MCID: PRD008
MIFTS: 66

Periodontitis malady

Gastrointestinal diseases category

Summaries for Periodontitis

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63Wikipedia, 32MalaCards
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Wikipedia:63 Periodontitis /ˌpɛrioʊdɒnˈtaɪtɪs/ or pyorrhea /ˌpaɪəˈriə/ is a set of inflammatory diseases... more...

MalaCards: Periodontitis, also known as chronic periodontitis, is related to periodontal disease and aggressive periodontitis. An important gene associated with Periodontitis is ASPN (asporin), and among its related pathways are Immune System and TRAF Pathway. The drug carbamide peroxide and the compounds vegf and retinoic acid have been mentioned in the context of this disorder. Affiliated tissues include bone, endothelial and heart, and related mouse phenotypes are immune system and homeostasis/metabolism.

Aliases & Classifications for Periodontitis

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Sources:
8Disease Ontology, 10DISEASES, 60UMLS, 22GTR, 44Novoseek, 34MeSH, 56SNOMED-CT, 39NCIt, 25ICD10
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Classifications:

Malacards categories (disease lists): (See all malacards categories)
Anatomical: Gastrointestinal diseases


Aliases & Descriptions:

periodontitis 8 10 60
chronic periodontitis 8 22 44 60
chronic pericementitis 8


External Ids:

Disease Ontology8 DOID:824
MeSH34 D010518
NCIt39 C34918
ICD1025 K05.3

Related Diseases for Periodontitis

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Sources:
17GeneCards, 18GeneDecks
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Diseases in the Periodontitis family:

Periodontitis 1, Juvenile

Diseases related to Periodontitis via text searches within MalaCards or GeneCards/GeneDecks gene sharing:

(show top 50)    (show all 364)
idRelated DiseaseScoreTop Affiliating Genes
1periodontal disease31.9ELANE, MMP1, MMP8, IL6, IL1B, IL1A
2aggressive periodontitis31.7CTSC, JPD
3gingivitis31.7TNFSF11, ELANE, MMP1, MMP8, IL1B, IL1A
4diabetes mellitus31.0IL6, IL1B, CD14
5arthritis30.9TNFSF11, IL1A, IL1B, IL6
6rheumatoid arthritis30.9CD14, LTF, TNFRSF11B, TNFSF11, TLR4, IL1RN
7gingival overgrowth30.7MMP1, IL1B, IL1A
8atherosclerosis30.7TLR4, TNFRSF11B, CD14, IL1RN, IL1A, IL1B
9obesity30.6IL6
10root resorption30.5TNFRSF11B
11osteoporosis30.5MMP8, IL6, IL1RN, TNFRSF11B, TNFSF11
12vascular disease30.4ELANE, IL6, IL1B, IL1A, IL1RN
13neutropenia30.4IL1RN, ELANE
14coronary artery disease30.3IL6, CD14, TNFRSF11B, TNFSF11
15acute myocardial infarction30.2MMP8, CD14, TNFSF11
16myocardial infarction30.2CD14, POSTN
17bacterial vaginosis30.1IL1B, IL1A, LTF
18juvenile rheumatoid arthritis30.1IL1RN, IL1A, IL6
19systemic lupus erythematosus30.1TLR4, LTF, IL1RN, IL6
20psoriasis30.0LTF, IL1A, IL1B, IL6, ELANE
21familial mediterranean fever30.0IL1B
22connective tissue disease30.0IL6
23inflammatory bowel disease29.9TLR4, DEFB1, LTF, CD14, IL1RN, IL1B
24asthma29.9TLR4, DEFB1, POSTN, CD14, IL1B, MMP8
25tuberculosis29.9IL1B, TLR4
26crohn's disease29.9LTF
27papillon-lefevre disease29.9CTSC, JPD
28pneumonia29.6TLR4, DEFB1, IL1B, IL6, MMP8, ELANE
29breast cancer29.6TNFSF11, TNFRSF11B, POSTN, CD14, MMP8, MMP1
30sarcoidosis29.6IL1A, IL1RN, CD14, DEFB1, IL1B
31psoriatic arthritis29.6MMP1, IL1B, IL1A, TNFRSF11B, TNFSF11
32multiple sclerosis29.6IL1RN, IL1B, IL6, MMP8
33ankylosing spondylitis29.6TLR4, TNFSF11, TNFRSF11B, IL1RN
34vasculitis29.6ELANE, CD14, LTF
35pulmonary emphysema29.6ELANE, MMP1, MMP8
36glomerulonephritis29.6IL1RN, IL1B, ELANE
37thrombocytopenia29.6IL6, IL1A, TLR4
38liver cirrhosis29.6CD14
39peptic ulcer29.6CD14
40prostatitis29.6LTF
41chondrosarcoma29.6MMP1
42dementia29.6TNFRSF11B
43oral submucous fibrosis29.6MMP1
44alpha 1-antitrypsin deficiency29.6ELANE
45gingival disease10.7
46periodontosis10.6
47periapical periodontitis10.5
48chronic apical periodontitis10.5
49gingival recession10.5
50dental caries10.4

