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The present study aims to discover single nucleotide polymorphisms (SNPs) at the apelin gene (APLN) in relation to arterial stiffness, and to explore its molecular mechanisms. A two-step genetic association study was conducted using 799 and 937 subjects in the screening and validation data, respectively. Four tagging SNPs of APLN were tested. SNP rs3115757 was significantly associated with stiffness parameters (β, Ep and PWV) in women, but not in men. The function of rs3115757 was tagged by rs3115758 which is located in miR-765 binding site in the 3' untranslated region of APLN. The reporter assay confirmed that different alleles of rs3115758 interfered with miR-765 binding and then modified APLN expression. Over-expression of miR-765 in endothelial cells decreased mRNA and protein levels of APLN, which further inhibited the phosphorylation of eNOS and ERK/Akt/AMPK signaling. Collectively, our data showed that rs3115758 accounts for the susceptibility of arterial stiffening through miR-765-induced APLN repression., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Fibroblast growth factor-10 (FGF10) can modulate extracellular matrix associated genes and, therefore, it could be a myopia susceptibility gene. This study used an animal model, single nucleotide polymorphisms (SNPs) association, and genetic functional assay to evaluate FGF10 gene for myopia., Methods: The expression levels of FGF10 gene were compared among the form deprivation myopic (FDM) eyes, the fellow eyes of the FDM group, and the healthy eyes of experimental mice. In the present study 1020 cases (≤-6.0 diopters [D]) and 960 controls (≥-1.5 D) were enrolled from a Chinese population. Eight tagging SNPs were genotyped to test for an association between genotypes and myopia. The luciferase reporter assay was conducted for the particular SNP to assess the allelic effect on gene expression., Results: The sclera of FDM eyes had a 2.57-fold higher level of FGF10 mRNA (P = 0.018) than the fellow eyes. Although no SNP was associated with high myopia, SNP rs339501 was significantly associated with extreme myopia (≤-10 D, P = 0.008) and the odds ratio (OR) was 1.58 for G allele carriers. The luciferase assay showed that the risk G allele significantly caused a higher expression level than the A allele (P = 0.011)., Conclusions: The evidence suggested FGF10 to be a risk factor for myopia. The sclera of myopic eyes had higher FGF10 levels. The risk G allele of SNP rs339501 was associated with extreme myopia in human and caused a higher gene expression in the luciferase assay. It is concluded that the FGF10 could have been involved in the development of myopia.

Background: Atherosclerosis shares common pathogenic features with myocardial infarction (MI) and ischemic stroke. BRCA-1 associated protein (BRAP), a newly identified risk gene for MI, aggravates the inflammatory response in atherosclerosis. The aim of this study was to test the association between the BRAP gene and stroke in a Taiwanese population., Methods: A total of 1,074 stroke patients and 1,936 controls were genotyped for the functional SNP rs11066001. In our previous studies, the rare allele of this SNP has been repeatedly shown to exert a recessive effect. Therefore, in the current study, we tested for the same recessive model. First, the genotype distributions between all the controls and all the stroke cases were compared. Then to reduce heterogeneity, we explored several population subsets by selecting young stroke subjects (using 45 years of age as the cutoff point), age- and sex-comparable controls, plaque-free controls, and stroke subtypes., Results: We did not find any significant association for the entire data set (OR = 0.94, p = 0.74) or for the subset analyses using age- and sex-comparable controls (p = 0.70) and plaque-free controls (p = 0.91). Analyses of the four stroke subtypes also failed to show any significant associations (p = 0.42 - 0.98). For both young and old subjects, the GG genotype of rs11066001 was similar in the stroke cases and unmatched controls (8.1% vs. 9.4% in young subjects and 8.0% vs. 7.8% in old subjects). Comparing stroke cases with plaque-free controls also failed to find any significant association., Conclusions: The BRAP polymorphism may not play an important role in ischemic stroke in the studied population.

