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Objectives: This study aimed to investigate the association between circulating interleukin-6 (IL-6) levels and Behçet's disease (BD), and associations between polymorphisms in IL-6 gene and BD susceptibility., Method: A search of relevant articles was conducted in the Medline, Embase, and Web of Sciences databases. Subsequently, a meta-analysis was performed to assess circulating IL-6 levels in both the BD and control groups. Additionally, we investigated the association between the functional IL-6 promoter -174 G/C polymorphism and the risk of developing BD., Results: Nineteen studies involving 923 patients with BD and 910 controls were included in this meta-analysis. The results demonstrated a significant elevation in circulating IL-6 levels in the BD group than in the control group (standardized mean difference [SMD] = 1.600, 95 % confidence interval [CI] = 0.732-2.496, P<0.001). Furthermore, IL-6 levels were significantly higher in the active disease group than in the inactive disease group (SMD=1.292, 95 % CI=0.059-2.525, P<0.001). Intriguingly, the meta-analysis revealed an association between BD and the IL-6 CC+CG genotype in Arabs (odds ratio [OR] = 0.588, 95 % CI=0.393-0.881, P=0.010), whereas no such association was observed in European or Asian populations., Conclusions: Our meta-analysis revealed significantly higher circulating IL-6 levels in patients with BD and found evidence of association between IL and 6 promoter -174 G/C and BD susceptibility., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Owing to their role in inflammatory reactions and immunological responses as well as their chromosomal location, interleukin (IL) 17A and 17F are regarded as candidate causal genes associated with asthma. The aim of this study was to determine whether IL17 polymorphisms are associated with susceptibility to asthma. We used the PubMed/Medline and Embase databases to search for studies reporting IL17 polymorphisms in patients with asthma and healthy controls. Meta-analyses were conducted to determine the associations between IL17A rs8193036 (-737C/T), rs2275913 (-197G/A), rs3819024 (A/G), rs3748067 (C/T), and rs4711998 (A/G) and IL17F rs763780 (7488A/G), rs2397084 (T/C), rs1889570 (C/T), rs11465553 (G/A), and rs1266828 (T/C) polymorphisms and asthma susceptibility. A total of 20 studies were included in this meta-analysis. Our results revealed the IL17A rs8193036 CC genotype was associated with asthma susceptibility (odds ratio [OR] = 1.490, 95% confidence interval [CI] = 1.027-2.161, p = .036). However, stratification by ethnicity indicated no association between this polymorphism and asthma in European and Asian subjects. Furthermore, no association was found between this polymorphism and asthma using the allele contrast, dominant or homozygous contrast models. No evidence of an association was found between any of the other IL17A and IL17F polymorphisms and asthma susceptibility in this meta-analysis. This meta-analysis showed that, among the studied polymorphisms, only the CC genotype of IL17A rs8193036 is associated with asthma susceptibility., (© 2023 John Wiley & Sons Ltd.)

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury 1-4 . These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries 5 . Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction., (© 2022. The Author(s).)

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry 1,2 . Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis 3 , and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach 4 , we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry 5 . Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries., (© 2022. The Author(s).)

Objective: The present study was designed to determine whether the protein tyrosine phosphatase non-receptor 22 ( PTPN22 ) C1858T variant is associated with susceptibility to vasculitis. Methods: A meta-analysis was conducted to evaluate the association between the PTPN22 C1858T variant and vasculitis. A trial sequential analysis was performed to evaluate the robustness of the meta-analysis. Results: A total of 17 studies were included in this meta-analysis which revealed a highly significant association between the PTPN22 T allele and vasculitis of multiple types (odds ratio [OR] = 4.850, 95% confidence interval [CI] = 3.043-7.729, p  < 0.001). Meta-analysis by vasculitis type showed an association between the T allele and risk of giant cell arteritis (GCA) and antineutrophil cytoplasmic antibody-associated vasculitis (AAV) (OR = 7.505, 95% CI = 3.605-15.62, p  < 0.001; OR = 6.121, 95% CI = 3.216-11.65, p  < 0.001). The meta-analysis also indicated an association between the T allele and Takayasu's arteritis, but not between the T allele and Behcet's disease or Henoch-Schönlein purpura. TSA indicated that the observed association is conclusive with the existing evidence. Conclusions: This meta-analysis confirms that the PTPN22 C1858T variant is associated with susceptibility to GCA and AAV.

Our aim was to determine whether protein tyrosine phosphatase nonreceptor 22 (PTPN22) C1858T polymorphism (rs2476601) is associated with susceptibility to juvenile idiopathic arthritis (JIA). MEDLINE and EMBASE databases were searched to identify articles in which PTPN22 C1858T polymorphism was reported to be identified in JIA patients and controls. A meta-analysis was conducted to evaluate the association between PTPN22 C1858T polymorphism and RA using allelic contrast. Trial sequential analysis (TSA) was performed. Sixteen separate comparisons involving 5696 JIA patients and 9483 controls (a total of 15,179 subjects) were considered in this meta-analysis. A meta-analysis was performed with all JIA patients as well as JIA patients in each ethnic group. Meta-analysis revealed an association between the T allele of PTPN22 C1858T polymorphism and JIA in all subjects (OR, 1.322; 95% CI, 1.233-1.418; p < .001). Analysis after stratification by ethnicity indicated that the T allele was significantly associated with JIA in the European population (OR, 1.312; 95% CI, 1.2211-1.410; p < .001). However, analysis performed in the non-European population showed no significant association between the T allele and JIA. TSA indicated that the observed association between the PTPN22 polymorphism and JIA in all subjects and the European population is consistent with the existing evidence. This meta-analysis confirms that PTPN22 C1858T polymorphism is associated with susceptibility to JIA in Europeans, and that no additional studies are needed to verify these results. However, current evidence in the non-European population is insufficient, and further studies are warranted., (© 2022 John Wiley & Sons Ltd.)

The correlation between copy number variation (CNV) and the susceptibility to systemic lupus erythematosus (SLE) has been reported for various immunity-related genes. However, the contribution of CNVs to SLE susceptibility awaits more investigation. To evaluate the copy numbers in immunity-related genes such as TNFAIP3, TNIP1, IL12B, TBX21 (T-bet), TLR7, C4A, C4B, CCL3L1, and CCL3L3, the modified real competitive polymerase chain reaction (mrcPCR) assay was employed, and the association between the copy numbers and SLE susceptibility was analyzed in 334 SLE patients and 338 controls. CCL3L3-null status was significantly associated with SLE susceptibility (OR > 18, P < 0.0001), which remained significant by Bonferroni's correction (corrected P = 0.0007). However, the significant association between C4B low-copy status and SLE susceptibility (OR = 1.6051, P = 0.0331) became non-significant by Bonferroni's correction (corrected P = 0.3938). Except for these results, no other significant association between SLE susceptibility and copy number status in other genes was observed. The CCL3L3-null status may be a significant factor for SLE susceptibility., (© 2021. The Author(s).)

