The TLR5 (Toll-Like Receptor 5) gene encodes a pattern recognition receptor that recognizes bacterial flagellin. When flagellin is detected, NF-kappaB is mobilized, which then activates inflammation-related factors (Hayashi et al., PMID: 11323673). TLR5 was first reported in relation to systemic lupus erythematosus (SLE) in 2005 (Hawn et al., PMID: 16027372).
Genetic evidence reviewed during the curation of this gene-disease relationship included one proband who also carried a de novo gain of function PIK3CD variant in addition to the TLR5 p.Tyr108His variant (Hou et al., PMID: 36810668). A patient with a non-SLE-related phenotype carried a maternally inherited microdeletion that included parts of TLR5 (Jun et al., PMID: 23542665). Linkage studies originally identified an association between the 1q41-1q42 region (which includes TLR5) and susceptibility to SLE. A case-control study (Hawn et al., PMID: 16027372) found a protective association between the common stop codon polymorphism c.1147C>T in TLR5 and risk of developing SLE. There have since been four additional case-control studies in 2007, 2009, 2015, and 2017 that have found no significant associations between healthy controls and patients with SLE for this variant (PMIDs: 17516623, 19473567, 26221343, 28763101).
Experimental evidence is limited to the common c.1174C>T variant. In isolated blood cells, impaired cytokine production in response to flagellin was found in c.1174C>T heterozygotes compared to controls. The authors hypothesized that the c.1174C>T variant provides protection from developing SLE by decreasing the production of proinflammatory cytokines (Hawn et al., PMID: 16027372). One study found increased expression of TLR5 in the kidneys of lupus nephritis patients both at the protein and mRNA levels (Elloumi et al., PMID: 28763101).
In summary, there is limited evidence to support the relationship between TLR5 and systemic lupus erythematosus. This classification was approved by the ClinGen Monogenic Systemic and Incomplete Lupus Erythematosus GCEP on the meeting date February 12, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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