Purpose: Fibroblast growth factor-2 (FGF2) has been implied in the development of myopia according to previous studies investigating FGF2 in the sclera and retinal pigment epithelium. This study measured retinal FGF2 gene expression in an animal model and also tested for the association between single nucleotide polymorphisms (SNPs) in FGF2 and high myopia., Methods: The guinea pigs were assigned to 2 groups: form deprivation myopia (FDM) for two weeks and normal control (free of form deprivation). Biometric measurement was performed and FGF2 expression levels were compared among the FDM eyes, the fellow eyes of the FDM group and the normal eyes in retina. We also enrolled 1,064 cases (≤-6.0 D) and 1,001 controls (≥-1.5 D) from a Chinese population residing in Taiwan. Six tagging SNPs were genotyped to test for an association between genotypes and high myopia., Results: The FDM eyes had the most prominent changes of refraction and axial length. Compared with the mRNA levels of FGF2 in the normal eyes, the FDM eyes had the highest levels of mRNA (p=0.0004) followed by the fellow eyes (p=0.002). The FDM and normal eyes became more myopic compared with the fellow eyes, but the fellow eyes became more hyperopic (p=0.004) in the end of the experiment which may be due to its relatively short axial length when compared with normal eyes (p=0.05). The SNP genotypes were all in Hardy-Weinberg equilibrium. However, none of the SNPs were significantly associated with high myopia (all p values >0.1)., Conclusions: We identified a significant change of FGF2 expression in the FDM eyes but FGF2 genetic variants are unlikely to influence susceptibility to myopia. There may be a systemic effect to influence gene expression and refraction on the fellow eyes, which may perturb emmetropization in the fellow eyes. Our data also suggest using normal eyes rather than the fellow eyes as the control eyes when study the form deprivation myopia.

Atopic dermatitis is a chronic inflammatory skin disease. Multiple genetic and environmental factors are thought to be responsible for susceptibility to AD. In this study, we collected 2,478 DNA samples including 209 AD patients and 729 control subjects from Taiwanese population and 513 AD patients and 1027 control subject from Japanese population for sequencing and genotyping ORAI1. A total of 14 genetic variants including 3 novel single-nucleotide polymorphisms (SNPs) in the ORAI1 gene were identified. Our results indicated that a non-synonymous SNP (rs3741596, Ser218Gly) associated with the susceptibility of AD in the Japanese population but not in the Taiwanese population. However, there is another SNP of ORAI1 (rs3741595) associated with the risk of AD in the Taiwanese population but not in the Japanese population. Taken together, our results indicated that genetic polymorphisms of ORAI1 are very likely to be involved in the susceptibility of AD.

Background: Gallstone disease (GSD) is a common disease that can be caused by environmental influences, common genetic factors and their interactions. Mucin glycoproteins may be one important factor for GSD. We conducted a case-control study to investigate the relationship between the mucin-like protocadherin (MUPCDH) gene polymorphisms and GSD., Methods: The study included 452 GSD cases and 491 healthy controls who had no evidence of gallstones by ultrasound examination. Two common tagging single nucleotide polymorphism (SNP) rs3758650 and rs7932167, and four non-synonymous SNPs rs34362213, rs2740375, rs7108757 and rs2740379 were genotyped. The genetic effects were evaluated using the multivariate regression model., Results: The genotypes of these SNPs were all in Hardy-Weinberg equilibrium. Three non-synonymous SNPs (rs34362213, rs7108757 and rs2740379) were monomorphic. The single SNP analysis showed two SNPs (rs7932167 and rs2740375) were not associated with GSD and only SNP rs3758650 had the association of the presence of GSD with an odds ratio (OR) of 1.59 (adjusted P=0.013) for the AG genotype and 5.82 (adjusted P=0.007) for the AA genotype when compared with the reference GG genotype. The haplotype analysis of the three polymorphic SNPs showed GCA was significant for GSD (adjusted p=0.001) with an odds ratio (OR) of 1.41 when compared to other haplotypes., Conclusions: The MUPCDH genetic polymorphism rs3758650 was considered a genetic marker to predict symptomatic GSD subjects. It may be of importance for GSD patients with the risk SNPs to be frequently checked because they may develop symptomatic GSD., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The BRCA-1 associated protein gene (BRAP) was recently identified as a susceptibility gene for myocardial infarction (MI). In the present study we aimed to decipher the association between the BRAP polymorphism and carotid atherosclerosis and the mechanism underlying its proatherogenic effect. A total of 1749 stroke/MI-free volunteers received carotid ultrasonic examinations for the measurement of intima-medial thickness (IMT) and plaque. The promoter polymorphism rs11066001 was selected because it affects the transcription of BRAP. We found that the GG genotype was associated with a 1.58-fold increased risk for having at least one plaque compared to carrying the A allele (P = 0.021). When subjects were divided by the cutoff value of IMT above the mean plus 1 standard deviation, there was an overrepresentation of the GG genotype in the subjects with thicker IMT (P = 0.004). The expression of BRAP increased significantly when human aortic smooth muscle cells (HASMCs) were treated with lipopolysaccharide (LPS). HASMCs were transfected with small interfering RNA against BRAP or scrambled sequences before treatment with LPS. Knockdown of BRAP led to attenuated HASMC proliferation and reduced secretion of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) in response to LPS. Downregulation of BRAP did not affect the protein levels of nuclear factor-κB (NF-κB), but prohibited its nuclear translocation. Coimmunoprecipitation experiments confirmed an interaction between BRAP and the two major components of the IKK signalosome, IκBβ and IKKβ. Collectively, BRAP conferred a risk for carotid plaque and IMT. Inflammatory stimuli upregulated BRAP expression, and BRAP activated inflammatory cascades by regulating NF-κB nuclear translocation.