Background: Although previous studies had reported an important role of interleukin 13 (IL13) and its genetic polymorphisms in atopic dermatitis (AD), many of these previous reports focused on the missense variant rs20541 (Gln144Arg) without fine mapping of the gene region., Objective: To analyze the potential associations of other IL13 variants and their haplotypes with AD and assess total serum immunoglobulin E (IgE) levels., Methods: We performed fine mapping of single-nucleotide polymorphisms (SNPs) within the IL13 gene in a pilot study of 495 children with AD and 444 healthy controls. Then, we conducted a replication study of 757 children with AD and 1620 healthy controls to evaluate the association between the rs20541 variant of IL13 and AD., Results: In the pilot study, the rs20541 and rs1295685 SNPs in the 3'-untranslated region of IL13 had significant associations with AD (P < .001 and .01, respectively). In addition, 2 haplotypes (BL2&#95;ht1 and BL2&#95;ht2), which harbored the significant rs20541 and rs1295685 SNPs, had an association with AD (minimum P = .006). BL2&#95;ht1 and BL2&#95;ht2 had nominal signals associated with the total serum IgE levels (P < .05) but not with the severity of AD (P > .05). In the replication study, rs20541 was associated with the total serum IgE levels but not with the severity of AD., Conclusion: An additional IL13 gene SNP, rs1295685, has a strong linkage disequilibrium with rs20541, and its haplotypes are associated with AD and the total serum IgE levels., (Copyright © 2020 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Recent large-scale genome-wide association studies have identified common genetic variations that may contribute to the risk of amyotrophic lateral sclerosis (ALS). However, pinpointing the risk variants in noncoding regions and underlying biological mechanisms remains a major challenge. Here, we constructed a convolutional neural network model with a large-scale GWAS meta-analysis dataset to unravel functional noncoding variants associated with ALS based on their epigenetic features. After filtering and prioritizing of candidates, we fine-mapped two new risk variants, rs2370964 and rs3093720, on chromosome 3 and 17, respectively. Further analysis revealed that these polymorphisms are associated with the expression level of CX3CR1 and TNFAIP1, and affect the transcription factor binding sites for CTCF, NFATc1 and NR3C1. Our results may provide new insights for ALS pathogenesis, and the proposed research methodology can be applied for other complex diseases as well.

The aim of this study was to determine whether interleukin-10 (IL-10) polymorphisms are associated with susceptibility to Behcet's disease (BD). A meta-analysis was conducted, examining the associations between the IL-10 - 1082 G/A, - 819 C/T, and - 592 C/A polymorphisms and BD in various ethnic groups. Fourteen studies involving 5992 patients and 8966 controls were considered in the meta-analysis. Meta-analysis of the IL-10 - 1082 G/A polymorphism showed no association between BD and the - 1082 G allele (odds ratio (OR) = 0.951, 95% confidence interval (CI) = 0.790-1.146, p = 0.601). Meta-analysis of the IL-10 - 819 C/T polymorphism revealed a significant association between BD and the - 819 C allele (OR = 0.751, 95% CI = 0.684-0.825, p < 0.001) in all study subjects. Stratification by ethnicity indicated a significant association between the - 819 C allele and BD in Turkish (OR = 0.779, 95% CI = 0.709-0.856, p < 0.001) and Asian (OR = 0.676, 95% CI = 0.631-0.725, p < 0.001), but not in Middle Eastern populations. Meta-analysis of the - 592 C allele showed an association with BD in all study subjects (OR = 0.792, 95% CI = 0.662-0.948, p = 0.011) Stratification by ethnicity indicated a significant association between the - 592 C allele and BD in Asian populations (OR = 0.656, 95% CI = 0.512-0.841, p = 0.001). This meta-analysis showed that the IL-10 - 819 C/T and - 592 C/A polymorphisms are associated with BD susceptibility, especially in Asian population.

Background: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Recent evidence suggests that genetic factors are related to the pathogenesis of IgAN. We conducted a genome-wide association study (GWAS) to identify novel genetic susceptibility loci for IgAN in a Korean population., Methods: We enrolled 188 biopsy-confirmed IgAN cases and 455 healthy controls for the discovery stage and explored associations between IgAN and single nucleotide polymorphisms (SNPs) using a customized DNA chip. The significant SNPs from the discovery samples were then selected for replication in an independent cohort with 310 biopsy-confirmed IgAN cases and 438 healthy controls., Results: In the first stage, two SNPs (rs10172700 in LOC105373592 and rs2296136 in ANKRD16) were selected for further association analysis in the next stage. In the replication cohort, rs2296136 in ANKRD16 was significantly associated with IgAN (odds ratio [OR] = 1.40, 95% confidence interval [CI] 0.99-1.98, p = 0.05 in log-additive model, OR = 1.55, 95% CI = 1.06--2.27, p = 0.02 in dominant model, and OR = 0.70, 95% CI = 0.17--2.84, p = 0.62 in recessive model). rs2296136 in ANKRD16 also showed a significant association with IgAN in the entire study population combining GWAS and replication study (p = 0.0045 in log-additive model, p = 0.0027 in dominant model, and p = 0.76 in recessive model)., Conclusions: The SNPs identified in the present study could be good candidate markers for predicting IgAN in Koreans, although further experimental validation is needed.

Objectives: We reviewed the associations between paraoxonase 1 (PON1) polymorphisms and susceptibility and PON1 activity in rheumatoid arthritis (RA) patients and compared PON1 activity between RA patients and controls., Methods: We conducted a meta-analysis of PON1 Q192R and L55M polymorphism and RA risk data and determined the associations between PON1 Q192R polymorphism and PON1 activity in RA patients. We also compared serum/plasma PON1 activity levels in RA patients and controls., Results: Twelve studies were included in this meta-analysis. No association was observed between RA and the PON1 192R allele in any study subject (OR = 0.967, 95% CI = 0.829-1.129, p = 0.674). Analysis using recessive, dominant, or homozygous contrast models revealed no association between the PON1 192R allele and RA. Meta-analysis showed no association between RA and the PON1 55M allele (OR = 1.400, 95% CI = 0.738-2.658, p = 0.308). In the meta-analysis, PON1 activity was significantly higher in the RR genotype than in the QQ (SMD = 2.975, 95% CI = 2.157-3.792, p < 0.001) and QR (SMD = 1.265, 95% CI = 0.898-1.633, p < 0.001) genotypes. PON1 activity was significantly lower in the RA group than in the control group (SMD = - 3.176, 95% CI = - 5.070 to - 1.283, p < 0.001)., Conclusions: We found no association between the PON1 Q192R and L55M polymorphisms and susceptibility to RA, while PON1 Q192R polymorphism was associated with PON1 activity in RA patients; we found significantly lower PON1 activity in RA patients.Key points• PON1 Q192R polymorphism is associated with PON1 activity in RA patients..• PON1 activity is significantly lower in RA patients..

Objective: The aim of this study was to determine whether the brain-derived neurotrophic factor ( BDNF) 196 G/A or catechol- O-methyltransferase ( COMT) Val158Met polymorphisms is associated with susceptibility to ADHD., Method: We conducted a meta-analysis of the associations between the BDNF 196 G/A and COMT Val158Met polymorphisms and ADHD., Results: Sixteen studies consisting of 3,594 patients with ADHD and 4,040 controls were included in this meta-analysis. Our results showed no association between ADHD and the BDNF 196A allele in all participants (odds ratio [OR] = 0.958, 95% confidence interval [CI] = [0.800, 1.146], p = .638), European or Asian population. Meta-analysis indicated no association between ADHD and the COMT G allele in all study participants (OR = 1.078, 95% CI = [0.962, 1.207], p = .196), European or Asian population., Conclusion: This meta-analysis showed a lack of association between the BDNF 196 G/A and COMT Val158Met polymorphisms and ADHD.

Objective: The aim of this study was to determine whether the serotonin transporter-linked polymorphic region (5-HTTLPR) L (long)/S (short) polymorphism is associated with susceptibility to ADHD., Method: We conducted a meta-analysis of case-control associations and the transmission disequilibrium test (TDT) between the 5-HTTLPR L/S polymorphism and ADHD., Results: A total of 19 comparison studies were included in this meta-analysis. Our meta-analysis of the case-control studies showed no association between ADHD and the 5-HTTLPR S allele, for all study participants (odds ratio [OR] = 1.075, 95% confidence interval [CI] = [0.990, 1.167], p = .085), or for the European or Asian population. The TDT indicated no association between ADHD and the 5-HTTLPR S allele, for all study participants (OR = 1.078, 95% CI = [0.962, 1.207], p = .196)., Conclusion: This meta-analysis of case-control studies and TDT showed a lack of association between the 5-HTTLPR L/S polymorphism and ADHD.

