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Systemic insulin-like growth factor 1 (IGF1) level is an important risk factor for various diseases. The inter-individual variation of serum IGF1 is determined by environmental and genetic factors, which are attributed to a microsatellite in IGF1 promoter. However, the exact nature of the underlying regulatory elements accounting for this association has not been characterized. Here, we defined the haplotype patterns, including both SNPs and the microsatellite, in the Chinese population, and investigated their regulatory effect on serum IGF1 level. This is the first study in which haplotype patterns of the microsatellite and SNPs in the IGF1 promoter are examined together. The linkage disequilibrium (LD) patterns of IGF1 were examined using tagSNPs of the IGF1 regulatory region. The microsatellite, three tagSNPs and haplotypes were correlated with serum IGF1 concentration in 450 normal premenopausal Chinese women. Common alleles of the microsatellite were in strong LD with the three tagSNPs and were associated with particular haplotypes composed of SNPs. Neither the CA repeat number nor SNPs alone showed a robust association with serum IGF1 concentration. On the other hand, the haplotype T-19-A-T was significantly associated with serum IGF1 level. No association was found between SNPs and microsatellite alone. However, the haplotype showed better correlation with serum IGF1 level. The results indicate that the previously observed correlation with microsatellite was because of a haplotype effect in the IGF1 promoter. Microsatellite or tagSNPs alone are not the primary regulatory elements of IGF1 expression. The exact regulatory genetic variant needs to be defined by functional genetic studies. [ABSTRACT FROM AUTHOR]

Melatonin is predominantly involved in signaling circadian and seasonal rhythms, and its synthesis is regulated by the environmental light/dark cycle. The selection pressure by geographically different environmental light/dark cycles, which is predominantly determined by sunshine duration, on the global distribution of genetic polymorphisms in the melatonin pathway is not well understood. Recent genetic association studies identified various disease-predisposition polymorphisms in this pathway. We investigated the correlations between the prevalence of these clinically important single nucleotide polymorphisms (SNPs) and sunshine duration among worldwide human populations from twelve regions in the CEPH-HGDP database rs4753426, a recently reported predisposition SNP for type 2 diabetes in the promoter of the MT2 melatonin receptor gene ( MTNR1B), which was not included in the CEPH-HGDP genotyping array, was additionally genotyped. This SNP showed a marginally significant correlation in 760 CEPH-HGDP DNA samples ( r = −0.5346, P = 0.0733), and it showed the most prominent association among the candidate melatonin pathway SNPs examined. To control for population structure, which may lead to a false positive correlation, we genotyped this SNP in a replication set of 1792 subjects from China. The correlation was confirmed among Chinese populations ( r = −0.8694, P = 0.0002), and was also statistically significant after correction of other climatic and geographical covariants in multiple regression analysis (β = −0.907, P = 1.94 × 10−5). Taken together, it suggests that the human melatonin signaling pathway, particularly MT2 melatonin receptor may have undergone a selective pressure in response to global variation in sunshine duration. [ABSTRACT FROM AUTHOR]

Early growth response-1 ( Egr-1) is expressed in human airways and found to modulate tumor necrosis factor, immunoglobulin E (IgE), airway responsiveness, and interleukin-13-induced inflammation in mice. We investigated the effects of Chinese-tagging single nucleotide polymorphisms (SNPs) of Egr-1 on asthma traits in 298 Chinese asthmatic children and 175 controls, and a replication community cohort of 191 controls. Tag SNP (−4071 A→G) and three additional SNPs (−1427 C→T, −151 C→T and IVS1 −42 C→T) were genotyped by restriction fragment length polymorphism (RFLP). Significant associations were found between plasma total IgE concentration and −4071 A→G (p = 0.008) and IVS1 −42 C→T (p = 0.027) in asthmatic patients. After Bonferroni correction, only −4071 A→G showed significant association. Multivariate regression analysis confirmed this significant association with a standardized coefficient β of 0.156 (95% CI: 0.046–0.317; p = 0.009) in asthmatics among the three SNPs with age and gender-adjusted. In −4071 A→G, IgElog was significantly higher in patients with the GG genotype than the AA genotype (p = 0.009). In addition, −4071 A→G was significantly associated with atopy (p = 0.016) and high total IgE concentration (p = 0.030) among asthmatics. Patients with the G allele had a 3.5-fold risk of having atopy and a 2.0-fold risk of having high total IgE concentration than those homozygous for the A allele. This is the first report to show significant association of Egr-1 polymorphisms with plasma total IgE and atopy in asthmatics. It may help to explore the pharmacogenetics of Egr-1 inhibitors. [ABSTRACT FROM AUTHOR]

