Genome-wide association study identifies Sjögren’s risk loci with functional implications in immune and glandular cells

Khatri, Bhuwan; Tessneer, Kandice L.; Rasmussen, Astrid; Aghakhanian, Farhang; Reksten, Tove Ragna; Adler, Adam J.; Alevizos, Ilias; Anaya, Juan Manuel; Aqrawi, Lara A.; Baecklund, Eva; Brun, Johan G.; Bucher, Sara Magnusson; Eloranta, Maija‐Leena; Engelke, Fiona; Forsblad‐d’Elia, Helena; Glenn, Stuart B.; Hammenfors, Daniel; Imgenberg‐Kreuz, Juliana; Jensen, Janicke Liaaen; Johnsen, Svein Joar Auglænd; Jonsson, Malin V.; Kvarnström, Marika; Kelly, Jennifer A.; Li, He; Mandl, Thomas; Martı́n, Javier; Nocturne, Gaëtane; Norheim, Katrine Brække; Palm, Øyvind; Skarstein, Kathrine; Stolarczyk, A. M.; Taylor, Kimberly E.; Teruel, María; Theander, Elke; Venuturupalli, Swamy; Wallace, Daniel J.; Grundahl, Kiely; Hefner, Kimberly S.; Radfar, Lida; Lewis, David M.; Stone, Donald U.; Kaufman, C. Erick; Brennan, Michael T.; Guthridge, Joel M.; James, Judith A.; Scofield, R. Hal; Gaffney, Patrick M.; Criswell, Lindsey A.; Jönsson, Roland; Eriksson, Per; Bowman, Simon; Omdal, Roald; Rönnblom, Lars; Warner, Blake M.; Rischmueller, Maureen; Witte, Torsten; Farris, A. Darise; Mariette, Xavier; Alarcón‐Riquelme, Marta E.; Shiboski, Caroline H.; Wahren‐Herlenius, Marie; Ng, Wan‐Fai; Sivils, Kathy L.; Adrianto, Indra; Nordmark, Gunnel; Lessard, Christopher J.

doi:10.1038/s41467-022-30773-y

Cited by 40 publications

(40 citation statements)

References 109 publications

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“…The role of genetic factors and in particular single nucleotide polymorphisms located on IFN pathways is well established. 17 19 In SLE, more than 100 genetic risk loci have been identified. Half of them are related to IFN pathways.…”

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confidence: 99%

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Interferon signature in systemic autoimmune diseases: what does it mean?

Nocturne

Mariette

2022

RMD Open

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confidence: 99%

“…Genetic, epigenetic and environmental factors may be involved. The role of genetic factors and in particular single nucleotide polymorphisms located on IFN pathways is well established 17 19. In SLE, more than 100 genetic risk loci have been identified.…”

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confidence: 99%

Interferon signature in systemic autoimmune diseases: what does it mean?

Nocturne

Mariette

2022

RMD Open

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“…Our study suggests that the TNFAIP3 risk haplotype associated with SLE and other autoimmune diseases (e.g. rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory skin disorder, inflammatory bowel disease, celiac disease, and Sjögren’s disease ( Graham et al, 2008 ; Trynka et al, 2009 ; Dieudé et al, 2010 ; Shimane et al, 2010 ; Musone et al, 2011 ; Koumakis et al, 2012 ; Zhou et al, 2015 ; Xu et al, 2019 ; Khatri et al, 2022 ) not only results in the loss of an important suppressor of immune stimulation but may also concomitantly activate the immune system through IL-20 and IFNγ signaling pathways in specific cellular contexts.…”

Section: Discussionmentioning

confidence: 72%

“…Haploinsufficiency of TNFAIP3 also leads to a monogenic autoinflammatory disorder in humans ( Zhou et al, 2015 ; Franco-Jarava et al, 2018 ; Tsuchida et al, 2019 ). Genome-wide association studies (GWAS) have associated the TNFAIP3 locus with at least 16 different human diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis, Sjögren’s disease, systemic sclerosis, and psoriasis ( Plenge et al, 2007 ; Thomson et al, 2007 ; Graham et al, 2008 ; Bates et al, 2009 ; Han et al, 2009 ; Nair et al, 2009 ; Trynka et al, 2009 ; Cai et al, 2010 ; Dieudé et al, 2010 ; Shimane et al, 2010 ; Strange et al, 2010 ; Adrianto et al, 2011 ; Musone et al, 2011 ; Koumakis et al, 2012 ; Xu et al, 2019 ; Ray et al, 2020 ; Khatri et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Systemic lupus erythematosus variants modulate the function of an enhancer upstream of TNFAIP3

Pasula

Gopalakrishnan

et al. 2022

Front. Genet.