PR interval is the period from the onset of P wave to the start of the QRS complex on electrocardiograms. A recent genomewide association study (GWAS) suggested that GAREM1 was linked to the PR interval on electrocardiograms. This study was designed to validate this correlation using additional subjects and examined the function of Garem1 in a mouse model. We analyzed the association of rs17744182, a variant in the GAREM1 locus, with the PR interval in 5646 subjects who were recruited from 2 Korean replication sets, Yangpyeong (n = 2471) and Yonsei (n = 3175), and noted a significant genomewide association by meta-analysis (P = 2.39 × 10 -8 ). To confirm the function of Garem1 in mice, Garem1 siRNA was injected into mouse tail veins to reduce the expression of Garem1. Garem1 transcript levels declined by 53% in the atrium of the heart (P = 0.029), and Garem1-siRNA injected mice experienced a significant decrease in PR interval (43.27 ms vs. 44.89 ms in control, P = 0.007). We analyzed the expression pattern of Garem1 in the heart by immunohistology and observed specific expression of Garem1 in intracardiac ganglia. Garem1 was expressed in most neurons of the ganglion, including cholinergic and adrenergic cells. We have provided evidence that GAREM1 is involved in the PR interval of ECGs. These findings increase our understanding of the regulatory signals of heart rhythm through intracardiac ganglia of the autonomic nervous system and can be used to guide the development of a therapeutic target for heart conditions, such as atrial fibrillation.

Aim: To systematically review evidence regarding the relationship between circulating macrophage migration inhibitory factor (MIF) levels and rheumatoid arthritis (RA), and the association between MIF gene polymorphisms and RA susceptibility., Design: We performed a meta-analysis on data of serum/plasma MIF levels in patients with RA and in controls, and on associations between the MIF -173 C/G and -794CATT 5-8 polymorphisms and RA susceptibility., Patients: Twelve studies, comprising a total of 362 RA cases and 531 controls evaluated for MIF levels, and 2367 RA cases and 2395 controls evaluated for MIF polymorphisms, were included., Results: MIF levels were significantly higher in the RA group than in the control group (standardised mean difference (95% CI) 0.923 (0.766 to 1.080), p<0.001). Stratification by ethnicity revealed significantly higher MIF levels in the RA group in Caucasian, Asian and Latin American populations. MIF levels were significantly higher in patients with RA, regardless of adjustment, sample size or data type evaluated. RA was identified to be significantly associated with the MIF -173 C allele (OR (95% CI) 1.271 (1.141 to 1.416), p<0.001), as well as with the -794CATT 7 allele (OR (95% CI) 1.229 (1.084 to 1.415), p=0.002) and the -794CATT 7 - MIF -173C haplotype RA (OR (95% CI) 1.433 (1.138 to 1.805), p=0.002)., Conclusions: Our meta-analyses revealed significantly higher circulating MIF levels in patients with RA, and found evidence of associations between the MIF -173 C/G and -794CATT 5-8 polymorphisms and RA susceptibility., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: To systematically review evidence regarding the relationship between circulating interleukin-17 (IL-17) levels and rheumatoid arthritis (RA), and associations between polymorphisms in IL-17 genes and RA susceptibility., Method: We performed a meta-analysis of serum/plasma IL-17 levels in patients with RA and controls, and evaluated evidence of associations between the rs2275913, rs3819024, rs4711998 and rs8193036 polymorphisms in IL-17A and the rs763780 and rs2397084 polymorphisms in IL-17F and risk for RA., Results: Fourteen studies including 3118 patients with RA and 2725 controls were included. Our meta-analysis revealed that IL-17 levels were significantly higher in the RA group than in the control group (p=3.1×10 -6 ). Subgroup analysis using sample size showed increased IL-17 levels in samples from both small (n≤100) and large (n>100) RA groups (p=1.1×10 -4 and p=0.008, respectively). We found evidence of associations between RA and alleles from the IL-17A rs2275913 and IL-17F rs763780 polymorphisms in Caucasians (p=0.003 and p=0.037, respectively). In addition, we found an association between RA and alleles of the IL-17A rs3819024 polymorphism in the pooled RA cohort compared with matched controls (p=0.033). However, no evidence of association was found between the IL-17F rs2397084, IL-17A rs4711998 and IL-17A rs8193036 polymorphisms and RA susceptibility., Conclusions: Our meta-analysis revealed significantly higher circulating IL-17 levels in patients with RA, and found evidence of associations between the IL-17A rs2275913, IL-17F rs763780 and IL-17A rs3819024 polymorphisms and pathogenesis of RA., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Uveitis is an eye inflammatory disease, which is sometimes associated with underlying systemic disease. Interleukin-23 plays an important role in autoimmune disease. The aim of this meta-analysis was to evaluate the association between the interleukin-23 receptor (IL-23R) and susceptibility to uveitis., Methods: Published literature from PUBMED and EMBASE were retrieved. Seven studies were included in this meta-analysis, covering a total of 1309 cases of uveitis and 2400 controls. Meta-analyses were conducted on the associations between uveitisand rs7517847, rs17375018, and rs11209032 polymorphisms in the IL-23R gene., Results: There were no significant associations between IL-23R polymorphisms and uveitis with regard to the following alleles: for G allele vs. T allele of rs7517847, OR 1.01, 95% CI 0.92-1.12, P = 0.83; for A allele vs. G allele of rs17375018, OR 0.68, 95% CI 0.47-0.99, P = 0.05; rs11209032 OR 1.12, 95% CI 0.84-1.51, P = 0.43. In contrast, there were significant associations between the AA + AG gene versus GG gene of rs17375018 and the AA gene versus AG + GG gene of rs11209032 polymorphism with uveitis (OR 0.59, 95% CI 0.35-0.99, P = 0.04; OR 1.32, 95% CI 1.10-1.59, P = 0.003)., Conclusions: This meta-analysis suggests that each allele of IL-23R, including rs7519847, rs17375018 and rs11209032 was negatively associated with uveitis. However, homozygote models, including the rs17375018 GG genotype and rs11209032 AA genotype, were significantly associated with uveitis.

Background: Prenatal maternal diet may influence disease susceptibility in offspring with specific genetic backgrounds. We hypothesized that interactions between prenatal antioxidant intake and polymorphisms in immunity genes influence respiratory tract infection (RTI) susceptibility in infants at 12 months of age., Methods: This study included 550 infants. In the Cohort for Childhood Origin of Asthma and Allergic Diseases (COCOA) birth cohort study, prenatal maternal diet was assessed by administering a food frequency questionnaire. Infants' cord blood was genotyped for CD14 (rs2569190), TLR4 (rs1927911), and GSDMB (rs4794820) polymorphisms by the TaqMan method., Results: Higher prenatal intake of total fruit and vegetables (FV) was associated with the decreased risk of RTI in offspring (P-trend=0.0430). In children with TT genotype at rs2569190, a higher prenatal intake of vitamins A and C, fruits, and total FV decreased RTI risk (P-trend <0.05), while in infants with TC+CC genotype, a higher prenatal intake of fruit increased RTI risk (P-trend <0.05). When analyzing the 3 genotypes, children with TT genotype at rs2569190 were more protected against RTIs compared with those with CC genotype with respect to vitamin C and fruits [odds ratio (OR)=5.04 and OR=10.30, respectively]. In children with CC genotype at rs1927911, RTI risk showed a dose-response association with a higher prenatal intake of vitamin C (P for interaction<0.05). A higher prenatal intake of fruits and total FV reduced RTI risk in infants with GA+AA genotype of rs4794820 (P for interaction<0.05)., Conclusions: Prenatal antioxidant intake may reduce RTI risk in infants and this relationship may be modified by CD14, TLR4, and GSDMB polymorphisms.

Background: Factor XIII plays an important role in the stabilization of the linkage between fibrins and in the pathophysiology of coronary artery disease (CAD). The association between factor XIII Val34Leu polymorphism and CAD risk remains controversial., Methods: We conducted a meta-analysis of 36 studies involving 26,940 cases and 34,694 controls. Subgroup analyses were performed with division of data into disease (myocardial infarction [MI], CAD without MI), age, and sex., Results: Factor XIII Val34Leu polymorphism was significantly associated with ove all CAD risk (odds ratio [OR] = 1.09, 95% confidence interval [CI] = 1.03-1.06, p = 0.004) and MI risk (OR = 1.15, 95% CI 1.07-1.25, p = 0.0003), but not with CAD without MI risk (OR = 1.00, 95% CI 0.87-1.15, p = 0.96). In the subgroup analysis by age and sex, there was no association between Val34Leu polymorphism and CAD., Conclusions: This meta-analysis found that factor XIII Val34Leu polymorphism was associated with CAD risk, especially MI, but not with CAD without MI. In addition, age and sex did not affect the relationship between factor XIII Val34Leu polymorphism and CAD risk.