Background: Apelin, which is a newly identified adipokine, is related to obesity and insulin resistance. A positive correlation between plasma apelin concentrations and obesity traits was reported., Objective: We tested associations between apelin gene (APLN) polymorphisms, BMI, and waist circumference (WC) and compared APLN expression levels in cells of different genotypes., Design: Four tagging single nucleotide polymorphisms (SNPs) and one promoter SNP were genotyped in 1627 Chinese subjects. Because APLN was located on the chromosome X, statistical analyses were conducted in a sex-specific manner. Adipocytes of different genotypes were derived from the omental fat tissue of 10 women. We treated the primary adipocytes with high glucose plus insulin because of a close relation between insulin resistance and obesity., Results: SNP rs3115757 was significantly associated with BMI and WC in women. Compared with the CG or GG genotype, the CC genotype had an OR of 2.07 (95% CI: 1.23, 3.49) for having a high WC (P = 0.006) and an OR of 2.29 (95% CI: 1.25, 4.19) for having a BMI (in kg/m(2)) ≥27 (P = 0.007). None of the SNPs was associated with BMI or WC in men. In adipocytes that carried the CC genotype of rs3115757, APLN messenger RNA levels and protein concentrations were higher in cells treated with high glucose plus insulin than in those with normal glucose. There was no difference between the 2 conditions in adipocytes of the CG or GG genotype., Conclusion: Both association and functional studies suggested that APLN polymorphisms were associated with risks of obesity phenotypes.

Objective: Kawasaki disease (KD) is characterized by systemic vasculitis of an unknown cause. A previous study has indicated that a polymorphism of the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene is involved in the susceptibility to KD. ORAI (also known as CRACM1) is one of the components of store-operated calcium channels involved in regulating immune and inflammatory reactions. This study was conducted to investigate if polymorphisms in ORAI1/CRACM1, a gene downstream from ITPKC, are associated with KD susceptibility and clinical outcomes., Materials and Methods: A total of 1,056 subjects (341 KD patients and 715 controls) were investigated to identify five tagging single nucleotide polymorphisms (tSNPs) in ORAI1/CRACM1 (rs12313273, rs6486795, rs7135617, rs12320939, and rs712853) by using the TaqMan Allelic Discrimination assay., Results: No significant associations between genotype and allele frequency of the five ORAI1/CRACM1 tSNPs were observed in the KD patients and controls. In KD patients, no significant associations between ORAI1/CRACM1 polymorphisms and coronary artery lesion (CAL) formation or intravenous immunoglobulin (IVIG) treatment response were observed. The results from haplotype analysis were insignificant., Conclusions: This study showed for the first time that ORAI1/CRACM1 polymorphisms are not associated with KD susceptibility, CAL formation, or IVIG treatment response in the Taiwanese population.

Purpose: The paired box 6 (PAX6) is involved in eye development and associated with several ocular diseases. Conflicting results have been reported regarding the association between PAX6 polymorphism and myopia. This case-control study and functional assay were conducted to identified a functional risk polymorphism for myopia., Methods: The study cohort included 1083 cases (≤ -6.0 D) and 1096 controls (≥ -1.5 D) from a Chinese population residing in Taiwan. Four common tag single-nucleotide polymorphisms (SNPs) and an SNP at the 3' untranslated region (UTR) were selected. Secondary analyses were conducted in which cases and controls were redefined based on different spherical refractions. Permutation was used to adjust for multiple testing. The luciferase reporter assay was conducted for the 3'UTR SNP to assess the allelic effect on gene expression., Results: SNPs rs644242 and rs662702 had marginal significance (P = 0.063), and further analyses showed that these SNPs were associated with extreme myopia (≤ -11 D). The OR for extreme myopia was 2.1 (empiric P = 0.007) for the CC genotype at SNP rs662702 at the 3'UTR. The functional assay for SNP rs662702 demonstrated that the C allele had a significantly lower expression level than did the T allele (P = 0.0001). SNP rs662702 was predicted to be located in the microRNA-328 binding site, which may explain the differential allelic effect on gene expression. CONCLUSIONS; In this study, a functional SNP was identified at the 3'UTR that influences the risk for extreme myopia. The functional assay suggested that the risk allele can reduce PAX6 protein levels which significantly increases the risk for myopia.

