Pooled genome wide association detects association upstream of FCRL3 with Graves’ disease

Khong, Jwu Jin; Burdon, Kathryn P.; Lu, Yi; Laurie, Kate; Leonardos, Lefta; Baird, Paul N.; Sahebjada, Srujana; Walsh, John P.; Gajdatsy, Adam; Ebeling, Peter R.; Hamblin, Peter S; Wong, Rosemary; Forehan, Simon; Fourlanos, Spiros; Roberts, Anthony; Doogue, Matthew; Selva, Dinesh; Montgomery, Grant W.; MacGregor, Stuart; Craig, Jamie E

doi:10.1186/s12864-016-3276-z

Cited by 13 publications

(9 citation statements)

References 60 publications

(85 reference statements)

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“…The third most important SNP in our data is CEP57 /rs4409785 (p = 1.03E − 03), which is an intergenic variant on chromosome 11q21. This SNP has also been reported to be associated with other immune-related diseases such as multiple sclerosis, vitiligo, and Graves' disease [ 32 – 34 ]. In GTEx expression data, rs4409785 was eQTL for JRKL (p − eQTL = 0.037) in EBV-transformed lymphocytes, and for AP001877.1 (p − eQTL = 0.0188), and MAML2 (p − eQTL = 0.034) in transformed fibroblast cells.…”

Section: Discussionmentioning

confidence: 99%

Investigating the GWAS-Implicated Loci for Rheumatoid Arthritis in the Pakistani Population

et al. 2020

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Rheumatoid arthritis (RA) is a complex and multifactorial autoimmune disorder with the involvement of multiple genetic and environmental factors. Genome-wide association studies (GWAS) have identified more than 50 RA genetic loci in European populations. Given the anticipated overlap of RA-relevant genes and pathways across different ethnic groups, we sought to replicate 58 GWAS-implicated SNPs reported in Europeans in Pakistani subjects. 1,959 unrelated subjects comprising 1,222 RA cases and 737 controls were collected from three rheumatology facilities in Pakistan. Genotyping was performed using iPLEX or TaqMan® methods. A total of 50 SNPs were included in the final association analysis after excluding those that failed assay design/run or postrun QC analysis. Fourteen SNPs (LINC00824/rs1516971, PADI4/rs2240336, CEP57/rs4409785, CTLA4/rs3087243, STAT4/rs13426947, HLA-B/MICA/rs2596565, C5orf30/rs26232, CCL21/rs951005, GATA3/rs2275806, VPS37C/rs595158, HLA-DRB1/rs660895, EOMES/rs3806624, SPRED2/rs934734, and RUNX1/rs9979383) were replicated in our Pakistani sample at false discovery rate (FDR) of <0.20 with nominal p values ranging from 4.73E-06 to 3.48E-02. Our results indicate that several RA susceptibility loci are shared between Pakistani and European populations, supporting the role of common genes/pathways.

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Section: Discussionmentioning

confidence: 99%

Investigating the GWAS-Implicated Loci for Rheumatoid Arthritis in the Pakistani Population

et al. 2020

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“…Twin studies have indicated that the genes account for 79% of the role in predisposition to GD [9]. Extensive genetic association studies have identified that many genes are associated with predisposition to GD, for example, human leukocyte antigen (HLA), cytotoxic T-lymphocyte-associated antigen-4 (CTLA4), protein tyrosine phosphatase 22 (PTPN22), Fc receptor like 3 (FCRL3), FoxP3, thyroid-stimulating hormone receptor (TSHR), and vitamin D receptor gene (VDR) [10][11][12][13][14][15][16][17]. At present, antithyroid drugs are regarded as the preferred methods to treat GD in China, but recurrence within 2 years after retreat of the drug is as high as 50 − 60% [18].…”

Section: Introductionmentioning

confidence: 99%

Predisposition to Graves’ disease and Graves’ ophthalmopathy by genetic variants of IL2RA