Objective: The aim of this study was to investigate whether interleukin-10 (IL-10) polymorphisms are associated with susceptibility to recurrent pregnancy loss (RPL)., Methods: We conducted a literature search using the PubMed and EMBASE databases and performed meta-analyses on the associations between IL-10 -1082 G/A, -819 C/T, and -592 C/A polymorphisms and RPL, using fixed- or random-effects models., Results: A total of 15 papers involving 1858 RPL patients and 1949 controls were considered in this study. Meta-analysis of IL-10 -1082 G/A polymorphism revealed no association between RPL and the IL-10 -1082 G allele (OR=0.999, 95% CI=0.815-1.223, p=0.989). However, meta-analysis of IL-10 -819 C/T polymorphism in all study subjects revealed an association between RPL and the IL-10 -819 C allele (OR=0.680, 95% CI=0.498-0.927, p=0.015). Stratification by ethnicity indicated an association between the IL-10 -819 C allele and RPL in the Asian group (OR=0.421, 95% CI=0.226-0.783, p=0.006), but not in the Caucasian and Arab groups (OR=1.053, 95% CI=0.218-5.077, p=0.949, and OR=0.800, 95% CI=0.606-1.081, p=0.152, respectively). Furthermore, a relationship between the IL-10 -592 C allele and RPL was identified in the Asian group (OR=0.763, 95% CI=0.633-0.919, p=0.004), but not in the Caucasian and Arab groups., Conclusions: The meta-analyses demonstrate that IL-10 -819 C/T and -592 C/A polymorphisms are associated with RPL susceptibility in Asian women, but not in the Caucasian and Arab populations., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10(-12)). We also confirmed significant association at three previously described loci (P < 5 × 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG.

The objective of the study was to determine by meta-analysis whether polymorphisms of the gene encoding peptidylarginine deiminase 4 (PADI4) are associated with susceptibility to rheumatoid arthritis (RA). A literature review was conducted to identify data sets that described analyses of genetic association between PADI4 polymorphisms and RA. Data sets were collated and a meta-analysis was performed, with a specific focus on associations within Caucasian and Asian populations. A total of 15,947 RA cases and 22,696 controls that were taken from 28 studies in 24 papers were included in this study. Meta-analysis showed a significant association between allele 2 of the PADI4&#95;94 polymorphism and RA in the overall population (odds ratio [OR] = 1.155, 95 % confidence interval [CI] = 1.069-1.249, p = 2.7 × 10(-5)). Stratification by ethnicity revealed an association between PADI4&#95;94 allele 2 and RA in Asians (OR = 1.273, 95 % CI = 1.193-1.359, p < 1.0 × 10(-9)), but not in Caucasians (OR = 1.024, 95 % CI = 0.973-1.078, p = 0.358). However, meta-analysis using homozygote contrast showed an association between PADI4&#95;94 allele 2 and RA in both Asians (OR = 2.311, 95 % CI = 1.1.858-2.875, p < 1.0 × 10(-9)) and Caucasians (OR = 1.523, 95 % CI = 1.157-2.004, p = 0.008). Meta-analysis also revealed an association between allele 2 of the PADI4&#95;104 polymorphism and RA in both Asians (OR = 1.547, 95 % CI = 1.247-1.919, p = 7.1 × 10(-6)) and Caucasians (OR = 1.096, 95 % CI = 1.025-1.172, p = 0.008). Finally, meta-analysis showed an association between allele 2 of the PADI4&#95;92 polymorphism and RA in Asians (OR = 1.263, 95 % CI = 1.153-1.384, p = 5.8 × 10(-8)), but not in Caucasians (OR = 1.123, 95 % CI = 0.980-1.287, p = 0.095). Meta-analysis indicated no association between allele 2 of either the PADI4&#95;90 or PADI4&#95;89 polymorphisms and RA in Asians. This meta-analysis revealed that the PADI4&#95;94 and PADI&#95;104 polymorphisms are associated with susceptibility to RA in Asians and Caucasians, and that the PADI4&#95;92 polymorphism is associated with susceptibility to RA in Asians, but not in Caucasians.

The aim of this study was to determine whether the functional major histocompatibility complex II transactivator (MHC2TA) -168 A/G polymorphism is associated with susceptibility to rheumatoid arthritis (RA). A meta-analysis was conducted to estimate the association between the MHC2TA-168 A/G polymorphism and RA. A total of 15 comparative studies, which included 14,158 patients and 13,642 controls, were included in the meta-analysis. Based on the meta-analysis, there was no association between RA and the MHC2TA -168 G allele in the study subjects (OR = 1.046, 95 % CI = 0.987-1.108, p = 0.130) or Caucasians (OR = 1.027, 95 % CI = 0.986-1.070, p = 0.193). However, the country-specific meta-analysis revealed an association between the MHC2TA -168 G allele and RA in the Swedish population (OR = 1.131, 95 % CI = 1.023-1.250, p = 0.016). A direct comparison between rheumatoid factor (RF)-positive and RF-negative patients revealed that the frequency of the G allele was significantly lower in RF-positive patients (OR = 0.783, 95 % CI = 0.628-0.975, p = 0.029) than in RF-negative patients. This meta-analysis demonstrated that the MHC2TA -168 A/G polymorphism is not associated with susceptibility to RA in Caucasians.

Objective: This study determined whether FCGR3B copy number variations (CNVs) were associated with susceptibility to autoimmune diseases., Methods: A meta-analysis was conducted to determine the association between FCGR3B CNVs and susceptibility to autoimmune diseases by comparing low FCGR3B CN (<2 to ≥2) and high FCGR3B CN (>2 to ≤2)., Results: In all, 28 comparative studies from 15 reports involving 12,160 patients and 11,103 controls were included in this meta-analysis. The meta-analysis showed a significant association between low FCGR3B CN and autoimmune diseases (OR=1.496, 95% CI=1.301-1.716, p=1.0×10(-9)). Subgroup analysis according to ethnicity indicated an association between low FCGR3B CN and autoimmune diseases in Caucasians (OR=1.482, 95% CI=1.219-1.801, p=7.7×10(-6)) and Asians (OR=1.498, 95% CI=1.306-1.717, p=1.0×10(-9)). Meta-analysis according to the type of autoimmune disease indicated a significant association of low FCGR3B CN with systemic lupus erythematosus (SLE; OR=1.797, 95% CI=1.562-2.068, p<1.0×10(-9)), primary Sjogren's syndrome (pSS; OR=2.263, 95% CI=1.316-3.892, p=0.003), and Wegener's granulomatosis (WG; OR=1.973, 95% CI=1.178-3.302, p=0.010), but not with rheumatoid arthritis (RA; OR=1.333, 95% CI=0.947-1.877, p=0.099). However, the meta-analysis showed no association between high FCGR3B CN and SLE, RA, pSS, and WG., Conclusions: Thus, the results of this meta-analysis indicated that low FCGR3B CN increased susceptibility to autoimmune diseases, especially SLE, pSS, and WG.