Graphical network of the top 20 diseases related to Periodontitis:



Diseases related to periodontitis

Clinical Features for Periodontitis

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Drugs & Therapeutics for Periodontitis

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Sources:
5CenterWatch, 41NIH Clinical Center, 6ClinicalTrials, 60UMLS, 40NDF-RT
See all sources

Approved drugs:

Search CenterWatch for Periodontitis

Drug clinical trials:

Search ClinicalTrials for Periodontitis

Search NIH Clinical Center for Periodontitis

Search CenterWatch for Periodontitis

Inferred drug relations via UMLS60/NDF-RT40:

Genetic Tests for Periodontitis

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Sources:
22GTR
See all sources

Genetic tests related to Periodontitis:

id Genetic test Affiliating Genes
1 Periodontitis, Chronic22

Anatomical Context for Periodontitis

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32MalaCards
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MalaCards organs/tissues related to Periodontitis:

32
Bone, Endothelial, Heart, T cells, Monocytes, Kidney, Testes, Whole blood, B cells, Colon, Tongue, Prostate, Nk cells, Thyroid, Bone marrow, Liver, Placenta, Smooth muscle, Breast, Brain, Cortex

Animal Models for Periodontitis or affiliated genes

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36MGI
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MGI Mouse Phenotypes related to Periodontitis:

36
idDescriptionMGI Source AccessionScoreTop Affiliating Genes
1MP:000538712.5ELANE, TLR4, TNFSF11, TNFRSF11B, CTSC, DEFB1
2MP:000537612.1TNFSF11, CTSC, POSTN, LTF, CD14, IL1RN
3MP:000200611.1POSTN, IL1B, IL6, MMP8, ELANE
4MP:000539011.0TNFSF11, TNFRSF11B, POSTN, CD14, IL1B, IL6

Publications for Periodontitis

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Sources:
50PubMed
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Articles related to Periodontitis:

(show top 50)    (show all 3375)
idTitleAuthorsYear
1
Salivary Cytokines and the Association Between Obstructive Sleep Apnea Syndrome and Periodontal Disease. (24410293)
2014
2
Assessment of IL-6, IL-8 and TNF-I+ levels in the gingival tissue of patients with periodontitis. (24137277)
2013
3
Infection in a complex network of apical ramifications as the cause of persistent apical periodontitis: a case report. (23953295)
2013
4
Polymicrobial infection with major periodontal pathogens induced periodontal disease and aortic atherosclerosis in hyperlipidemic ApoE(null) mice. (23451182)
2013
5
Evaluation of Systemic Levels of Neutrophilic Enzymes in Hypertensive Patients With Chronic Periodontitis. (24224962)
2013
6
Periodontitis in pregnant baboons: systemic inflammation and adaptive immune responses and pregnancy outcomes in a baboon model. (23710643)
2013
7
Level of information about the relationship between diabetes mellitus and periodontitis--results from a nationwide diabetes information program. (23497572)
2013
8
Comparative evaluation of cytokines in gingival crevicular fluid and saliva of patients with aggressive periodontitis. (23592001)
2013
9
Design of a multiple drug delivery system directed at periodontitis. (23948165)
2013
10
Non-surgical periodontal therapy decreases serum elastase levels in aggressive but not in chronic periodontitis. (23432024)
2013
11
Extracellular matrix mineralization in periodontal tissues: Noncollagenous matrix proteins, enzymes, and relationship to hypophosphatasia and X-linked hypophosphatemia. (23931057)
2013
12
Discovering medical conditions associated with periodontitis using linked electronic health records. (23495669)
2013
13
Five-year changes in periodontal disease measures among postmenopausal females: the Buffalo OsteoPerio study. (22813344)
2013
14
CDC: Half of American adults have periodontal disease. (23256312)
2012
15
MAPK usage in periodontal disease progression. (22315682)
2012
16
Interleukin-6 gene promoter methylation in rheumatoid arthritis and chronic periodontitis. (22122521)
2012
17
Gingival blood glucose may screen for type 2 diabetes in patients with periodontal disease. (22935284)
2012
18
Effect of azithromycin, as an adjunct to nonsurgical periodontal treatment, on microbiological parameters and gingival crevicular fluid biomarkers in generalized aggressive periodontitis. (22571226)
2012
19
Myeloperoxidase staining in the diagnosis of aggressive periodontitis. (21976840)
2011
20
Effects of TGF-I^1 on the proliferation and differentiation of human periodontal ligament cells and a human periodontal ligament stem/progenitor cell line. (20931341)
2010
21
Genetic variants associated with neutrophil function in aggressive periodontitis and healthy controls. (20367096)
2010
22
Characteristic changes of periodontal ligament-derived cells during passage. (18973549)
2009
23
Increased TLR4 expression in murine placentas after oral infection with periodontal pathogens. (19101032)
2009
24
The use of 2 antibiotic regimens in aggressive periodontitis: comparison of changes in clinical parameters and gingival crevicular fluid biomarkers. (19093057)
2008
25
CC chemokine ligand 17 in periodontal diseases: expression in diseased tissues and production by human gingival fibroblasts. (18557811)
2008
26
Presence and significance of interleukin-1 polymorphism in patients who present with acute coronary syndrome, angina, and chronic periodontitis: an epidemiologic pilot study. (18166103)
2008
27
Periodontal disease increases the risk of severe pre-eclampsia among pregnant women. (17590155)
2007
28
Measurement of mechanical allodynia and local anesthetic efficacy in patients with irreversible pulpitis and acute periradicular periodontitis. (17804314)
2007
29
Periodontal findings and blood analysis of blood donors: a pilot study. (17618329)
2007
30
Total antioxidant capacity and antioxidant enzymes in serum, saliva, and gingival crevicular fluid of preeclamptic women with and without periodontal disease. (17668980)
2007
31
Studies on periodontitis and analyses of individuals at risk for periodontal diseases. (16838563)
2006
32
CD14 and TLR4 gene polymorphisms in adult periodontitis. (16246938)
2005
33
Expression of the receptor of advanced glycation end products in gingival tissues of type 2 diabetes patients with chronic periodontal disease: a study utilizing immunohistochemistry and RT-PCR. (15642057)
2005
34
Expression of vascular endothelial growth factor in human periodontal tissues: comparison of healthy and diabetic patients. (12666706)
2003
35
Tumor necrosis factor-alpha gene (TNF-alpha) -1031/-863, -857 single-nucleotide polymorphisms (SNPs) are associated with severe adult periodontitis in Japanese. (12795791)
2003
36
Prevalence of periodontopathic bacteria in aggressive periodontitis patients in a Japanese population. (14653392)
2003
37
Plasminogen-activator-inhibitor-1 promoter polymorphism as a risk factor for adult periodontitis in non-smokers. (12140748)
2002
38
Isotypic antibody response to plaque anaerobes in periodontal disease. (12546101)
2002
39
Aggressive periodontitis: 5-year follow-up of treatment. (12083543)
2002
40
Enamel matrix derivative induces matrix synthesis by cultured human periodontal fibroblast cells. (11327061)
2001
41
Growth factors and cytokines modulate gene expression of cell-surface proteoglycans in human periodontal ligament cells. (11169984)
2001
42
Heterogeneity of host immunological risk factors in patients with aggressive periodontitis. (11338294)
2001
43
A chemically modified nonantimicrobial tetracycline (CMT-8) inhibits gingival matrix metalloproteinases, periodontal breakdown, and extra-oral bone loss in ovariectomized rats. (10415737)
1999
44
Endothelial cell adhesion molecules in human dental pulp: a comparative immunohistochemical study on chronic periodontitis. (10687524)
1999
45
The correlation of gingival crevicular fluid interleukin-8 levels and periodontal status in localized juvenile periodontitis. (9848541)
1998
46
Effect of fibronectin on the synthesis of extracellular matrix proteins in periodontal ligament cells]. (9592289)
1996
47
Measurements of interleukin-6 in gingival crevicular fluid from adults with destructive periodontal disease. (8277408)
1993
48
Factors associated with active and inactive root caries in patients with periodontal disease. (1747889)
1991
49
Tissue levels of bone resorptive cytokines in periodontal disease. (1920018)
1991
50
Treatment of advanced periodontitis, severe gingival recession, and crowding of teeth in the lower anterior region of the mouth. (6587121)
1983