Purpose: Store-operated calcium entry has been considered an important factor to regulate inflammatory reactions in nonexcitable cells. However, the effects of genetic polymorphisms of ORAI1, a main component of store-operated calcium channels, on nephrolithiasis and stone recurrence remain unclear. We investigated the association between calcium containing nephrolithiasis and genetic variants of ORAI1 gene in Taiwanese patients., Materials and Methods: A case-control study was performed in 136 patients with nephrolithiasis and 500 controls. Five tagging single nucleotide polymorphisms of ORAI1 were selected for genotyping. ORAI1 genotypes were determined by TaqMan® assay. Hardy-Weinberg equilibrium in cases and controls was assessed, and genetic effects were evaluated by the chi-square test and sliding window haplotype analysis. Subset analysis was done according to family history., Results: Two single nucleotide polymorphisms (rs12313273 and rs6486795) of the ORAI1 gene were associated with the risk of nephrolithiasis. The C allele carrier for rs12313273 was strongly related to recurrent stone forming in patients. On sliding window analysis the results of the 2 (rs12313273 and rs7135617) and the 3 (rs12313273, rs7135617 and rs6486795) single nucleotide polymorphism haplotypes had more significant effects on the risk of nephrolithiasis than the single nucleotide polymorphism rs12313273., Conclusions: To our knowledge this is the first study identifying the novel polymorphisms of the ORAI1 gene, which may predispose to the risk of calcium nephrolithiasis and disease recurrence., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Kawasaki disease (KD) is characterized by systemic vasculitis with unknown etiology. Previous studies from Japan indicated that a gene polymorphism of ITPKC (rs28493229) is responsible for susceptibility to KD. We collected DNA samples from 1,531 Taiwanese subjects (341 KD patients and 1,190 controls) for genotyping ITPKC. In this study, no significant association was noted for the ITPKC polymorphism (rs28493229) between the controls and KD patients, although the CC genotype was overrepresented. We further combined our data with previously published case/control KD studies in the Taiwanese population and performed a meta-analysis. A significant association between rs28493229 and KD was found (Odds Ratio:1.36, 95% Confidence Interval 1.12-1.66). Importantly, a significant association was obtained between rs28493229 and KD patients with aneurysm formation (P = 0.001, under the recessive model). Taken together, our results indicated that C-allele of ITPKC SNP rs28493229 is associated with the susceptibility and aneurysm formation in KD patients in a Taiwanese population.

Background: Gallstone is a complex disease caused by multiple environmental and genetic factors. One of these is mucin glycoproteins. This case-control study aimed to investigate the association between single nucleotide polymorphisms (SNPs) at the MUC1-4 genes and gallstone., Methods: The study included 475 cases and 941 controls. Eight tagging SNPs were selected: one at MUC1, two at MUC2, and five at MUC4. There was no available tagging SNP at MUC3. Genetic effects were initially evaluated by multivariate logistic regression. The combined effects from multiple genes were further evaluated, as well as the sex-specific effect. Permutation was used to correct for multiple testing., Results: The genotypes were all in Hardy-Weinberg equilibrium. SNP rs7396030 at MUC2 yielded a p value of 0.03. Further sex-specific analysis showed significance solely with male subjects (p=0.005). Similarly, SNP rs4072037 at MUC1 was only significant (p=0.035) in males. The permutation empirical p values were 0.005 for rs7396030 and 0.02 for rs4072037. For males, the combined genetic effect yielded an OR of 4.68 (p=0.0008)., Conclusions: The SNPs at MUC1 and MUC2 are significantly associated with gallstone in men but not in women. These genes can work jointly to further increase susceptibility to gallstone in a Chinese population., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Kawasaki disease (KD) is characterized by systemic vasculitis of unknown etiology. A study from Japan reported that G to A substitution of a single-nucleotide polymorphism (SNP) located in the 5'-untranslated region of caspase 3 (CASP3) (rs72689236), which was associated with nuclear factor of activated T cell-mediated T-cell activation, is responsible for susceptibility to KD. This study was conducted to investigate whether the polymorphism of CASP3 is responsible for susceptibility and coronary artery lesion (CAL) formation in KD in the Taiwanese population. A total of 1092 subjects (341 KD patients and 751 controls) were investigated to identify an SNP of rs72689236 using Invader assays (Third Wave Technologies). Our data provided a borderline significant association between the genotypes and allele frequency of rs72689236 in control subjects and KD patients (P=0.0535 under the dominant model; P=0.0575 under the allelic model). The A allele of rs72689236 in KD patients and in patients with CAL and intravenous immunoglobulin resistance was seen in a higher frequency. Importantly, a significant association was obtained between rs72689236 and KD patients with aneurysm formation (P=0.009, under the recessive model). The A allele of rs72689236 is very likely to be a risk allele in the development of aneurysm in patients with KD.