Purpose: The purpose of this study was to identify candidate single-nucleotide polymorphisms (SNPs) that might play a role in susceptibility to pancreatic cancer, elucidate their potential mechanisms, and generate SNP-to-gene-to-pathway hypotheses., Methods: A genome-wide association study (GWAS) dataset of pancreatic cancer that included 496,959 SNPs from 3,851 pancreatic cancer patients and 3,934 control subjects of European descent was used in this study. The Identify candidate Causal SNPs and Pathways (ICSNPathway) method was applied to the GWAS dataset., Results: ICSNPathway analysis identified 18 candidate SNPs, 11 genes (including HNF1A and HNF4G), and 30 pathways, which revealed 11 hypothetical biological mechanisms. The strongest hypothetical biological mechanism was one wherein rs2230739 alters the role of ADCY9 in various pathways and processes, including cyclase activity, phosphorus oxygen lyase activity, hsa04912, hsa04540, hsa04020, and hsa00230 (0.010 ≤ p < 0.001; 0.038 ≤ false discovery rate (FDR) ≤ 0.016). The second strongest mechanism was that rs16859886 modulates ADCY10 to affect its role in pathways including cyclase activity, phosphorus oxygen lyase activity, nucleobase, nucleoside, and nucleotide metabolic processing, and hsa00230 (0.010 ≤ p < 0.001; 0.038 ≤ FDR ≤ 0.016)., Conclusions: By using the ICSNPathway to analyze pancreatic cancer GWAS data, 18 candidate SNPs, 11 genes (including ADCY9, ADCY10, HNF1A, and HNF4G), and 30 pathways were identified that might contribute to the susceptibility of patients to pancreatic cancer.

Objective: The aim of this study was to determine whether the functional interleukin-18 (IL-18) promoter -607 C/A (rs1946518) and -137 G/C (rs187238) polymorphisms are associated with susceptibility to type 1 diabetes (TID)., Methods: A meta-analysis was conducted to assess the associations between the IL-18 -607 C/A and -137 G/C polymorphisms and T1D in overall and by ethnic group., Results: A total of 6075 cases and 5744 controls from ten studies were considered in this meta-analysis. In all study subjects, the meta-analysis showed no association between T1D and the IL-18 -607 C allele (OR=1.083, 95% CI=0.930-1.260, p=0.307). However, stratification by ethnicity indicated an association between the IL-18 -607 C allele and T1D in Asians (OR=1.506, 95% CI=1.172-1.936, p=0.001), but not in Europeans (OR=0.988, 95% CI=0.808-1.209, p=0.907). Analysis using recessive and dominant models and homozygote contrast showed the same -607 C allele pattern in Asians and Europeans. Meta-analysis of the IL-18 -137 G/C polymorphism showed no association between T1D and the IL-18 -137 G allele in all study subjects (OR=1.066, 95% CI=0.926-1.2289, p=0.375). Stratification by ethnicity indicated no association between the IL-18 -137 G allele and T1D in Europeans and Asians (OR=1.021, 95% CI=0.961-1.085, p=0.504; OR=0.851, 95% CI=0.5821-1.245, p=0.406)., Conclusions: Our meta-analysis demonstrates that the IL-18 -607 C/A polymorphism may be associated with susceptibility to T1D in Asians, but not in Europeans., (Copyright © 2015 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to determine whether the tumor necrosis factor-α (TNF-α) promoter -308 A/G polymorphism is associated with susceptibility to Alzheimer's disease (AD) in multi-ethnic populations. MEDLINE and EMBASE databases and manual literature search were used to identify published articles in which TNF-α polymorphism was determined in AD patients and control subjects. Meta-analysis was conducted on the association between the TNF-α -308 A/G polymorphism and AD using allele contrast and the recessive, dominant, and additive models. A total of 16 studies involving 3,826 AD patients and 4,327 control subjects were examined. The meta-analysis showed no association between the TNF-α -308 A allele and AD when all the subjects were considered [odds ratio (OR) = 1.275, 95 % CI 0.966-1.685, p = 0.087]. After stratification by ethnicity, the meta-analysis indicated that the A allele is significantly associated with AD in East Asian (OR = 1.743, 95 % CI 1.256-2.418, p = 0.001), but not in the European (OR = 0.963, 95 % CI 0.822-1.128, p = 0.637) or Middle Eastern populations (OR = 3.921, 95 % CI 0.411-37.42, p = 0.235). Meta-analysis under dominant, recessive, and additive models also showed a similar pattern of results as with the A allele. This meta-analysis shows that the TNF-α -308 A/G polymorphism may represent a significant risk factor for AD in East Asians but not in the European or Middle Eastern populations.

Introduction: The purpose of this study was to examine whether the insertion (I) and deletion (D) polymorphism of the angiotensin-converting enzyme (ACE) confers susceptibility to schizophrenia and Parkinson's disease (PD)., Materials and Methods: A meta-analysis was performed of the associations between the ACE I/D polymorphism and schizophrenia and PD., Results: Thirteen studies with 2024 cases and 2230 controls comprising eight studies on schizophrenia and five on PD were included in the meta-analysis. The meta-analysis revealed no association between the ACE D allele and schizophrenia (OR = 0.990, 95% CI = 0.889-1.102, p = 0.856) or PD (OR = 1.067, 95% CI = 0.907-1.255, p = 0.433). Stratification by ethnicity indicated no association between the ACE D allele and schizophrenia in European, Asian, or Turkish ethnic groups (OR = 0.896, 95% CI = 0.566-1.419, p = 0.640; OR = 1.057, 95% CI = 0.903-1.238, p = 0.492; OR = 1.111, 95% CI = 0.889-1.389, p = 0.354, respectively). Ethnicity-specific meta-analysis was not conducted for PD because only one ethnic PD study was available., Conclusions: This meta-analysis found no association between the ACE I/D polymorphism and schizophrenia or PD., (© The Author(s) 2014.)

Background and Aim: Considering the significant racial and ethnic diversity in genetic variation, it is unclear whether the genome-wide association studies-identified colorectal cancer (CRC)-susceptibility single-nucleotide polymorphisms (SNPs) discovered in European populations are also relevant to the Korean population. However, studies on CRC-susceptibility SNPs in Koreans are limited., Methods: To investigate the racial and ethnic diversity of CRC-susceptibility genetic variants, we genotyped for the established European CRC-susceptibility SNPs in 198 CRC cases and 329 controls in Korea. To identify novel genetic variants using genome-wide screening in Korea, Illumina HumanHap 370K/610K BeadChips were performed on 105 CRC patients, and candidate CRC-susceptibility SNPs were selected. Subsequently, genotyping for replication was done in 189 CRC cases and 190 controls., Results: Among the European CRC-susceptibility SNPs, rs4939827 in SMAD7 was associated with a significant decreased risk of Korean CRC (age-/gender-adjusted odds ratio [95% confidence interval]: additive model, 0.67 [95% CI, 0.47-0.95]; dominant model, 0.59 [95% CI, 0.39-0.91]). rs4779584 and rs10795668 were associated with CRC risk in females and males, respectively. Among candidate CRC-susceptibility SNPs selected from genome-wide screening, novel SNP, rs17051076, was found to be associated with a significantly increased risk of microsatellite instability-high CRC (age-/gender-adjusted odds ratio [95% confidence interval]: additive model, 4.25 [95% CI, 1.51-11.98]; dominant model, 3.52 [95% CI, 1.13-10.94]) in the replication study., Conclusions: rs4939827, rs4779584, and rs10795668 may contribute to the risk of CRC in the Korean population as well as in European populations. Novel rs17051076 could be associated with microsatellite instability-high CRC in Koreans. These associations support the ethnic diversity of CRC-susceptibility SNPs and should be taken into account in large-scale studies., (© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Background: Crohn's disease (CD) is an intractable inflammatory bowel disease of unknown cause. Recent genome-wide association studies of CD in Korean and Japanese populations suggested marginal sharing of susceptibility loci between Caucasian and Asian populations. As the 7 identified loci altogether explain 5.31% of the risk for CD, the objective of this study was to identify additional CD susceptibility loci in the Korean population., Methods: Using the ImmunoChip custom single-nucleotide polymorphism array designed for dense genotyping of 186 loci identified through GWAS, we analyzed 722 individuals with CD and 461 controls for 96,048 SNP markers in the discovery stage, followed by validation in an additional 948 affected individuals and 977 controls., Results: We confirmed 6 previously reported loci in Caucasian: GPR35 at 2q37 (rs3749172; P = 5.30 × 10, odds ratio [OR] = 1.45), ZNF365 at 10q21 (rs224143; P = 2.20 × 10, OR = 1.38), ZMIZ1 at 10q22 (rs1250569; P = 3.05 × 10, OR = 1.30), NKX2-3 at 10q24 (rs4409764; P = 7.93 × 10, OR = 1.32), PTPN2 at 18p11 (rs514000; P = 9.00 × 10, OR = 1.33), and USP25 at 21q11 (rs2823256; P = 2.49 × 10, OR = 1.35), bringing the number of known CD loci (including 3 in the HLA) in Koreans to 15. The 6 additional loci increased the total genetic variance for CD risk from 5.31% to 7.27% in Koreans., Conclusions: Although the different genetic backgrounds of CD between Asian and Western countries has been well established for the major susceptibility genes, our findings of overlapping associations offer new insights into the genetic architecture of CD.

