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1.
Genome-wide meta-analysis reveals novel susceptibility loci for thyrotoxic periodic paralysis.
Hoi-Yee Li, G, Cheung, CL, Zhao, SX, Song, HD, Wai-Chee Kung, A
European journal of endocrinology. 2020;(6):607-617
Abstract
OBJECTIVE Thyrotoxic periodic paralysis (TPP) is a rare and potentially fatal complication of hyperthyroidism. By meta-analysis of genome-wide association studies, we aim to discover novel susceptibility loci and understand the pathogenesis of TPP. METHODS This meta-analysis comprised 319 TPP cases and 3516 healthy controls from three independent cohorts (two from Hong Kong; one from Shanghai). Genetic variants in each cohort were separately genotyped, imputed and analyzed for association with TPP. Fixed-effect meta-analysis was performed to combine the data. Using the three independent genome-wide significant variants, a weighted genetic risk score (GRS) was developed. RESULTS Of 7 077 246 variants tested for association with TPP, 260 variants reached genome-wide significance and were represented by independent variants from four distinct genomic loci, but a risk locus for Graves' disease at 6p21.33-p21.22 was excluded from subsequent analyses. Two novel loci near TRIM2 (4q31.3; rs6827197: OR = 4.075; P = 3.46 × 10-9) and AC140912.1 (16q22.3; rs6420387: OR = 1.861; P = 2.66 × 10-8) were identified. Together with previously reported KCNJ2 (17q24.3; rs312743: OR = 2.564; P = 1.15 × 10-21), the three susceptibility variants explained 4.36% of the genetic liability. Expression quantitative trait loci analyses showed the variants altered expression of TRIM2 in nerve and KCNJ2 in skeletal muscle. The weighted GRS had an area under curve of 0.827 and 0.682 in the derivation and validation cohorts in Hong Kong. CONCLUSIONS We identified two novel TPP risk loci near TRIM2 and AC140912.1. While rare mutations in TRIM2 and KCNJ2 were implicated in monogenic disorders characterized by muscle paralysis, our study suggested common variants near these genes might dysregulate gene expression and lead to milder phenotypes.
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Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation.
Chen, MH, Yanek, LR, Backman, JD, Eicher, JD, Huffman, JE, Ben-Shlomo, Y, Beswick, AD, Yerges-Armstrong, LM, Shuldiner, AR, O'Connell, JR, et al
Platelets. 2019;(2):164-173
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Abstract
Previous genome-wide association studies (GWAS) have identified several variants associated with platelet function phenotypes; however, the proportion of variance explained by the identified variants is mostly small. Rare coding variants, particularly those with high potential for impact on protein structure/function, may have substantial impact on phenotype but are difficult to detect by GWAS. The main purpose of this study was to identify low frequency or rare variants associated with platelet function using genotype data from the Illumina HumanExome Bead Chip. Three family-based cohorts of European ancestry, including ~4,000 total subjects, comprised the discovery cohort and two independent cohorts, one of European and one of African American ancestry, were used for replication. Optical aggregometry in platelet-rich plasma was performed in all the discovery cohorts in response to adenosine diphosphate (ADP), epinephrine, and collagen. Meta-analyses were performed using both gene-based and single nucleotide variant association methods. The gene-based meta-analysis identified a significant association (P = 7.13 × 10-7) between rare genetic variants in ANKRD26 and ADP-induced platelet aggregation. One of the ANKRD26 SNVs - rs191015656, encoding a threonine to isoleucine substitution predicted to alter protein structure/function, was replicated in Europeans. Aggregation increases of ~20-50% were observed in heterozygotes in all cohorts. Novel genetic signals in ABCG1 and HCP5 were also associated with platelet aggregation to ADP in meta-analyses, although only results for HCP5 could be replicated. The SNV in HCP5 intersects epigenetic signatures in CD41+ megakaryocytes suggesting a new functional role in platelet biology for HCP5. This is the first study to use gene-based association methods from SNV array genotypes to identify rare variants related to platelet function. The molecular mechanisms and pathophysiological relevance for the identified genetic associations requires further study.
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Finding lost genes in GWAS via integrative-omics analysis reveals novel sub-networks associated with preterm birth.
