{{Rsnum
|rsid=4986791
|Gene=TLR4
|Chromosome=9
|position=117713324
|Orientation=plus
|ReferenceAllele=C
|MissenseAllele=T
|GMAF=0.02984
|Assembly=GRCh38
|GenomeBuild=38.1
|dbSNPBuild=141
|geno1=(C;C)
|geno2=(C;T)
|geno3=(T;T)
|Gene_s=TLR4
}}{{ population diversity
| geno1=(C;C)
| geno2=(C;T)
| geno3=(T;T)
| CEU | 93.8 | 6.2 | 0.0
| HCB | 100.0 | 0.0 | 0.0
| JPT | 100.0 | 0.0 | 0.0
| YRI | 95.7 | 4.3 | 0.0
| ASW | 94.5 | 5.5 | 0.0
| CHB | 100.0 | 0.0 | 0.0
| CHD | 99.1 | 0.9 | 0.0
| GIH | 80.0 | 19.0 | 1.0
| LWK | 0.0 | 0.0 | 0.0
| MEX | 85.7 | 14.3 | 0.0
| MKK | 99.4 | 0.6 | 0.0
| TSI | 88.1 | 11.9 | 0.0
| HapMapRevision=28
}}[[rs4986791]], a SNP also known as Thr399Ile (and also 1196C/T) in the [[TLR4]] gene, is often studied along with a cosegregating SNP known as Asp299Gly, [[rs4986790]]. ([[TLR4]] encodes a receptor involved in the innate immune response.) Together, these SNPs have been reported to be associated with a wide variety of both infectious and non-infectious diseases, although there are conflicting or even contradictory results also reported in some cases. The risk allele for [[rs4986791]] is (T).

Reported associations include {{PMID|15766650}}:

* [[Diabetic neuropathy]]
** These SNPs may be protective {{PMID|14693986}}

* [[Heart disease]]
** Men with the risk alleles for both SNPs are at increased risk for myocardial infarction in this study of over 2000 individuals. {{PMID|15576653}}
** [[rs4986790]](G) carriers are not at increased risk for myocardial infartions, at least in this study of ~200 individuals. {{PMID|15547160}}
** [[rs4986790]](G) carriers are less likely to have heart attacks, in this study of ~400 individuals. {{PMID|14563652}}
** Individuals with the risk alleles for both SNPs have a lower incidence of carotid stenosis {{PMID|12124407}}

* [[Premature birth]]
** Individuals with the risk alleles for both SNPs are at higher risk for having their pregnancies associated with [[premature birth]]. {{PMID|12193670}}

* [[Bacterial vaginosis]]
** Pregnant [[rs4986790]](G) carriers are at increased risk for higher pH and a 10 fold higher level of certain bacteria {{PMID|15358455}}

* [[Bacterial infection]]
** Individuals with the risk alleles for both SNPs are more prone to gram-negative bacterial infections {{PMID|12404174}}

* [[Septic shock]]
** Individuals with the risk alleles for both SNPs are at higher risk for [[septic shock]] {{PMID|11996613}}

* [[Respiratory syncytial virus infection]]
** Individuals with the risk alleles for both SNPs are at higher risk for this type of viral infection. {{PMID|15143473}}

* [[Asthma]]
** Although not seen to influence the incidence of developing [[asthma]], [[rs4986790]](G) carriers who had [[asthma]] are reported to be more severely affected. {{PMID|14735148}}

* [[Allograft rejection]]
** Carriers of the risk alleles of either [[rs4986790]] or [[rs4986791]] have a lower rate of acute [[allograft rejection]] following lung transplantation. {{PMID|12773319}}

* [[Allograft complications]]
** A study of 300+ recipients of hematopoietic-cell transplants concluded that the adjusted hazard ratio for a recipient of developing a life-threatening invasive aspergillosis infection was 6.16x higher (CI: 1.97-19.26, p=0.002) if the donor carried these TLR4 risk alleles. This risk was statistically significant for unrelated recipients of transplants (odds ratio, 5.0, CI: 1.04-24.01, p=0.04) but did not quite meet the p=0.05 significance criteria for related recipients (odds ratio, 2.29, CI: 0.93-5.68, p=0.07). {{PMID|18946062|OA=1
}}

