucleotide polymorphisms (SNPs, rs3780315, rs581724 and rs7876024) in the TEK gene were genotyped in 1189 unrelated individuals, out of which 435 were asthmatic children and 754 healthy controls. Different types of asthma, allergies and co‐morbidities were defined in 320 patients. Among the fully phenotyped 320 asthmatic patients 178 (55.6%) also had allergic rhinitis and 100 (31.3%) had conjunctivitis. Among the rhinitis patients 98 (55.1%) also had conjunctivitis. Two patients had conjunctivitis without rhinitis. The genotyped SNPs showed no association with asthma. However, SNP rs581724 was significantly associated with allergic conjunctivitis in a recessive way (p=0.007; OR=2.3 (1.3‐4.4)) within the asthmatic population. The risk remained significant when the whole population (asthmatics and healthy controls) was included in the calculation (p = 0.003; OR = 2.1 (1.3‐3.6)). The minor allele of the rs581724 SNP which is associated with the increased risk to conjunctivitis is also associated with reduced Tie2 expression. There was a significant association between SNP rs581724 and the occurrence of allergic conjunctivitis in asthmatic children. If additional studies can confirm the role of the Tie2 pathway in allergic conjunctivitis, it can be a potential novel therapeutic target in the disease.