Wang

Tan

et al. 2021

J Mol Med

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Previous studies have identified that Th17/Treg cells were involved in the occurrence and development of Graves' disease (GD). This study aimed at clarifying the association between GD susceptibility and nine single nucleotide polymorphisms (SNPs) of Th17/Treg cell-related genes, including IL2RA, miR27a, miR182, and FoxO1. A two-stage association study was performed in 650 GD patients and 1300 healthy controls. PCR-RFLP assays, real-time PCR, and ELISA were performed. In the first stage, association analysis has identified that IL2RA/rs3118470 TT genotype (Pc = 0.027, OR = 1.688) and IL2RA/rs2104286 AA genotype (Pc = 0.027, OR = 1.658) has significantly increased frequencies in patients with GD than control subjects. In the second stage, the result of rs2104286 was consistent with the first-stage results (AA genotype: Pc = 0.006, OR = 1.618). The combined data showed that IL2RA/rs2104286 AA genotype had increased frequencies in patients with GD (Pc = 8.772 × 10 −6 , OR = 1.636). Stratification analysis also revealed that rs2104286 AA genotype was significantly associated with Graves' ophthalmopathy (GO) susceptibility (Pc = 9.150 × 10 −4 , OR = 1.851). Functional studies showed that carriers of the rs2104286 AA genotype had lower IL2RA mRNA expression than AG genotype carriers (P = 0.021). Cytokine analyses revealed that the rs2104286 AA genotype individuals had lower IL-10 levels (P = 0.015) and increased IL-17 levels than AG genotype carriers (P = 1.467 × 10 −4 ). In conclusion, our findings suggested that IL2RA/rs2104286 was associated with GD and GO susceptibility in Southwest Chinese Han population, which may be involved in the occurrence of GD and GO by affecting the mRNA expression of IL2RA gene and the cytokine production. Key messages• We identified that IL2RA/rs2104286 locus contributed to the predisposition of Graves' disease (GD) and Graves' ophthalmopathy (GO). • Functional analyses suggested that IL2RA/rs2104286 may participate in the occurrence of GD and GO by affecting the mRNA expression of IL2RA and cytokine (IL-10 and IL-17) secretion. • We found that IL2RA (rs3118470, rs7093069), miR27a/ rs895819, miR182/rs76481776, and FoxO1 (rs2297626, rs17592236, rs9549241, rs12585277) loci polymorphisms were not associated with GD susceptibility.

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“…Using pooled-DNA GWAS, both known and novel genetic variants have been identified in various diseases or traits. 39 , 40 Of relevance to our study, the pooled-DNA GWAS approach has been successfully used in studies including smaller numbers of participants. 41 , 42 , 43 Altogether, the aim of our study was to determine whether GWAS using DNA-pooling methodology could identify genetic variants associated with IR in obese children and adolescents.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel alleles associated with insulin resistance in childhood obesity using pooled-DNA genome-wide association study approach

Kotnik

Knapič

Kokošar³

et al. 2017

Int J Obes

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Background:Recently, we witnessed great progress in the discovery of genetic variants associated with obesity and type 2 diabetes (T2D), especially in adults. Much less is known regarding genetic variants associated with insulin resistance (IR). We hypothesized that novel IR genes could be efficiently detected in a population of obese children and adolescents who may not exhibit comorbidities and other confounding factors.Objectives:This study aimed to determine whether a genome-wide association study (GWAS), using a DNA-pooling approach, could identify novel genes associated with IR.Subjects:The pooled-DNA GWAS analysis included Slovenian obese children and adolescents with and without IR matched for body mass index, gender and age. A replication study was conducted in another independent cohort with or without IR.Methods:For the pooled-DNA GWAS, we used HumanOmni5-Quad SNP array (Illumina). Allele frequency distributions were compared with modified t-tests and χ2-tests and ranked using PLINK. Top single nucleotide polymorphisms (SNPs) were validated using individual genotyping by high-resolution melting analysis and TaqMan assay.Results:We identified five top-ranking SNPs from the pooled-DNA GWAS analysis within the ECE1, IL1R2, GNPDA1, HLA-J and PYGB loci. All except SNP rs9261108 (HLA-J locus) were confirmed in the validation phase using individual genotyping. The SNP rs2258617 within PYGB remained statistically significant for both recessive and additive models in both cohorts and in a merged analysis of both cohorts and present the strongest novel candidate gene for IR.Conclusion:We report for the first time a pooled-DNA GWAS approach to identify five novel SNPs or genes for IR in a paediatric population. The four loci confirmed in the second validation phase study warrant further studies, especially the strongest SNP rs2258617 within PYGB, and provide targets for further basic research of IR mechanisms and for the development of potential new IR and T2D therapies.

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Pooled genome wide association detects association upstream of FCRL3 with Graves’ disease

Cited by 13 publications

References 60 publications

Investigating the GWAS-Implicated Loci for Rheumatoid Arthritis in the Pakistani Population

Investigating the GWAS-Implicated Loci for Rheumatoid Arthritis in the Pakistani Population

Predisposition to Graves’ disease and Graves’ ophthalmopathy by genetic variants of IL2RA

Identification of novel alleles associated with insulin resistance in childhood obesity using pooled-DNA genome-wide association study approach

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