{{omim
|desc=ENDOTOXIN HYPORESPONSIVENESS
|id=603030
|quiet=1
|rsnum=4986791
|variant=0002
}}

{{ neighbor
| rsid = 4986790
| distance = 300
}}

{{PharmGKB
|RSID=rs4986791
|Name_s=TLR4: T399I
|Gene_s=TLR4
|Feature=
|Evidence=PubMed ID:18946062
|Annotation=A study in 336 recipients of hematopoietic-cell transplants and their unrelated donors suggests an association between the donor TLR4 haplotype S4 (this SNP and SNP D299G in a strong linkage disequilibrium) and the risk of invasive aspergillosis among recipients of hematopoietic-cell transplants from unrelated donors.
|Drugs=
|Drug Classes=
|Diseases=Aspergillosis Infection
|Curation Level=Curated
|PharmGKB Accession ID=PA162356101
}}

{{PMID Auto
|PMID=21283657
|Title=Gallbladder Cancer Predisposition: A Multigenic Approach to DNA-Repair, Apoptotic and Inflammatory Pathway Genes
|OA=1
}}

{{PMID Auto
|PMID=21081146
|Title=Impact of Toll-like receptor 4 polymorphisms on risk of cancer
}}

{{PMID Auto
|PMID=21837802
|Title=Confirmation of an association between single nucleotide polymorphisms in the VDR gene with respiratory syncytial virus related disease in South African Children
}}

{{PMID Auto
|PMID=22286521
|Title=Polymorphism of the TLR4 Gene Reduces the Risk of Hepatitis C Virus-Induced Hepatocellular Carcinoma
}}

{{PMID Auto
|PMID=22645142
|Title=Variants of Toll-like receptor 4 predict cardiac recovery in patients with dilated cardiomyopathy
|OA=1
}}

{{ClinVar
|rsid=4986791
|Reversed=0
|FwdREF=C
|FwdALT=T
|REF=C
|ALT=T
|RSPOS=120475602
|CHROM=9
|GMAF=0.0298
|dbSNPBuildID=118
|SSR=0
|SAO=1
|VP=0x050368000000150517110101
|GENEINFO=TLR4:7099
|GENE_NAME=TLR4
|GENE_ID=7099
|WGT=0
|VC=SNV
|CLNALLE=1
|CLNHGVS=NC_000009.11:g.120475602C>T
|CLNORIGIN=1
|CLNSIG=5
|Tags=PM;PMC;S3D;SLO;VLD;G5;HD;GNO;KGPhase1;KGPROD;OTHERKG;PH3;LSD;OM
|CAF=0.9702; 0.02984
|CLNACC=RCV000007043.1; RCV000086999.1
|CLNDBN=Endotoxin hyporesponsiveness; not provided
|CLNDSDB=MedGen
|CLNDSDBID=C1864267
|CLNSRC=OMIM Allelic Variant
|CLNSRCID=603030.0002
|COMMON=1
|Disease=Endotoxin hyporesponsiveness; not provided
}}

{{PMID Auto
|PMID=16820586
|Title=Inflammatory gene polymorphisms and risk of postoperative myocardial infarction after cardiac surgery.
|OA=1
}}

{{PMID Auto
|PMID=16954131
|Title=Toll-like receptor 4 gene polymorphisms and myocardial infarction: no association in a Caucasian population.
}}

{{PMID Auto
|PMID=17667860
|Title=Toll-like receptor 2 polymorphism is associated with preterm birth.
}}

{{PMID Auto
|PMID=17699831
|Title=Toll-like receptor 4 polymorphism associated with the response to whole-cell pertussis vaccination in children from the KOALA study.
|OA=1
}}

{{PMID Auto
|PMID=18172114
|Title=Comprehensive analysis of the candidate genes CCL2, CCR2, and TLR4 in age-related macular degeneration.
|OA=1
}}