Brubaker, D, Liu, Y, Wang, J, Tan, H, Zhang, G, Jacobsson, B, Muglia, L, Mesiano, S, Chance, MR
Human molecular genetics. 2016;(23):5254-5264
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Abstract
Maternal genome influences associate with up to 40% of spontaneous preterm births (PTB). Multiple genome wide association studies (GWAS) have been completed to identify genetic variants associated with PTB. Disappointingly, no highly significant SNPs have replicated in independent cohorts so far. We developed an approach combining protein-protein interaction (PPI) network data with tissue specific gene expression data to "find" SNPs of modest significance to identify candidate genes of functional importance that would otherwise be overlooked. This approach is based on the assumption that "high-ranking" SNPs falling short of genome wide significance may nevertheless indicate genes that have substantial biological value in understanding PTB. We mapped highly-ranked candidate SNPs from a meta-analysis of PTB-GWAS to coding genes and developed a PPI network enriched with PTB-SNP carrying genes. This network was scored with gene expression data from term and preterm myometrium to identify subnetworks of PTB-SNP associated genes coordinately expressed with labour onset in myometrial tissue. Our analysis consistently identified significant sub-networks associated with the interacting transcription factors MEF2C and TWIST1, genes not previously associated with PTB, both of which regulate processes clearly relevant to birth timing. Other genes in the significant sub-networks were also associated with inflammatory pathways, as well as muscle function and ion channels. Gene expression level dysregulation was confirmed for eight of these networks by qRT-PCR in an independent set of term and pre-term subjects. Our method identifies novel genes dysregulated in PTB and provides a generalized framework to identify GWAS SNPs that would otherwise be overlooked.
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NRIP1/RIP140 siRNA-mediated attenuation counteracts mitochondrial dysfunction in Down syndrome.
Izzo, A, Manco, R, Bonfiglio, F, Calì, G, De Cristofaro, T, Patergnani, S, Cicatiello, R, Scrima, R, Zannini, M, Pinton, P, et al
Human molecular genetics. 2014;(16):4406-19
Abstract
Mitochondrial dysfunction, which is consistently observed in Down syndrome (DS) cells and tissues, might contribute to the severity of the DS phenotype. Our recent studies on DS fetal hearts and fibroblasts have suggested that one of the possible causes of mitochondrial dysfunction is the downregulation of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α or PPARGC1A)--a key modulator of mitochondrial function--and of several nuclear-encoded mitochondrial genes (NEMGs). Re-analysis of publicly available expression data related to manipulation of chromosome 21 (Hsa21) genes suggested the nuclear receptor interacting protein 1 (NRIP1 or RIP140) as a good candidate Hsa21 gene for NEMG downregulation. Indeed, NRIP1 is known to affect oxidative metabolism and mitochondrial biogenesis by negatively controlling mitochondrial pathways regulated by PGC-1α. To establish whether NRIP1 overexpression in DS downregulates both PGC-1α and NEMGs, thereby causing mitochondrial dysfunction, we used siRNAs to decrease NRIP1 expression in trisomic human fetal fibroblasts. Levels of PGC-1α and NEMGs were increased and mitochondrial function was restored, as shown by reactive oxygen species decrease, adenosine 5'-triphosphate (ATP) production and mitochondrial activity increase. These findings indicate that the Hsa21 gene NRIP1 contributes to the mitochondrial dysfunction observed in DS. Furthermore, they suggest that the NRIP1-PGC-1α axe might represent a potential therapeutic target for restoring altered mitochondrial function in DS.
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The association between the Lys751Gln polymorphism in the XPD gene and the risk of bladder cancer.
Xiong, T, Yang, J, Wang, H, Wu, F, Liu, Y, Xu, R, Lv, Z, Xue, P, Cao, W, Zhang, Y
Molecular biology reports. 2014;(4):2629-34
Abstract
The Lys751Gln polymorphism in the XPD gene have been suggested as a risk factor for bladder cancer, however the results were inconclusive. The aim of the current study is to assess the association by meta-analysis. A total of 15 case-control studies concerning the association between the XPD Lys751Gln polymorphism and bladder cancer risk were included in the meta-analysis. The results suggested that the Lys751Gln polymorphism was not associated with an increased risk of bladder cancer in the dominant model (OR = 1.03, 95 % CI 0.95-1.11, P = 0.53 for Lys/Gln+Gln/Gln vs. Lys/Lys) in overall analysis. In the subgroup analysis by ethnicity, no significant association was found in Caucasians or Asians. Other comparatives suggested a slight significant association between the polymorphism with the risk of bladder cancer in the recessive comparative (OR = 1.14, 95 % CI 1.02-1.29, P = 0.03). The current meta-analysis indicated that the Lys751Gln polymorphism in the XPD gene might be a risk factor for bladder cancer. In the future, more large-scale case-control studies are needed to validate our results.
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The functional polymorphism of NBS1 p.Glu185Gln is associated with an increased risk of lung cancer in Chinese populations: case-control and a meta-analysis.