Objective: The aim of this study was to explore whether the FOXP3 -3279 A/C polymorphism and (GT)n microsatellite polymorphisms are associated with susceptibility to autoimmune diseases., Methods: A meta-analysis was conducted on the associations between the FOXP3 -3279 A/C polymorphism and (GT)15 and (GT)16 polymorphisms and autoimmune diseases., Results: Twenty-two comparative studies with a total of 7962 patients and 7453 controls were included in the meta-analysis. Meta-analysis revealed an association between autoimmune disease and the FOXP3 -3279 AA + AC genotype (OR = 1.480, 95% CI = 1.263-1.614, p < 1.0 × 10(-9)), and stratification by ethnicity indicated a significant association between the FOXP3 -3279 AA + AC genotype and autoimmune diseases in Asians (OR = 1.416, 95% CI = 1.225-1.637, p = 2.5 × 10(-7)) and non-Caucasians (OR = 1.432, 95% CI = 1.245-1.647, p = 7.5 × 10(-8)). In addition, corrected p values for multiple testing remained significant. Meta-analysis revealed no association between autoimmune disease and the FOXP3 (GT)15 allele (OR = 1.051, 95% CI = 0.933-1.183, p = 0.413). Similarly, the FOXP3 (GT)16 allele showed no associations with autoimmune disease., Conclusions: This meta-analysis indicates that the FOXP3 -3279 A/C polymorphism is associated with susceptibility to autoimmune disease in Asians and non-Caucasians.

Objective: To explore whether the functional chemokine receptor 5 delta32 (CCR5-Δ32) polymorphism is associated with susceptibility to cancer., Methods: A meta-analysis was conducted on the association between the CCR5-Δ32 polymorphism and cancer using (i) allele contrast and (ii) the dominant model., Results: Thirteen articles, including 16 comparative studies on a total of 3087 patients and 3735 controls, were included in the meta-analysis. These studies encompassed breast cancer (n = 3), bladder cancer (n = 3), cervical cancer (n = 2), pancreatic cancer (n = 2), prostate cancer (n = 2), head and neck cancer (n = 2), lymphoma (n = 1), gallbladder cancer (n = 1), skin cancer (n = 1) and mixed cancer (n = 1). The meta-analysis revealed an association between cancer and the CCR5-Δ32 allele (OR = 1.368, 95% CI = 1.064-1.758, p = 0.014), and stratification by ethnicity showed an association between the CCR5-Δ32 allele and cancer in Indians (OR = 2.480, 95% CI = 1.247-4.932, p = 0.010). The meta-analysis also revealed an association between breast cancer and the CCR5-Δ32 allele (OR = 1.689, 95% CI = 1.012-2.821, p = 0.045). However, allele contrast and the dominant model failed to reveal an association between the CCR5-Δ32 polymorphism and bladder cancer, cervical cancer, pancreatic cancer, prostate cancer, and head and neck cancer., Conclusions: This meta-analysis demonstrates that the CCR5-Δ32 polymorphism is associated with susceptibility to cancer in Indians and is associated with breast cancer.

Objective: The aim of this study was to explore whether polymorphisms of intercellular adhesion molecule-1 (ICAM-1) are associated with susceptibility to Crohn's disease (CD) and ulcerative colitis (UC)., Methods: The authors conducted a meta-analysis on the associations between the polymorphisms K469E and G241R of ICAM-1 and susceptibility to CD and UC., Results: A total of 8 studies with 801 patients with CD, 672 patients with UC, and 1,828 controls were included in the meta-analysis. The meta-analysis revealed no association between CD and the ICAM-1 469E allele among the subjects (OR = 1.175, 95% CI = 0.901-1.533, p = 0.233). However, stratification by ethnicity indicated an association between the ICAM-1 469E allele and CD in Europeans (OR = 1.425, 95% CI = 1.013-2.002, p = 0.042). Meta-analysis using the homozygosity also showed an association with CD in Europeans (OR = 2.054, 95% CI = 1.036-4.073, p = 0.039). The meta-analysis revealed no association between UC and the ICAM-1 K469E polymorphism. No association between CD or UC and the ICAM-1 G241R polymorphism was observed., Conclusions: This meta-analysis demonstrates that the ICAM-1 K469E polymorphism may be associated with susceptibility to CD in Europeans, but no association was found between ICAM-1 K469E and UC. In contrast, the G241R polymorphism was not found to be associated with susceptibility to either CD or UC.

This study aimed to investigate whether paraoxonase 1 (PON1) Q192R and L55M polymorphisms are associated with susceptibility to amyotrophic lateral sclerosis (ALS). We conducted a meta-analysis of the associations between the PON1 Q192R and L55M polymorphisms and ALS. A total of 2,831 patients and 3,123 controls from eight studies of the PON1 Q192R polymorphism and seven studies of the PON1 L55M T polymorphism were considered for this study. Meta-analysis showed no association between ALS and the PON1 192R allele (OR = 1.052, 95 % CI = 0.923-1.207, p = 0.447), and the PON1 55M allele (OR = 1.015, 95 % CI = 0.884-1.164, p = 0.837) in all study subjects. Similarly, no association was found between ALS and the PON1 Q192R and L55M polymorphisms using recessive, dominant or homozygote contrast models. Stratification by ethnicity indicated no association between ALS and the PON1 192R allele (OR = 1.058, 95 % CI = 0.910-1.231, p = 0.464) and the PON1 55M allele (OR = 1.027, 95 % CI = 0.889-1.185, p = 0.721) in the European population. This meta-analysis showed lack of associations between PON1 Q192R and L55M polymorphisms and susceptibility to ALS in the European population.

Aim: The aim of this study is to investigate whether TNF-α polymorphisms are associated with the responsiveness to anti-TNF-α therapy in patients with spondyloarthropathy, psoriasis, and Crohn's disease., Methods: We conducted a meta-analysis on the association between the TNF-α polymorphisms and responsiveness of patients., Results: The meta-analysis indicated an association between the TNF-α -308 G allele (OR = 2.005; 95% CI: 1.417-2.838; p = 8.6 × 10(-5)), TNF-α -238 G allele (OR = 2.196; 95% CI: 1161-4.154; p = 0.016), and TNF-α -857 C allele (OR = 1.779; 95% CI: 1.130-2.802; p = 0.013) and response to TNF-α blockers in Caucasians., Conclusion: Individuals carrying the TNF-α -308 G, -238 G, or -857 C common alleles show better responses to TNF-α blockers than those with minor alleles in Caucasians.

Objective: This study determined whether interleukin-10 (IL-10) polymorphisms are associated with susceptibility to vasculitis., Methods: A meta-analysis was conducted of the associations between the IL-10 -1082 G/A, -819 C/T, and -592 C/A polymorphisms and the haplotype of the IL-10-1082 G/A, -819 C/T, -592 C/A polymorphisms and vasculitis., Results: A total of 21 comparative studies involving 4121 patients and 5504 controls were considered in the meta-analysis. Meta-analysis revealed no association between the IL-10-1082 G allele and vasculitis in all study subjects (OR = 0.927, 95% CI = 0.780-1.102, p = 0.389). However, disease-specific meta-analysis showed an association between Wegener's granulomatosis (WG) and the IL-10-1082 G allele (OR = 0.729, 95% CI = 0.547-0.971, p = 0.031). Meta-analysis revealed an association between vasculitis and the IL-10-819 C allele (OR = 0.804, 95% CI = 0.706-0.916, p = 0.001) in all study subjects and Behcet's disease (BD) (OR = 0.724, 95% CI = 0.679-0.781, p < 1.0 × 10(-9)). Meta-analysis of the IL-10-592 C allele showed an association with vasculitis in all study subjects (OR = 0.805, 95% CI = 0.619-0.938, p = 0.005) and BD (OR = 0.718, 95% CI = 0.661-0.781, p < 1.0 × 10(-9)). Meta-analysis of the IL-10 haplotype revealed an association between the GCC haplotype and vasculitis in Europeans (OR = 1.239, 95% CI = 1.105-1.513, p = 0.035)., Conclusions: This meta-analysis showed that IL-10 polymorphisms are associated with vasculitis susceptibility, especially in WG and BD.