{{PMID Auto
|PMID=18298826
|Title=Association between variations in the TLR4 gene and incident type 2 diabetes is modified by the ratio of total cholesterol to HDL-cholesterol.
|OA=1
}}

{{PMID Auto
|PMID=18307517
|Title=Common studied polymorphisms do not affect plasma cytokine levels upon endotoxin exposure in humans.
|OA=1
}}

{{PMID Auto
|PMID=18325643
|Title=Associations between SNPs in toll-like receptors and related intracellular signaling molecules and immune responses to measles vaccine: preliminary results.
|OA=1
}}

{{PMID Auto
|PMID=18382655
|Title=Maternal TLR4 and NOD2 gene variants, pro-inflammatory phenotype and susceptibility to early-onset preeclampsia and HELLP syndrome.
|OA=1
}}

{{PMID Auto
|PMID=18396467
|Title=Genetic variation and haplotype structures of innate immunity genes in eastern India.
|OA=1
}}

{{PMID Auto
|PMID=18422738
|Title=Study of Toll-like receptor gene loci in sarcoidosis.
|OA=1
}}

{{PMID Auto
|PMID=18549840
|Title=Cholesterol ester transfer protein, interleukin-8, peroxisome proliferator activator receptor alpha, and Toll-like receptor 4 genetic variations and risk of incident nonfatal myocardial infarction and ischemic stroke.
|OA=1
}}

{{PMID Auto
|PMID=18753640
|Title=Toll-like receptor 3 and geographic atrophy in age-related macular degeneration.
|OA=1
}}

{{PMID Auto
|PMID=18975326
|Title=Toll-like receptor 2 variants are associated with acute reactive arthritis.
}}

{{PMID Auto
|PMID=18987746
|Title=Association of interacting genes in the toll-like receptor signaling pathway and the antibody response to pertussis vaccination.
|OA=1
}}

{{PMID Auto
|PMID=19085953
|Title=Functional linkage of cirrhosis-predictive single nucleotide polymorphisms of Toll-like receptor 4 to hepatic stellate cell responses.
|OA=1
}}

{{PMID Auto
|PMID=19134200
|Title=No evidence of major effects in several Toll-like receptor gene polymorphisms in rheumatoid arthritis.
|OA=1
}}

{{PMID Auto
|PMID=19277200
|Title=Toll-like receptor 4 (TLR4) and typhoid fever in Vietnam.
|OA=1
}}

{{PMID Auto
|PMID=19543401
|Title=Toll-like receptor polymorphisms and susceptibility to urinary tract infections in adult women.
|OA=1
}}

{{PMID Auto
|PMID=19567509
|Title=Genetic variants and prostate cancer risk: candidate replication and exploration of viral restriction genes.
|OA=1
}}

{{PMID Auto
|PMID=19586676
|Title=Multiple variants in toll-like receptor 4 gene modulate risk of liver fibrosis in Caucasians with chronic hepatitis C infection.
|OA=1
}}

{{PMID Auto
|PMID=20011079
|Title=Lack of association between toll-like receptor 4 gene polymorphisms and sarcoidosis-related uveitis in Japan.
|OA=1
}}

{{PMID Auto
|PMID=20016852
|Title=Genetic variation of the human urinary tract innate immune response and asymptomatic bacteriuria in women.
|OA=1
}}

{{PMID Auto
|PMID=20026892
|Title=[Association of Toll-like receptor gene with Crohn's disease in Koreans].
}}

{{PMID Auto
|PMID=20463618
|Title=Role of polymorphic variants as genetic modulators of infection in neonatal sepsis.
|OA=1
}}

{{PMID Auto
|PMID=20492496
|Title=Significant association between toll-like receptor gene polymorphisms and gallbladder cancer.
}}

{{PMID Auto
|PMID=20525286
|Title=Influence of genetic variations in TLR4 and TIRAP/Mal on the course of sepsis and pneumonia and cytokine release: an observational study in three cohorts.
|OA=1
}}

{{PMID Auto
|PMID=20671584
|Title=Toll-like receptor 4 gene polymorphisms show no association with the risk of clinical or angiographic restenosis after percutaneous coronary intervention.
}}