Genetic Variations for Periodontitis

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Expression for genes affiliated with Periodontitis

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Sources:
1BioGPS, 15Gene Expression Omnibus DataSets
See all sources
Expression patterns in normal tissues for genes affiliated with Periodontitis

Search GEO for disease gene expression data for Periodontitis.

Pathways for genes affiliated with Periodontitis

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Sources:
53Reactome, 51QIAGEN, 37NCBI BioSystems Database, 29KEGG, 12EMD Millipore, 52R&D Systems, 59Tocris Bioscience, 4Cell Signaling Technology
See all sources

Pathways related to Periodontitis according to GeneCards/GeneDecks:

(show all 41)
idSuper pathways (with members indented)ScoreTop Affiliating Genes
1
Hide members
11.6TLR4, CTSC, DEFB1, CD14, IL1RN, IL1A
2
Hide members
11.3TLR4, TNFSF11, TNFRSF11B, CD14, IL1A, IL1B
3
Immune response Bacterial infections in normal airways
Hide members
11.3IL6, IL1B, IL1A, IL1RN, CD14, TLR4
4
Hide members
11.2TLR4, TNFSF11, TNFRSF11B, CD14, IL1A
511.2TLR4, CD14, IL1A, IL1B, IL6
6
Hide members
11.2IL6, IL1B, IL1A, CD14, TLR4
711.2TLR4, CD14, IL1A, IL1B, IL6
811.2IL6, IL1B, IL1A, CD14, TLR4
911.2TLR4, CD14, IL1A, IL1B, IL6
1011.1TNFSF11, TNFRSF11B, IL1A, IL1B
1111.1TLR4, TNFSF11, CD14, IL1B
1211.1IL6, IL1B, IL1A, CD14
13
Hide members
11.1IL6, IL1B, IL1A, IL1RN
1411.1IL6, IL1B, IL1A, IL1RN
15
Hide members
11.1IL1RN, IL1A, IL1B, IL6
16
Hide members
11.1IL6, IL1B, IL1A, TLR4
17
Hide members
11.1TLR4, IL1A, IL1B, IL6
1811.1TLR4, IL1A, IL1B, IL6
19
Hide members
11.0IL6, IL1B, CD14, TLR4
2011.0TLR4, CD14, IL1B, IL6
2111.0TLR4, CD14, IL1B, IL6
22
Hide members
11.0TLR4, CD14, IL1B, IL6
23
Transcription Role of VDR in regulation of genes involved in osteoporosis
Hide members
10.9TNFSF11, TNFRSF11B, IL1A
2410.9ELANE, MMP8, LTF
25
Hide members
10.9IL1B, IL1A, IL1RN
26
Hide members
10.9IL1B, IL1A, TLR4
2710.9IL1B, TNFSF11, TLR4
2810.9IL1A, IL1B, IL6
2910.9IL6, IL1B, TNFSF11
3010.9TLR4, CD14, IL1A
31
Hide members
10.9TLR4, IL1B, IL6
32
Hide members
10.9TLR4, IL1B, IL6
3310.9IL6, CD14, TLR4
34
Cytokine production by Th17 cells in CF (Mouse model)
10.9TLR4, CD14, IL6
3510.8TNFRSF11B, TNFSF11
3610.8IL1A, IL1B
3710.8TNFSF11, TLR4
3810.8IL1B, IL6
3910.8TLR4, CD14
4010.6IL1A
4110.6TLR4

Compounds for genes affiliated with Periodontitis

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Sources:
44Novoseek, 24HMDB, 59Tocris Bioscience, 11DrugBank, 28IUPHAR, 2BitterDB, 49PharmGKB
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Compounds related to Periodontitis according to GeneCards/GeneDecks:

(show top 50)    (show all 153)
idCompoundScoreTop Affiliating Genes
1vegf4412.6IL1RN, TNFRSF11B, TNFSF11, POSTN, MMP1, MMP8
2retinoic acid44 2413.6IL6, MMP8, MMP1, IL1A, IL1RN, CD14
3polymyxin b4412.4LTF, DEFB1, TNFRSF11B, TNFSF11, TLR4, CD14
4cysteine4412.2TLR4, TNFSF11, TNFRSF11B, CTSC, CD14, LTF
5calcitriol44 59 11 2415.0TNFSF11, IL1A, CD14, IL1B, IL6, MMP1
6sb 20358044 5913.0TNFRSF11B, IL1A, TNFSF11, IL1B, TLR4, IL6
7fibrinogen4412.0TLR4, TNFRSF11B, CD14, MMP8, LTF, IL1RN
8genistein44 28 59 2 11 2417.0TNFSF11, TNFRSF11B, IL1A, IL1B, IL6, MMP8
9cyclosporin a44 28 5913.9TNFRSF11B, TNFSF11, MMP1, LTF, ELANE, MMP8
10infliximab44 49 1113.9IL6, TNFSF11, TNFRSF11B, IL1RN, IL1B, MMP1
11neopterin4411.9LTF, ELANE, IL6, IL1B, IL1A, CD14
12dexamethasone44 49 28 1114.9DEFB1, IL6, CD14, LTF, TLR4, TNFSF11
13heparin44 28 11 2414.9IL1RN, CD14, LTF, CTSC, IL1A, TNFRSF11B
14serine4411.9TNFRSF11B, IL1RN, MMP1, CTSC, IL1A, TNFSF11
15hyaluronic acid44 2412.9ELANE, IL6, IL1B, IL1A, MMP1, IL1RN
16fmlp4411.9IL1RN, CD14, LTF, IL1B, TLR4, ELANE
17prostaglandin4411.9IL1RN, IL1A, MMP1, IL1B, TNFRSF11B, TNFSF11
18clodronate44 49 1113.8IL1B, MMP8, MMP1, TNFSF11, TNFRSF11B, IL6
19creatinine4411.8IL1A, MMP1, CD14, TNFSF11, IL1RN, TNFRSF11B
20ns 39844 5912.8TNFSF11, TNFRSF11B, IL1RN, IL1A, MMP1, IL1B
21etanercept44 49 1113.7MMP1, IL1RN, TNFSF11, TNFRSF11B, IL6, IL1B
22peptidoglycan44 2812.7TNFSF11, IL1RN, TLR4, IL1B, IL6, CD14
23vitamin d4411.7IL6, TLR4, TNFSF11, TNFRSF11B, CD14, ELANE
24leukotriene b444 59 2413.7IL1RN, ELANE, IL6, IL1B, IL1A, LTF
25histamine44 28 2413.7LTF, CTSC, TLR4, CD14, IL1RN, IL1B
26pentoxifylline44 1112.6ELANE, MMP1, CD14, IL1RN, LTF
27rantes4411.6IL6, IL1B, IL1A, CD14, TLR4
28tgf beta14411.6IL6, IL1RN, TNFRSF11B, IL1B, TLR4, MMP1
29zymosan4411.6TLR4, ELANE, IL1RN, CD14, LTF
30leflunomide49 44 1113.6MMP1, IL6, IL1B, IL1RN, TNFSF11
31lipoteichoic acid4411.5CD14, IL1RN, IL6, TLR4, IL1B
32il 104411.5IL1B, IL1A, IL1RN, IL6, TLR4
33hydrocortisone44 2 59 1114.5TNFRSF11B, LTF, MMP1, ELANE
34anakinra44 1112.4IL6, IL1B, IL1RN, TNFRSF11B
35doxycycline44 1112.4MMP1, MMP8, LTF, TNFSF11, ELANE
36superoxide44 2412.4MMP8, ELANE, LTF, IL1B
37hbd24411.4IL6, DEFB1, TLR4, IL1B
38ibuprofen44 28 49 11 2415.3IL1RN, LTF, MMP1, IL6, IL1B
39gold sodium thiomalate4411.3CD14, IL1RN, IL1B, IL1A
40pamidronate44 49 1113.3MMP1, TNFSF11, TNFRSF11B, IL6
41pdtc4411.3TLR4, IL1B, IL1A, MMP1, IL6
42tenidap44 2812.2IL1A, LTF
43norepinephrine44 11 2413.1MMP1, ELANE, LTF
44h2o24411.1LTF, IL1RN, MMP8, MMP1
45endotoxin4411.1LTF
46indomethacin44 59 28 1114.0LTF
47gm-csf44 2812.0CD14
48pmma4411.0TNFRSF11B, TNFSF11, IL6, LTF
49cuprophan4410.8CD14, ELANE
50aprotinin44 1111.6LTF, MMP1, ELANE