The aim of this study was to explore whether the catechol-O-methyltransferase (COMT) Val158Met polymorphism is associated with susceptibility to fibromyalgia and fibromyalgia impact questionnaire (FIQ) score in fibromyalgia patients. We conducted a meta-analysis of the associations of the COMT Val158Met polymorphism with fibromyalgia risk as well as FIQ score in fibromyalgia patients. A total of 993 fibromyalgia patients and 778 controls from 10 studies on the COMT Val158Met polymorphism and 538 fibromyalgia patients from 5 studies on the COMT Val158Met polymorphism and FIQ score were included in this meta-analysis. The meta-analysis revealed an association between fibromyalgia and the COMT Met/Met + Val/Met genotype in all study subjects (odds ratio (OR) 1.635, 95 % confidence interval (CI) 1.029-2.597, p = 0.037). However, stratification by ethnicity indicated no association between the Met/Met + Val/Met genotype and fibromyalgia in the European and Turkish populations (OR 1.202, 95 % CI 0.876-1.649, p = 0.255; OR 2.132, 95 % CI 0.764-5.949, p = 0.148, respectively). Analysis using other genetic models showed no association between the COMT Val158Met polymorphism and fibromyalgia. The meta-analysis also revealed that the FIQ score was significantly higher in individuals with the COMT Met/Met genotype than in those with the Val/Val genotype [weighted mean difference (WMD) = 14.39, 95 % CI 3.316-25.48, p = 0.011] and the Val/Met genotype (WMD = 5.108, 95 % CI 2.212-4.891, p = 0.021). This meta-analysis identified an association between fibromyalgia risk and the COMT Val158Met polymorphism as well as the FIQ score in fibromyalgia patients.

The goal of this study was to examine whether vitamin D receptor (VDR) polymorphisms are associated with susceptibility to Parkinson's disease (PD) and Alzheimer's disease (AD). A meta-analysis was performed to investigate the association between VDR FokI, BsmI, TaqI, ApaI, rs4334089, or rs11568820 polymorphism and susceptibility to PD or AD. Thirteen studies, including seven on PD and six on AD, were included in this meta-analysis. The meta-analysis revealed an association between the BB + Bb genotype and PD in the Asian population (OR 0.478, 95 % CI 0.259-0.884, p = 0.018). We also observed a significant association between PD and the FokI F allele (OR 1.413, 95 % CI 1.144-1.746, p = 0.001). Meta-analysis of the A allele, the AA vs. Aa + aa, and the AA vs. aa for the ApaI polymorphism revealed significant associations with AD (OR 0.729, 95 % CI 0.0.591-0.900, p = 0.034; OR 0.591, 95 % CI 0.431-0.810, p = 0.001; OR 0.580, 95 % CI 0.361-0.931, p = 0.024, respectively). This meta-analysis demonstrates that the VDR BsmI polymorphism is associated with PD susceptibility in Asians, and the FokI polymorphism is associated with PD. Furthermore, we identified associations between the VDR TaqI and ApaI polymorphisms and AD susceptibility.

Exome DNA sequencing of blood samples from a Li-Fraumeni family with a TP53 germline mutation (codon 236 deletion) and multiple nervous system tumors revealed additional germline mutations. Missense mutations in the MSH4 DNA repair gene (c.2480T>A; p.I827N) were detected in three patients with gliomas (two anaplastic astrocytomas, two glioblastomas). Two family members without a TP53 germline mutation who developed peripheral schwannomas also carried the MSH4 germline mutation, and in addition, a germline mutation of the LATS1 gene (c.286C>T; p.R96W). LATS1 is a downstream mediator of the NF2, but has not previously been found to be related to schwannomas. We therefore screened the entire coding sequence of the LATS1 gene in 65 sporadic schwannomas, 12 neurofibroma/schwannoma hybrid tumors, and 4 cases of schwannomatosis. We only found a single base deletion at codon 827 (exon 5) in a spinal schwannoma, leading to a stop at codon 835 (c.2480delG; p.*R827Kfs*8). Mutational loss of LATS1 function may thus play a role in some inherited schwannomas, but only exceptionally in sporadic schwannomas. This is the first study reporting a germline MSH4 mutation. Since it was present in all patients, it may have contributed to the subsequent acquisition of TP53 and LATS1 germline mutations., (Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to explore whether vascular endothelial growth factor (VEGF) polymorphisms are associated with susceptibility to vasculitis., Methods: Meta-analyses were conducted on the associations between the -634 C/G, +936 C/T, -1154 A/G, and -2578 A/C polymorphisms of VEGF and vasculitis., Results: Eight studies on VEGF polymorphisms and vasculitis involving 2740 subjects (vasculitis 834, controls 1906) were included in this meta-analysis. The meta-analysis showed no association between vasculitis and the VEGF -634 C allele (OR=1.161, 95% CI=0.921-1.464, p=0.207) among study subjects. Meta-analysis showed no association between vasculitis and the VEGF+936 T allele (OR=1.121, 95% CI=0.905-1.390, p=0.295). However, stratification by ethnicity indicated a significant association between the VEGF+936 T allele and vasculitis in Europeans, but not in Asians (OR=1.486, 95% CI=1.038-2.128, p=0.030; OR=0.958, 95% CI=0.773-1.253, p=0.755). Meta-analysis showed no association between vasculitis and the VEGF -1154 A/G and 2578 A/C polymorphisms., Conclusions: This meta-analysis suggests that the VEGF+936 T allele is associated with susceptibility to vasculitis in Europeans, but not in Asians., (Copyright © 2014 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to explore whether the cytotoxic T lymphocyte associated antigen-4 (CTLA-4) polymorphisms are associated with susceptibility to ulcerative colitis (UC) and Crohn's disease (CD)., Methods: The authors conducted a meta-analysis on associations between CTLA-4 +49 A/G, -318 C/T, CT60 A/G polymorphisms, and (AT)n repeat in the 3' untranslated region (UTR) and UC and CD susceptibility., Results: A total of 15 comparison studies were considered in our meta-analysis. Meta-analysis revealed no association between UC and the CTLA-4 +49 G and CTLA-4 -318 T alleles in all subjects (OR=0.982, 95% CI=0.851-1.1339, p=0.804; OR=0.500, 95% CI=0.223-1.124, p=0.094). No association was found between UC and the CTLA-4 CT60 A/G polymorphism in Europeans. However, a significant association was observed between the longer allele (⩾118bp) of the (AT)n and UC in Asian population (OR=6.073, 95% CI=4.246-8.684, p=1.0×10(-9)). Meta-analysis of the CTLA-4 +49 A/G, -318 C/T, CT60 A/G polymorphisms showed no association with CD., Conclusions: This meta-analysis demonstrates that the CTLA-4 (AT)n repeat in 3' UTR may be associated with susceptibility to UC in Asians, while no association was found between the CTLA-4 +49 A/G, -318 C/T, and CD60 A/G polymorphism and susceptibility to UC and CD., (Copyright © 2014 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to explore whether the catechol-O-methyltransferase (COMT) Val158Met or the peroxisome proliferator-activated receptor-gamma (PPARγ) Pro12Ala polymorphisms are associated with susceptibility to Alzheimer's disease (AD). We conducted a meta-analysis of the associations between the COMT Val158Met and the PPARγ Pro12Ala polymorphisms and AD in subjects. Meta-analysis showed no association between AD and the COMT G allele in any of the study subjects [odds ratio (OR) = 0.972, 95 % confidence intervals (95 % CI) = 0.893-1.059, p = 0.515]. Stratification by ethnicity indicated an association between the COMT GG+GA genotype and AD in an Asian group (OR = 0.702, 95 % CI = 0.517-0.953, p = 0.023), but not in Europeans (OR = 1.058, 95 % CI = 0.868-1.289, p = 0.579). Homozygote contrast analysis showed the same pattern for the COMT GG+GA genotype. Meta-analysis showed no association between AD and the PPARγ polymorphism (OR for the C allele = 0.963, 95 % CI = 0.818-1.134, p = 0.649). This meta-analysis identified an association between AD and the COMT Val158Met polymorphism in Asians but not in Europeans, but it revealed no association between AD and the PPARγ Pro12Ala polymorphism.