Fang, W, Qiu, F, Zhang, L, Deng, J, Zhang, H, Yang, L, Zhou, Y, Lu, J
Mutation research. 2014;:61-8
Abstract
NBS1 plays pivotal roles in maintaining genomic stability and cancer development. The exon variant rs1805794G>C (p.Glu185Gln) of NBS1 has been frequently studied in several association studies. However, the results were conflicting. Also, the function of this variant has never been well studied. In the current study, we performed a two centers case-control study and function assays to investigate the effect of the variant rs1805794G>C on lung cancer risk in Chinese, and a meta-analysis to summarize the data on the association between rs1805794G>C and cancer risk. We found that compared with the rs1805794GG genotype, the C genotypes (CG/CC) conferred a significantly increased risk of lung cancer in Chinese (OR=1.40, 95% CI=1.21-1.62) and interacted with medical ionizing radiation exposure on increasing cancer risk (Pinteraction=0.015). The lymphocyte cells from the C genotype individuals developed more chromatid breaks than those from the GG genotype carriers after the X-ray radiation (P=0.036). Moreover, the rs1805794C allele encoding p.185Gln attenuated NBS1's ability to repair DNA damage as the cell lines transfected with NBS1 cDNA expression vector carrying rs1805794C allele had significantly higher DNA breaks than those transfected with NBS1 cDNA expression vector carrying rs1805794G allele (P<0.05). The meta-analysis further confirmed the association between the variant rs1805794G>C and lung cancer risk, that compared with the GG genotype, the carriers of C genotypes had a 1.30-fold risk of cancer (95% CI=1.14-1.49, P=8.49×10(-5)). These findings suggest that the rs1805794G>C of NBS1 may be a functional genetic biomarker for lung cancer.
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Association between the NBS1 Glu185Gln polymorphism and lung cancer risk: a systemic review and meta-analysis.
Wang, L, Cheng, J, Gao, J, Wang, J, Liu, X, Xiong, L
Molecular biology reports. 2013;(3):2711-5
Abstract
Nijmegen Breakage Syndrome protein 1 (NBS1) is one of the most important DNA repair proteins playing important roles in maintaining the genomic stability of NDA. Previous studies regarding the association between NBS1 8360G>C (Glu185Gln) polymorphism and lung cancer reported conflicting results. To derive a more precise estimation of this association, a systemic review and meta-analysis was performed. We performed a meta-analysis using eligible case-control studies to summarize the data on the association between the NBS1 Glu185Gln polymorphism and lung cancer risk. Odds ratios (ORs) with corresponding 95 % confidence intervals (95 %CIs) were pooled to assess the association between NBS1 Glu185Gln polymorphism and lung cancer risk. Six case-control studies with a total of 2,348 lung cancer cases and 2,401 controls without canner were included into the meta-analysis. Overall, there was an association between NBS1 Glu185Gln polymorphism and lung cancer risk under the dominant comparison model (fixed-effects OR GluGln/GlnGln vs. GluGlu = 1.21, 95 % CI 1.07-1.37, P = 0.002, I (2) = 8.1 %). Subgroup analysis by race suggested a significant association between NBS1 Glu185Gln polymorphism and lung cancer risk in Asians (fixed-effects OR GluGlnGlnGln vs. GluGlu = 1.22, 95 % CI 1.06-1.41, P = 0.005) but not in Caucasians (fixed-effects OR GluGlnGlnGln vs. GluGlu = 1.17, 95 % CI 0.91-1.50, P = 0.220). This meta-analysis supports that there is an association between NBS1 Glu185Gln polymorphism and lung cancer risk. More studies are needed to further verify this association.
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p73 G4C14-to-A4T14 gene polymorphism and interaction with p53 exon 4 Arg72Pro on cancer susceptibility: a meta-analysis of the literature.
De Feo, E, Simone, B, Kamgaing, RS, Gallì, P, Hamajima, N, Hu, Z, Li, G, Li, Y, Matsuo, K, Park, JY, et al
Mutagenesis. 2012;(3):267-73
Abstract
The p73 gene (1p36-33) is involved in cancer development through cell growth inhibition by inducing apoptosis in a p53-like manner. The p73 G4C14-to-A4T14 dinucleotide polymorphism, consisting of two single-nucleotide polymorphisms in the non-coding region of exon 2 that are in complete linkage disequilibrium, has been extensively studied in association with cancer risk. We performed a meta-analysis of published studies that examined the association between this p73 G4C14-to-A4T14 polymorphism and cancer by searching for relevant studies on Medline and Embase up to February 28, 2010. Pooling data from 19 case-control studies that included 6510 cancer cases and 5711 controls, we found that carriers of the p73 G4C14-to-A4T14 homozygous variant genotype (AT/AT) had an increased global risk of cancer [odds ratio (OR) = 1.30, 95% confidence interval (CI), 1.03-1.65]. There was no evidence of an effect modification of p73 AT/AT by age, gender, ethnicity or smoking status in subgroup analyses; however, a 1.35-fold statistically significant increased risk was found among individuals <55 years old. In case-only analysis, the homozygous p73 G4C14-to-A4T14 variant of p73 genotype was associated with the presence of the p53 exon 4 Arg72Pro allele (OR = 1.30, 95% CI, 1.02-1.64), which is suggestive of a biological interaction between the two genes in carcinogenesis. In conclusion, the p73 G4C14-to-A4T14 homozygous variant genotype might be a risk factor for cancer, especially in combination with the p53 exon 4 Arg72Pro polymorphism. Further studies looking at p73 G4C14-to-A4T14 and p53 exon 4 Arg72Pro interaction are required to support our findings.