GO Terms for genes affiliated with Periodontitis

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Sources:
16Gene Ontology
See all sources

Cellular components related to Periodontitis according to GeneCards/GeneDecks:

idNameGO IDScoreTop Affiliating Genes
1extracellular regionGO:00557612.1ELANE, TNFSF11, TNFRSF11B, DEFB1, LTF, CD14
2extracellular spaceGO:00561511.5TNFSF11, TNFRSF11B, CD14, IL1RN, IL1A, IL1B
3secretory granuleGO:03014110.9ELANE, IL1B, LTF
4proteinaceous extracellular matrixGO:00557810.9TNFRSF11B, POSTN, MMP8, MMP1, ASPN

Biological processes related to Periodontitis according to GeneCards/GeneDecks:

(show all 18)
idNameGO IDScoreTop Affiliating Genes
1immune responseGO:00695511.8IL1B, IL1A, IL1RN, DEFB1, CTSC, TNFSF11
2positive regulation of NF-kappaB transcription factor activityGO:05109211.5TLR4, TNFSF11, LTF, IL1B, IL6
3extracellular matrix organizationGO:03019811.5TNFRSF11B, POSTN, MMP8, MMP1, ELANE
4proteolysisGO:00650811.3CTSC, LTF, MMP8, MMP1, ELANE
5positive regulation of I-kappaB kinase/NF-kappaB cascadeGO:04312311.3IL1B, LTF, TNFSF11, TLR4
6cytokine-mediated signaling pathwayGO:01922111.2IL6, IL1B, IL1A, TNFSF11
7positive regulation of nitric oxide biosynthetic processGO:04542911.2IL6, IL1B, TLR4
8positive regulation of interleukin-6 productionGO:03275511.2IL6, IL1B, TLR4
9positive regulation of JNK cascadeGO:04633011.1TLR4, TNFSF11, IL1B
10fever generationGO:00166011.1IL1B, IL1A
11inflammatory responseGO:00695411.1IL6, IL1B, IL1A, CD14
12negative regulation of chemokine biosynthetic processGO:04507911.0IL6, ELANE
13collagen catabolic processGO:03057411.0MMP8, MMP1, ELANE
14cellular response to lipoteichoic acidGO:07122311.0CD14, TLR4
15positive regulation of sequence-specific DNA binding transcription factor activityGO:05109110.9IL6, IL1B, TNFSF11
16positive regulation of interleukin-8 biosynthetic processGO:04541610.9ELANE, TLR4
17extracellular matrix disassemblyGO:02261710.8MMP8, MMP1, ELANE
18positive regulation of interleukin-2 biosynthetic processGO:04508610.5IL1B, IL1A

Molecular functions related to Periodontitis according to GeneCards/GeneDecks:

idNameGO IDScoreTop Affiliating Genes
1cytokine activityGO:00512511.1IL6, IL1B, IL1A, TNFRSF11B, TNFSF11
2serine-type endopeptidase activityGO:00425211.1ELANE, MMP8, LTF, CTSC
3interleukin-1 receptor bindingGO:00514910.6IL1RN, IL1A, IL1B

Products for genes affiliated with Periodontitis

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  • Antibodies
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  • Lysates
  • Antibodies

Sources for Periodontitis

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3CDC
13ExPASy
14FMA
22GTR
23HGMD
24HMDB
25ICD10
26ICD10 via Orphanet
27ICD9CM
28IUPHAR
29KEGG
34MeSH
35MESH via Orphanet
36MGI
39NCIt
40NDF-RT
43NINDS
44Novoseek
46OMIM
47OMIM via Orphanet
50PubMed
51QIAGEN
57SNOMED-CT via Orphanet
60UMLS
61UMLS via Orphanet