ABSTRACT The aim of this study was to explore whether brain-derived neurotrophic factor (BDNF) polymorphisms 196 G/A and 270 C/T confer susceptibility to Parkinson's disease (PD). The authors conducted a meta-analysis of the associations between the BDNF 196 G/A and 270 C/T polymorphisms and PD in subjects. They considered 12 studies in the case of the BDNF 196 G/A polymorphism and 4 studies in the case of the BDNF 270 C/T polymorphism. Meta-analysis showed no association between PD and the BDNF 196A allele in all study subjects (odds ratio [OR] = 1.066, 95% CI [0.972, 1.169], p = .173). However, ethnicity-specific meta-analysis identified an association between the BDNF 196 AA + AG genotype and PD in Europeans, but not in Asians (OR = 1.212, 95% CI [1.007, 1.458], p = .042; OR = 1.0567, 95% CI [0.913, 1.221], p = .465). Meta-analysis showed no association between PD and the BDNF 270 C/T polymorphism (OR for the T allele = 1.213, 95% CI [0.923, 1.595], p = .165). This meta-analysis identified an association between the BDNF 196 G/A polymorphism in Europeans, but not in Asians, but failed to identify an association between the BDNF 270 C/T polymorphism and PD.

Objective: Crohn's disease (CD) is an intractable inflammatory bowel disease (IBD) of unknown cause. Recent meta-analysis of the genome-wide association studies (GWAS) and Immunochip data identified 163 susceptibility loci to IBD in Caucasians, however there are limited studies in other populations., Methods: We performed a GWAS and two validation studies in the Korean population comprising a total of 2311 patients with CD and 2442 controls., Results: We confirmed four previously reported loci: TNFSF15, IL23R, the major histocompatibility complex region, and the RNASET2-FGFR1OP-CCR6 region. We identified three new susceptibility loci at genome-wide significance: rs6856616 at 4p14 (OR=1.43, combined p=3.60×10(-14)), rs11195128 at 10q25 (OR=1.42, combined p=1.55×10(-10)) and rs11235667 at 11q13 (OR=1.46, combined p=7.15×10(-9)), implicating ATG16L2 and/or FCHSD2 as novel susceptibility genes for CD. Further analysis of the 11q13 locus revealed a non-synonymous single nucleotide polymorphism (SNP) (R220W/rs11235604) in the evolutionarily conserved region of ATG16L2 with stronger association (OR=1.61, combined p=2.44×10(-12)) than rs11235667, suggesting ATG16L2 as a novel susceptibility gene for CD and rs11235604 to be a potential causal variant of the association. Two of the three SNPs (rs6856616 (p=0.00024) and rs11195128 (p=5.32×10(-5))) showed consistent patterns of association in the International IBD Genetics Consortium dataset. Together, the novel and replicated loci accounted for 5.31% of the total genetic variance for CD risk in Koreans., Conclusions: Our study provides new biological insight to CD and supports the complementary value of genetic studies in different populations.

The best validated susceptibility variants for Parkinson's disease are located in the α-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined 4 SNCA variants (rs181489, rs356219, rs11931074, and rs2583988), the MAPT H1-haplotype-defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (n = 10,322) and Asian (n = 2289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all p ≥ 0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with Parkinson's disease is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: This study determined whether interleukin 1 (IL1) polymorphisms are associated with susceptibility to systemic lupus erythematosus (SLE)., Methods: A meta-analysis was conducted on the associations between the IL1A, IL1B, and IL1 receptor antagonist (IL1RN) polymorphisms and SLE., Results: A total of 15 studies involving 1956 SLE cases and 2347 controls were included in the meta-analysis. The meta-analysis showed an association between SLE and the IL1A -889 T allele in the overall population and Europeans (OR = 0.858, 95% CI = 0.737-0.986, p = 0.032; OR = 0.827, 95% CI = 0.687-0.994, p = 0.043). Meta-analysis of the IL1RN polymorphism revealed an association with SLE in all study subjects (OR for IL1RN*2 = 1.539, 95% CI = 1.266-1.871, p = 1.5 × 10(-2)) and in Europeans and Asians (OR = 1.483, 95% CI = 1.187-1.852, p = 0.001; OR = 1.787, 95% CI = 1.167-2.736, p=0.008). No associations were found between SLE and the IL1B -511 C/T, 3953 C/T, and IL1A +4845 G/T polymorphisms., Conclusions: This meta-analysis suggests IL1A -889 C/T polymorphism is associated with susceptibility to SLE in Europeans, and that the IL1RN*2 allele is associated with susceptibility to SLE in Europeans and Asians., (Copyright © 2013 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to determine whether the functional chemokine receptor 5 delta32 (CCR5-Δ32) polymorphism is associated with multiple sclerosis (MS) susceptibility., Methods: Meta-analysis was conducted to determine the association between the CCR5-Δ32 polymorphism and overall incidence of MS as well frequency of relapsing-remitting (RR), primary progressive (PP), and secondary progressive (SP) MS subtypes., Results: In total, 3869 subjects from eight studies (MS 1666, controls 2203) were considered for meta-analysis. Meta-analysis showed no association between MS and the CCR5-Δ32 allele polymorphism (OR=1.102, 95% CI=0.830-1.462, p=0.502) with a mean frequency of 11.3% in MS patients and 10.4% in controls. Stratification by ethnicity indicated no association between the CCR5-Δ32 allele and MS in Europeans (OR=0.958, 95% CI=0.811-1.132, p=0.618). Meta-analysis by the disease subtype showed no association between RR-MS and the CCR5-Δ32 allele (OR=1.234, 95% CI=0.908-1.677, p=0.178). In addition, no association was found between the CCR5-Δ32 polymorphism and PP or SP-MS., Conclusions: Meta-analysis of 3869 subjects indicates a lack of association between the CCR5-Δ32 polymorphism and MS risk in Europeans.

Objective: To investigate the existence of genetic influences on the incidence of mandibular prognathism (MP) in Korean Class III patients., Materials and Methods: The probands consisted of 100 Class III patients with MP (51 men and 49 women; mean age, 22.1 ± 5.2 years; SNA, 81.2° ± 3.2°; SNB, 84.1° ± 3.9°) who underwent orthognathic surgery. Using three-generation pedigree charts, questionnaires, and clinical examinations, general information and information regarding MP for a total of 3777 relatives of the probands (1911 men and 1866 women) was ascertained. Familial correlations of MP between possible pairs in the pedigree were estimated. Heritability (h(2)) of MP under various models was estimated. Segregation analysis was conducted under the assumption of the nonpolygenic multivariate logistic model and finite polygenic mixed model. One-, two-, and three-susceptibility-type models were evaluated., Results: Among 3777 relatives, 199 (97 men and 102 women) were affected with MP (5.3%). Correlation coefficients of MP incidence in full siblings and in parent-offspring were .2003 and .2036, respectively (all P < .001). The h(2) of MP was estimated as 21.5% after adjusting for sex and founder effects. Two- and three-susceptibility-type models showed that the general model fit better than the other models. MP incidence did not have a major gene transmission model and was influenced by numerous minor effect genes and their additive effects., Conclusion: These results suggest that the inherited susceptibility to MP in Korean Class III patients might be due to the summation of minor effects from a variety of different genes and/or influence of environmental factors, rather than Mendelian transmission of major genes.