Backgrounds: Insulin resistance plays a major role in the pathogenesis of the metabolic syndrome. Inflammation is the leading cause of insulin resistance, and interleukin 10 (IL-10) is one of the anti-inflammatory cytokines. We conducted a case-control study to investigate the association between the IL-10 polymorphisms and the metabolic syndrome., Methods: One thousand two hundred two unrelated subjects residing in southern Taiwan were retrospectively recruited from a community-based health screening program. Two hundred sixty subjects were defined as the metabolic syndrome (3-5 risk components) and 549 subjects as controls (0-1 risk component) on the basis of the Asian version of the Adult Treatment Panel III criteria. A functional IL-10 single nucleotide polymorphism (SNP; rs1800871) and 2 tagging SNPs (rs3790622, rs3021094) were genotyped by TaqMan method., Results: We analyzed the association between the genotypes and the presence of the metabolic syndrome or metabolic traits by χ² test and multivariant logistic regression. None of the IL-10 SNPs were found to be significantly related with the metabolic syndrome or its risk components. All the 3 SNPs were in single linkage disequilibrium block. Haplotype analysis did not yield significant association between IL-10 gene and the metabolic syndrome (global P = 0.88)., Conclusions: Because we used tagging SNPs and a modest clinical cohort, we concluded that the IL-10 gene polymorphisms may be unlikely to play an important role for the metabolic syndrome.

Background: Chromosome 9p21 has recently been shown to be a risk region for a broad range of vascular diseases. Since carotid intima-media thickness (IMT) and plaque are independent predictors for vascular diseases, the association between 9p21 and these two phenotypes was investigated., Methodology/principal Findings: Carotid segment-specific IMT and plaques were obtained in 1083 stroke- and myocardial infarction-free volunteers. We tested the genotypes and haplotypes of key single nucleotide polymorphisms (SNPs) on chromosome 9p21 for the associations with carotid IMT and plaque. Multivariate permutation analyses demonstrated that carriers of the T allele of SNP rs1333040 were significantly associated with thicker common carotid artery (CCA) IMT (p=0.021) and internal carotid artery (ICA) IMT (p=0.033). The risk G allele of SNP rs2383207 was associated with ICA IMT (p=0.007). Carriers of the C allele of SNP rs1333049 were found to be significantly associated with thicker ICA IMT (p=0.010) and the greater risk for the presence of carotid plaque (OR=1.57 for heterozygous carriers; OR=1.75 for homozygous carriers). Haplotype analysis showed a global p value of 0.031 for ICA IMT and 0.115 for the presence of carotid plaque. Comparing with the other haplotypes, the risk TGC haplotype yielded an adjusted p value of 0.011 and 0.017 for thicker ICA IMT and the presence of carotid plaque respectively. Further analyzing the data separated by sex, the results were significant only in men but not in women., Conclusions: Chromosome 9p21 had a significant association with carotid atherosclerosis, especially ICA IMT. Furthermore, such genetic effect was in a gender-specific manner in the Han Chinese population.

Background: Vascular endothelial growth factor (VEGF) plays a pivotal role in angiogenesis. This study tested the association between functional VEGF +405 C>G (rs2010963), -2578C>A (rs699947) polymorphisms, and coronary collaterals in patients with coronary artery disease (CAD)., Method: The collateral scoring system developed by Rentrop was used to classify 393 patients according to their collaterals as either "poor" (grades 0 and 1) or "good" (grades 2 and 3). Gene polymorphisms were analyzed by TaqMan assay., Results: The frequency of +405C and -2578A alleles was higher in the good collaterals group (p=0.007 and 0.005, respectively). For the +405C>G allele, the odds ratio (OR) of good collaterals for CC to GG genotype was 2.54 (p=0.003). For the -2578A allele, the OR of good collaterals for AA to CC genotype was 2.31 (p=0.038). Univariate and logistic regression analysis found 2 polymorphisms in the additive model for associations with collateral development: +405C>G (p=0.005 and 0.010) and -2578C>A (p=0.006 and 0.006). The VEGF +405C>G polymorphism and DM revealed an interactive effect on collateral development (p=0.027)., Conclusions: The VEGF +405C>G and -2578C>A polymorphisms might be novel genetic factors affecting collateral development in Chinese patients., (2010 Elsevier B.V. All rights reserved.)