{{PMID Auto
|PMID=21385363
|Title=Polymorphisms in genes controlling inflammation and tissue repair in rheumatoid arthritis: a case control study.
|OA=1
}}

{{PMID Auto
|PMID=22300618
|Title=Toll-like 4 receptor variant, Asp299Gly, and reduced risk of hemorrhagic cystitis after hematopoietic stem cell transplantation.
}}

{{PMID Auto
|PMID=22348075
|Title=Influence of common non-synonymous Toll-like receptor 4 polymorphisms on bronchopulmonary dysplasia and prematurity in human infants.
|OA=1
}}

{{GET Evidence
|gene=TLR4
|aa_change=Thr399Ile
|aa_change_short=T399I
|impact=pathogenic
|qualified_impact=Insufficiently evaluated pathogenic
|inheritance=unknown
|quality_scores=Array
|dbsnp_id=rs4986791
|overall_frequency_n=510
|overall_frequency_d=10758
|overall_frequency=0.0474066
|n_genomes=1
|n_genomes_annotated=0
|n_haplomes=1
|n_articles=0
|n_articles_annotated=0
|in_omim=Y
|pph2_score=0.016
|nblosum100=3
|autoscore=2
|webscore=N
}}

{{PMID Auto
|PMID=23084080
|Title=The TLR4 gene polymorphisms and susceptibility to cancer: A systematic review and meta-analysis
}}

{{PMID Auto
|PMID=22494793
|Title=Innate immunity gene single nucleotide polymorphisms and otitis media
}}

{{PMID Auto
|PMID=23151015
|Title=Toll-like receptor 3 gene polymorphisms and severity of pandemic A/H1N1/2009 influenza in otherwise healthy children
|OA=1
}}

{{PMID Auto
|PMID=23086128
|Title=Profiles of gene polymorphisms in cytokines and Toll-like receptors with higher risk for gastric cancer
}}

{{PMID Auto
|PMID=23867959
|Title=Toll-like receptor genetic variants are associated with Gram-negative infections in VLBW infants
}}

{{PMID Auto
|PMID=24028589
|Title=TLR2, TLR3, TLR4 and CD14 gene polymorphisms associated with oral lichen planus risk
}}

{{PMID Auto
|PMID=24447403
|Title=TLR4 polymorphism is not associated with biopsy proven giant cell arteritis
}}

{{PMID Auto
|PMID=23071570
|Title=Gene-gene interaction and functional impact of polymorphisms on innate immune genes in controlling Plasmodium falciparum blood infection level.
|OA=1
}}

{{PMID Auto
|PMID=23161283
|Title=SNPs in toll-like receptor (TLR) genes as new genetic alterations associated with congenital toxoplasmosis?
|OA=1
}}

{{PMID Auto
|PMID=23289617
|Title=Genetic variation of TLR2 and TLR4 among the Saudi Arabian population: insight into the evolutionary dynamics of the Arabian Peninsula.
}}

{{PMID Auto
|PMID=23417289
|Title=Coding variants of TLR2 and TLR4 genes do not substantially contribute to prosthetic joint infection.
}}

{{PMID Auto
|PMID=23459936
|Title=Exploring the genetic basis of chronic periodontitis: a genome-wide association study.
|OA=1
}}

{{PMID Auto
|PMID=25177689
|Title=The Association of Toll-Like Receptor 4 Polymorphism with Hepatitis C Virus Infection in Saudi Arabian Patients
}}

{{PMID Auto
|PMID=25213166
|Title=An association between single nucleotide polymorphisms within TLR and TREM-1 genes and infective endocarditis
}}

{{PMID Auto
|PMID=24349054
|Title=No correlation between PNPLA3 rs738409 genotype and fatty liver and hepatic cirrhosis in Japanese patients with HCV
}}
{{on chip | 23andMe v1}}
{{on chip | 23andMe v2}}
{{on chip | 23andMe v3}}
{{on chip | 23andMe v4}}
{{on chip | FTDNA2}}
{{on chip | FTDNA}}
{{on chip | HumanOmni1Quad}}
{{on chip | Illumina Human 1M}}