Heroin users exhibit abnormal pain sensitivity called opioid-induced hyperalgesia that may weaken their determination to abstain. The dopamine receptor D4 gene ( DRD4) is associated with heroin dependence; one of its polymorphisms is a C/T variation 521 bp upstream to the gene (−521C/T). We investigated whether this polymorphism was related to opioid dependence through modulation of cold-pain responses. We recruited 84 heroin-dependent Chinese male subjects and 168 healthy male Chinese controls. Genotyping was performed by PCR-RFLP. A significantly higher T allele frequency was observed in the heroin group ( P= 0.041). Of the cohort recruited, 43 current heroin users and 66 controls were further subjected to a cold-pressor test (CPT) to determine their pain threshold and tolerance. TT controls demonstrated a significantly lower pain threshold than did their CC/CT counterparts ( P= 0.022) and TT opioid users ( P= 0.006). Moreover, CC/CT controls had a significantly higher pain tolerance than TT controls ( P= 0.042) and CC/CT opioid users ( P= 0.010). The data suggest that DRD4−521C/T plays an important role in opioid dependence through modulating cold-pain responses. TT individuals might have a higher tendency to use opioids because they experience pain less strongly after chronic opioid use. [ABSTRACT FROM AUTHOR]

Objective Thyrotoxic periodic paralysis (TTP) has been associated with genetic variations in the gene encoding the alpha 1 subunit of the L-type calcium channel (CACNA1S). Mutations in CACNA1S are known to account for the majority of cases of familial hypokalaemic periodic paralysis (HOKPP). In this study we have examined 48 genetic polymorphisms in the CACNA1S gene and genotyped a tagging set of representative polymorphisms to determine the role of this gene in TPP. Design and patients A genetic association study was carried out with 98 TPP patients and 162 male thyrotoxic controls. Among 47 polymorphisms evaluated for linkage disequilibrium (LD) and the spectrum of haplotypes in the Chinese population , 31 were selected as tagging single-nucleotide polymorphisms (SNPs) for genotyping the whole sample. A new genotyping protocol was used to analyse an insertion/deletion (I/D) polymorphism. Results We studied the LD among 47 polymorphisms in the CACNA1S gene, which comprised a set of high-density markers with an average of one SNP every 2 kb. Subsequently, 31 tagSNPs were genotyped for all the samples. The gene is composed of three LD blocks. With this block structure, we were confident that variations of the gene were comprehensively covered by the tagSNPs. No significant association was found between the polymorphisms and TPP. Conclusion We established the LD structure of this calcium channel subunit gene (CACNA1S) for the first time. However, its genetic variations are not associated with TPP in Chinese patients. [ABSTRACT FROM AUTHOR]

Mannose-binding lectin (MBL), a member of the innate immune system, initiates complement deposition on microbial surfaces. MBL deficiency is associated with severe respiratory infections. Polymorphisms in the MBL gene ( mbl2) were associated with the susceptibility and severity of autoimmune diseases. This study investigated whether mbl2 polymorphisms at positions -550 and -221 and at codon-54 are associated with asthma phenotypes in Chinese children. Asthmatics aged 5–18 yr and non-allergic controls were eligible, and their plasma total and allergen-specific immunoglobulin E (IgE) concentrations were measured by micro-particle immunoassay and fluorescent enzyme immunoassay. mbl2 polymorphisms were genotyped by restriction fragment length polymorphism. Three hundred and seventeen asthmatic children and 140 controls were recruited, with their mean (s.d.) log-transformed plasma total IgE being 2.61 (0.61) and 1.77 (0.77), respectively (p < 0.0001). Polymorphisms at -550 and codon-54 (p < 0.0001 for both) but not at -221 (p = 0.534) of mbl2 were significantly associated with plasma MBL concentrations. mbl2 genotypes were not associated with asthma, atopy, sensitization to individual aeroallergens or spirometric variable. Subjects with LYB haplotype had the lowest plasma MBL concentrations (p < 0.0001), but two- and three-loci mbl2 haplotypes were also not associated with asthma diagnosis. However, patients with LY and LYB haplotypes were less likely to be atopic (p = 0.006 and 0.031). Subjects with LY and LYA were also less likely to be sensitized to cockroach (p = 0.035 and 0.047). The latter three associations became insignificant when adjusted for multiple comparisons. Despite the importance of MBL in innate immunity, our mbl2 polymorphisms only show weak association with asthma and atopy in children. [ABSTRACT FROM AUTHOR]