Background: Glutathione peroxidase 3 (GPX3) can enhance an antioxidant's capacity and reduce genomic damage caused by oxidants and thus influence tumorigenesis. We investigated the role of GPX3 as a risk of gastric cancer., Methods: We first conducted a case-control study to test for the association between 5 tagging single nucleotide polymorphisms (SNPs) of GPX3 and the risk of gastric cancer in Chinese. Multivariate logistic regression analysis was performed to estimate the genetic effect with adjustments for age and sex. Functional studies were performed by using the luciferase reporter assay to assess functional consequences of the significant SNPs., Results: Among five SNPs (rs3763013, rs8177412, rs3805435, rs3828599, and rs2070593) genotyped in 227 cases and 844 controls, 3 SNPs were significant: intronic SNP rs3805435 (OR=0.70, P=0.037), intronic SNP 3828599 (OR=0.68, P=0.025), and 3' UTR SNP rs2070593 (OR=0.48, P=0.001). The two intronic SNPs rs3805435 and SNP rs3828599 were in linkage disequilibrium (D'=0.91)., Conclusions: The reporter assays showed significant difference in the luciferase expression between protective and risk alleles of 2o intronic SNPs (P=0.004), whereas the 3'UTR SNP did not influence the luciferase expression. The intronic SNPs at GPX3 can influence gene expression leading to an alteration of gastric cancer risk., (Copyright 2010 Elsevier B.V. All rights reserved.)

Objective: To investigate the involvement of inflammation in the development of endometriosis., Design: Case-control study to investigate the association between endometriosis and four inflammation-related genes: interleukin (IL)-6, IL-10, IL-1 beta, and cyclooxygenase-2., Setting: University hospital., Patient(s): We had 196 cases with pathologically proved endometriosis and 397 disease-free women as control subjects., Intervention(s): A total of 12 single nucleotide polymorphisms (SNPs) were selected for genotyping, including functional SNPs and common tagging SNPs., Main Outcome Measure(s): Logistic regression and haplotype analyses were performed to evaluate the genetic effect with adjustment for other covariates., Result(s): Genotypes at each SNP were in Hardy-Weinberg equilibrium in either case or control subjects, except for rs1800871 at IL-10 in the case subjects (P=.04). We found that the individuals carrying minor allele C of a functional promoter SNP rs1800871 at IL-10 was associated with a reduced risk by approximately twofold compared with the common TT genotype. The T allele was reported to have a lower gene expression level than the C allele, suggesting inadequate suppression of inflammation leading to endometriosis development. Haplotype analysis of the IL-10 gene did not yield a better result. Other genes were not associated with endometriosis., Conclusion(s): This study suggests that the functional promoter polymorphism at IL-10 may play a role in the development of endometriosis.

Background: The antioxidant enzyme glutathione peroxidase 3 (GPX3) can lessen the oxidative stress in the thyroid gland. We tested for the association between tagging single nucleotide polymorphisms (tSNPs) of the GPX3 gene and the risk of differentiated thyroid cancer (DTC)., Methods: A total of 6 tSNPs (rs3763013, rs8177412, rs3805435, rs3828599, rs3792796, and rs2070593) of GPX3 were genotyped in Chinese DTC cases (n = 268) and controls (n = 378). Multivariate logistic regression was performed to estimate the genetic effect with adjustment for age and sex., Results: There was no significant finding of genotype analysis in each tSNP associated with DTC, papillary thyroid carcinoma, or patients with regional lymph node metastasis. In the older group (age > or =45 years), subjects who carried at least 1 G allele of rs3805435 had a decreased risk of DTC compared with patients of AA homozygote (sex- and age-adjusted odds ratio [OR] = 0.50, P = .009). An individual with at least 1 T allele of rs3828599 had a decreased risk of DTC compared with an individual of the CC homozygote (sex- and age-adjusted OR = 0.53, P = .018). An individual carrying the TC genotype of rs8177412 in the older group had an increased risk of DTC than controls (sex- and age-adjusted OR = 1.73, P = .037)., Conclusion: We found that the G allele of rs3805435 or the T allele of rs3828599 may exert a protective effect for DTC in the older population, whereas the C allele of rs8177412 confers an increased risk effect for DTC.