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TNFAIP3/A20 is a prominent autoimmune disease risk locus that is correlated with hypomorphic TNFAIP3 expression and exhibits complex chromatin architecture with over 30 predicted enhancers. This study aimed to functionally characterize an enhancer ∼55 kb upstream of the TNFAIP3 promoter marked by the systemic lupus erythematosus (SLE) risk haplotype index SNP, rs10499197. Allele effects of rs10499197, rs58905141, and rs9494868 were tested by EMSA and/or luciferase reporter assays in immune cell types. Co-immunoprecipitation, ChIP-qPCR, and 3C-qPCR were performed on patient-derived EBV B cells homozygous for the non-risk or SLE risk TNFAIP3 haplotype to assess haplotype-specific effects on transcription factor binding and chromatin regulation at the TNFAIP3 locus. This study found that the TNFAIP3 locus has a complex chromatin regulatory network that spans ∼1M bp from the promoter region of IL20RA to the 3′ untranslated region of TNFAIP3. Functional dissection of the enhancer demonstrated co-dependency of the RelA/p65 and CEBPB binding motifs that, together, increase IL20RA and IFNGR1 expression and decreased TNFAIP3 expression in the context of the TNFAIP3 SLE risk haplotype through dynamic long-range interactions up- and downstream. Examination of SNPs in linkage disequilibrium (D’ = 1.0) with rs10499197 identified rs9494868 as a functional SNP with risk allele-specific increase in nuclear factor binding and enhancer activation in vitro. In summary, this study demonstrates that SNPs carried on the ∼109 kb SLE risk haplotype facilitate hypermorphic IL20RA and IFNGR1 expression, while suppressing TNFAIP3 expression, adding to the mechanistic potency of this critically important locus in autoimmune disease pathology.

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“…These genetic variations are identified by cutting-edge research technique Genome-Wide Association Studies (GWASs) through comprehensive sequencing and analysis of the complete genome of thousands of SNPs at once, allowing for the identification of common SNPs that are linked to certain diseases [12]. Focusing on SNPs throughout the entire genome is an exciting new direction in the study of complex, common illnesses in which several genes contribute in identifying the genes to a person's risk, pharmacological reactions, susceptibility to contaminants and environmental factors; in prognosis and diagnosis of illness or trait [13].…”

Section: Introductionmentioning

confidence: 99%

Genome-wide association study for single nucleotide polymorphism associated with mural and cumulus granulosa cells of PCOS (polycystic ovary syndrome) and non-PCOS patients

Pant

Chitme

Sircar³

et al. 2023

Futur J Pharm Sci

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Background The genetic make-up of local granulosa cells and their function in the pathophysiology of polycystic ovary syndrome (PCOS) is crucial to a full comprehension of the disorder. The major purpose of this study was to compare the Single Nucleotide Polymorphism (SNP) of cumulus granulosa cells (CGCs) and mural granulosa cells (MGCs) between healthy individuals and women with PCOS using genome-wide association analysis (GWA). A case–control study was conducted in a total of 24 women diagnosed with PCOS and 24 healthy non-PCOS women of reproductive age aggregated into 4 samples of 6 patients each. GWA studies entail several processes, such as cell separation, cellular DNA extraction, library preparation followed by interpretation using bioinformatics databases. SNP locations were identified by reference gene also involves the use of Matrix-assisted laser desorption/ionisation-time of flight (MALDI-TOF) mass spectrometry (MS) (MALDI-TOF-MS) for the first sorting. Hybridization with the gene chip was followed by reading the SNP genotypes according to the publications in the literature. TASSEL (Trait Analysis by aSSociation, Evolution and Linkage) program and methods were used for GWA studies. Results An aggregate of 21,039 SNP calls were obtained from our samples. Genes of autoimmune illnesses, obesity, inflammatory illnesses, nervous system diseases such as retinitis pigmentosa, autism, neural tube defects, and Alzheimer's disease; and various malignancies such as lung cancer, colorectal cancer, breast cancer were also identified in these cells. Gene ranking score reveals that granulosa cells carry key genes of neurological system and reproductive systems especially in brain and testis, respectively. Conclusions Mural and Cumulus Granulosa cells were shown to have the PCOS directly and indirectly related genes MMP9, PRKAA2, COMT and HP. We found that the expression of ARID4B, MUC5AC, NID2, CREBBP, GNB1, KIF2C, COL18A1, and HNRNPC by these cells may contribute to PCOS. Graphical abstract

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Genome-wide association study identifies Sjögren’s risk loci with functional implications in immune and glandular cells

Cited by 40 publications

References 109 publications

Interferon signature in systemic autoimmune diseases: what does it mean?

Interferon signature in systemic autoimmune diseases: what does it mean?

Systemic lupus erythematosus variants modulate the function of an enhancer upstream of TNFAIP3

Genome-wide association study for single nucleotide polymorphism associated with mural and cumulus granulosa cells of PCOS (polycystic ovary syndrome) and non-PCOS patients

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