Activation of macrophages through CD14 by microbes is crucial in inducing immunity by type 1 T helper cells. A C-to-T polymorphism at position -159 of CD14 was associated with serum total IgE level in Caucasians but not in Japanese subjects. The objective of this study is to determine whether this polymorphic marker is associated with atopy and asthma phenotypes in Chinese children. Restriction fragment length polymorphism was used to characterize CD14/-159 genotypes. Microparticle immunoassay was used to measure serum total IgE level; fluorescent enzyme immunoassay was performed to measure serum concentrations of specific IgE to aeroallergens; and enzyme-linked immunosorbent assay was used to measure serum levels of soluble CD14 (sCD14). Lung function in asthmatics was assessed by spirometry. Two hundred and fifty-eight patients and 92 control children were recruited. Their mean serum total IgE concentrations were 331 and 74 kIU/l, respectively (p < 0.0001). Atopy, defined as the presence of at least one allergen-specific IgE in serum, was found in 220 (85%) patients and in 41 (45%) controls (p < 0.0001). Serum sCD14 levels were significantly associated with CD14/-159 genotypes (p = 0.004). Atopic subjects with CC genotype in CD14/-159 had the highest serum total IgE levels compared with CT and TT genotypes, with the respective mean values being 661, 427 and 380 kIU/l (p = 0.015). Similarly, a higher proportion of subjects with CC genotype had increased serum total IgE concentration (p = 0.039). This polymorphic marker was not associated with asthma or aeroallergen sensitization in our cohort. Our results suggest that the C-159T of CD14 was associated with serum total IgE concentration in atopic Chinese children. [ABSTRACT FROM AUTHOR]

Thromboxane A2 and its receptor (TBXA2R) are involved in the constriction of vascular and respiratory smooth muscles. The T924C polymorphism in the TBXA2R gene was recently found to be associated with asthma in Japanese adults but not in children. Its relationship with atopy or asthma severity in children has not been defined. To investigate this further, we first assessed the severity of asthma in Chinese children using a standardized questionnaire modified from the Disease Severity Score and spirometric evaluation. Then, peripheral blood was analyzed for serum total and aeroallergen-specific immunoglobulin E (IgE) levels, and TBXA2R T924C genotypes were determined by restriction fragment length polymorphism (RFLP) analysis. One-hundred and fifty three asthmatic patients and 57 control children were recruited, of respective mean ages 9.9 and 11.0 years (p = 0.07). The mean logarithmic serum total IgE concentration was 2.57 and 2.09, respectively, for the asthmatic group and control group (p < 0.0001). Atopy was detected in 132 (86%) asthmatics and 33 (58%) controls. A significant association was observed between T924C and the diagnosis of atopic asthma (p = 0.044; odds ratio: 1.84). In addition, those asthmatics homozygous for the mutant allele in T924C had a lower forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC ) (p = 0.032 and 0.002, respectively). Among our asthmatic patients, the TBXA2R T924C polymorphism correlated with the concentration of cat-specific IgE in serum (p = 0.046). Nonetheless, this gene marker did not show an association with the serum total IgE concentration or any clinical indicator of asthma severity. In conclusion, our results suggest that the T924C marker in the TBXA2R gene is associated, in Chinese children, with an increased susceptibility of developing atopic asthma. This marker is also associated with the extent of allergic sensitization to cat, as well as with reduced... [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the revelation of the thyrotoxic periodic paralysis (TPP) on 17q24.3 near KCNJ2 gene with the use of the genome-wide association studies (GWAS).