Background and Purpose: Carotid intima-media thickness (IMT) is a surrogate marker of subclinical atherosclerosis and a strong predictor of stroke and myocardial infarction. The object of this study was to determine the association between carotid IMT and 702 single nucleotide polymorphisms in 145 genes., Methods: B-mode carotid ultrasound was performed among 408 Hispanics from the Northern Manhattan Study. The common carotid artery IMT and bifurcation IMT were phenotypes of interest. Genetic effects were evaluated by the multivariate regression model adjusting for traditional vascular risk factors. For each individual, we calculated a gene risk score (GRS) defined as the total number of the significant single nucleotide polymorphisms in different genes. Subjects were then divided into 3 GRS categories using the 2 cutoff points: mean GRS +/-1 SD., Results: We identified 6 significant single nucleotide polymorphisms in 6 genes for common carotid artery IMT and 7 single nucleotide polymorphisms in 7 genes for bifurcation IMT using the probability value of 0.005 as the significant level. There were no common significant genes for both phenotypes. The most significant genes were the tissue plasminogen activator (P=0.0005 for common carotid artery IMT) and matrix metallopeptidase-12 genes (P=0.0004 for bifurcation IMT). Haplotype analysis did not yield a more significant result. Subjects with GRS >or=9 had significantly increased IMT than those with GRS

Purpose: DNA BER pathway is related with carcinogenesis. We hypothesized that functional polymorphisms of three BER genes, XRCC1, apurinic/apyrimidinic endonuclease (APE1), and ADPRT, confer risks for DTC and its progression., Experimental Design: Five common nonsynonymous single nucleotide polymorphisms (Arg194Trp, Arg280His, and Arg399Gln for XRCC1; Asp148Glu for APE1; and Val762Ala for ADPRT) were genotyped in Chinese DTC cases and controls., Results: The XRCC1-194Trp/Trp genotype showed a significantly increased risk for DTC (odds ratio, 1.85; 95% confidence interval, 1.11-3.07; P = 0.018). Subset analysis based on regional LN metastasis showed that the genetic effect came primarily from the subjects with LN metastasis (odds ratio, 4.54; 95% confidence interval, 2.11-9.79; P = 0.0001), but no significant association for subjects without LN metastasis. The other four single nucleotide polymorphisms did not show significant results. Haplotype analysis of XRCC1 polymorphisms yielded a significant result (P = 0.004), especially in the subjects with LN metastasis (P = 0.0002). Moreover, we found that XRCC1-194Trp and ADPRT-762Ala variants collectively contributed to an increased risk of the disease and LN metastasis, with the combined variant homozygotes exhibiting the highest 3.18-fold risk for DTC (P = 0.046) and 9.25-fold risk for DTC with LN metastasis (P = 0.004)., Conclusions: The XRCC1 polymorphisms, especially the 194Trp allele, may have an effect on DTC development and progression. This variant can interact with ADPRT-762Ala variant to further substantially increase susceptibility to the disease and regional LN metastasis. Identifying these risk genetic markers could provide more insight into the DTC pathogenesis and may also provide information to develop better prevention and therapeutic strategies.

Objective: To systematically investigate the role of matrix metalloproteinase-2 (MMP2) tagging single nucleotide polymorphisms (SNPs) and promoter functional polymorphism in the development of nasal polyps in a Chinese population in Taiwan., Design: We conducted a case-control study in 136 cases of chronic rhinosinusitis with bilateral nasal polyps and 136 controls. Seventeen SNPs were selected, including 16 tagging SNPs and 1 promoter functional SNP. The genotypes were determined by TaqMan technology. Hardy-Weinberg equilibrium was tested for each SNP, and genetic effects were evaluated according to 3 modes of inheritance. Subset analysis based on the recurrence of nasal polyps was also performed., Setting: Medical university center hospital., Results: All 17 SNPs were in Hardy-Weinberg equilibrium. When comparing the patients with recurrent nasal polyps and controls, none of the SNPs reached the significant level of P < .05 except rs857403. The AT genotype of rs857403 had an adjusted odds ratio of 2.07 (95% confidence interval, 1.09-3.95) (P = .03). However, the result became nonsignificant after including an additional 691 controls. Therefore, we considered that the initial significance was a false-positive finding. Neither haplotype analysis nor subset analysis yielded any significant result., Conclusion: The MMP2 gene does not play a crucial role in conferring risk for nasal polyps in a Taiwanese population.

Reduced scleral collagen accumulation has been found in the development of myopia. Single nucleotide polymorphisms (SNPs) at the type I collagen alpha-1 gene (COL1A1) may cause different susceptibilities to myopia. We conducted a case-control study to systematically examine COL1A1 as a candidate gene for high myopia. A case was defined as spherical refraction or=-1.5 D. The study comprised 471 cases and 623 controls, and ten tagging SNPs were genotyped. None of the SNPs reached the significant level of 0.05. Subset analysis on cases with a strong family history did not demonstrate significant results. We could not find an interaction between gene and near work. Exploratory analyses by changing the cutoff values to re-define cases and controls did not improve the results. Haplotype analysis did not yield significant association with myopia. This study failed to demonstrate COL1A1 as a significant risk factor for high myopia.