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TNFAIP3 gene polymorphisms are associated with response to TNF blockade in psoriasis.
Tejasvi, T, Stuart, PE, Chandran, V, Voorhees, JJ, Gladman, DD, Rahman, P, Elder, JT, Nair, RP
The Journal of investigative dermatology. 2012;(3 Pt 1):593-600
Abstract
The tumor necrosis factor-alpha-induced protein 3 (TNFAIP3) gene has been associated with psoriasis, rheumatoid arthritis, type 1 diabetes mellitus, systemic lupus erythematosus, and celiac disease. TNFAIP3 encodes A20, a tumor necrosis factor (TNF)-α-inducible zinc finger protein thought to limit NF-κB-mediated immune responses. In this study, we report association of response of psoriasis to TNF blockers with two TNFAIP3 single-nucleotide polymorphisms (rs2230926 in exon 7 and rs610604 in intron 3) and their haplotypes. Treatment response was self-evaluated using a 0-5 visual analog scale in 433 psoriasis patients who received TNF blockers. Confirmation was sought in 199 psoriasis and psoriatic arthritis patients from Toronto who were followed up prospectively. Response variables were dichotomized separately in the two cohorts, yielding similar proportions of good responses. Whereas significant associations were observed only for the Michigan cohort, fixed-effects meta-analysis retained significant association between dosage of the G allele of rs610604 and good combined response to all TNF blockers (odds ratio (OR) = 1.50, P(corr) = 0.050) and etanercept (OR = 1.64, P(corr) = 0.016). The rs2230926 T-rs610604 G haplotype was similarly associated. By demonstrating an association with therapeutic response, these results provide a clinically relevant functional correlate to the recently described genetic association between psoriasis and TNFAIP3.
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The association between BANK1 and TNFAIP3 gene polymorphisms and systemic lupus erythematosus: a meta-analysis.
Fan, Y, Tao, JH, Zhang, LP, Li, LH, Ye, DQ
International journal of immunogenetics. 2011;(2):151-9
Abstract
The past decade has witnessed hundreds of reports declaring or not being able to replicable genetic association with systemic lupus erythematosus (SLE) susceptibility. BANK1 is a gene that encodes a B-cell-specific scaffold protein and its activation can affect B-cell-receptor-induced calcium mobilization from intracellular calcium stores. TNFAIP3 encodes the ubiquitin-modifying enzyme, also known as A20, which is a cytoplasmic zinc finger protein that inhibits nuclear factor kappa-B (NFKB) activity and tumour necrosis factor (TNF)-mediated programmed cell death. The association of BANK1 and TNFAIP3 polymorphism with SLE has been reported in several studies. The aim of this study was to assess whether combined evidence shows the association between BANK1 and TNFAIP3 polymorphism and SLE. We report the results of a meta-analysis of genome-wide association scans and replication in independent sets for BANK1 and TNFAIP3 polymorphism and SLE that includes 12,416 subjects with SLE and 19,113 control subjects. Meta-odds ratios (ORs) and 95% confidence intervals (CIs) based on random effects models. Both of BANK1 and TNFAIP3 harbour several controversial single nucleotide polymorphisms (SNPs). We selected and identified three SNPs of BANK1 associated with SLE (rs17266594, P = 1.949e-10; OR = 1.380; 95% CI: 1.250-1.525; rs10516487, P = 2.642e-13; OR = 1.317; 95% CI: 1.223-1.417; rs3733197, P = 3.452e-06; OR = 1.193; 95% CI: 1.107-1.286); one SNP of TNFAIP3 associated with SLE (rs2230926, P = 1.502e-12; OR = 1.826; 95% CI: 1.545-2.157). This meta-analysis demonstrates a significant association between BANK1 and TNFAIP3 gene polymorphism and SLE in multiple ethnic populations. These findings reinforce the value of large sample series for discovery and follow-up of genetic variants contributing to the aetiology of SLE.