We performed linkage and linkage disequilibrium (LD) mapping analyses to compare the power between microsatellite and single nucleotide polymorphism (SNP) markers. Chromosome-wide analyses were performed for a quantitative electrophysiological phenotype, ttth1, on chromosome 7. Multipoint analysis of microsatellite markers using the variance component (VC) method showed the highest LOD score of 4.20 at 162 cM, near D7S509 (163.7 cM). Two-point analysis of SNPs using the VC method yielded the highest LOD score of 3.98 in the Illumina SNP data and 3.45 in the Affymetrix SNP data around 152-153 cM. In family-based single SNP and SNP haplotype LD analysis, we identified seven SNPs associated with ttth1. We searched for any potential candidate genes in the location of the seven SNPs. The SNPs rs1476640 and rs768055 are located in the FLJ40852 gene (a hypothetical protein), and SNP rs1859646 is located in the TAS2R5 gene (a taste receptor). The other four SNPs are not located in any known or annotated genes. We found the high density SNP scan to be superior to microsatellites because it is effective in downstream fine mapping due to a better defined linkage region. Our study proves the utility of high density SNP in genome-wide mapping studies.

Objective: To investigate whether single-nucleotide polymorphisms in the promoter regions of endotoxin-responsive genes CD14 and tumor necrosis factor-alpha (TNF-alpha) are associated with biliary atresia (BA) and idiopathic neonatal cholestasis (INC)., Methods: We obtained genomic DNA from 90 patients with established diagnosis of BA and 28 patients with INC. Forty-two adult patients with hepatitis B-related cirrhosis and 143 healthy children served as control populations. The genotypes of CD14/C(-159)T and TNF-alpha/G(-308)A (G allele, TNF*1; A allele, TNF*2) were determined by using a restriction enzyme-based assay. Plasma soluble CD14 levels were determined in different disease stages and genotypes of BA., Results: The frequencies of T allele and T/T homozygosity of the CD14/-159 promoter polymorphism were significantly higher in patients with BA (T allele: 61.7%; T/T genotype: 42.2%) and in patients with INC (T allele: 67.9%; T/T genotype: 53.6%) but not in control populations. Decrease of plasma soluble CD14 from the early stage of BA when the patients received a Kasai operation to the late stage of liver cirrhosis was observed in carriers of the T/T and T/C genotypes but not in carriers of the C/C genotype. The TNF-alpha/-308 promoter polymorphisms (TNF*1 and TNF*2) were not associated with BA., Conclusion: These findings show that the single-nucleotide polymorphism at CD14/-159 is associated with the development of BA and INC. Endotoxin susceptibility may play a role in the pathogenesis of infantile cholestasis.

We studied the A/G single nucleotide polymorphism (SNP) at position 49 in exon 1 of the cytotoxic T lymphocyte-associated molecule-4 gene in 148 Chinese Graves' disease (GD) patients and 171 controls. Our primary aim was to test for the association of this SNP with the relapse of the hyperthyroidism after antithyroid withdrawal. Our secondary aim was to investigate the relationship between GD patients and controls according to the SNP genotypes. All GD patients were divided into the following three groups according to the time of relapse after drug discontinuation: group 1, early relapse within 9 months; group 2, relapse between 10 and 36 months; and group 3, relapse 3 or more years after discontinuation of treatment. There was a significant difference of genotype frequencies (P < 0.001) and allele frequencies (P < 0.001) among the three groups of patients. The frequency of the G/G genotype decreased from 79% to 64% and 39% in groups 1, 2, and 3, respectively. Compared with controls, a strong association (P < 0.001) of G allele was found for group 1, and moderate significance (P = 0.04) was found for group 2, but no association (P = 0.33) was found for group 3. At the end of treatment, the percentage of patients with persistent TSH-receptor antibody was statistically different (A/A, 9.0%; A/G, 20.8%; G/G, 45.5%; P = 0.004). Using 3 yr as the cutoff point for multivariate logistic regression analysis, we found that the G/G genotype (adjusted odds ratio, 3.1 compared with A/G plus A/A; 95% confidence interval, 1.3-7.1), larger goiter size at the end of treatment, and positive TSH-receptor antibody at the end of treatment were independent risk factors of recurrence. We conclude that the A/G polymorphism of the cytotoxic T lymphocyte-associated molecule-4 gene affects the progress of GD. The G/G genotype is associated with poor outcome.