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Lesion size is associated with genetic polymorphisms in TLR1, TLR6, and TIRAP genes in patients with major abscesses and diabetic foot infections.

ABSTRACT: Genetic variation in Toll-like receptors (TLRs) has previously been associated with susceptibility to complicated skin and skin structure infections (cSSSIs). The aim of this study was to investigate associations between the severity of cSSSIs, i.e., major abscesses and diabetic foot infections (DFIs), and a set of genetic polymorphisms in the Toll-like receptor pathway. A total of 121 patients with major abscesses and 132 with DFIs participating in a randomized clinical trial were genotyped for 13 nonsynonymous single-nucleotide polymorphisms (SNPs) in genes coding for TLRs and the signaling adaptor molecule TIRAP. Infection severity was defined by lesion size at clinical presentation for both types of infections. The PEDIS infection score was also used to define severity of DFIs. Linear regression models were used to study factors independently associated with severity. In patients with large abscesses, hetero- or homozygosity for the allelic variant TLR6 (P249S) was associated with significantly smaller lesions while homozygosity for the allelic variant TLR1 (R80T) was associated with significantly larger lesions. PRRs genes were not significantly associated with PEDIS. However, patients with DFI hetero- or homozygous for the allelic variant TLR1 (S248N) had significantly larger lesions. Polymorphisms in TLR1 and TLR6 influence the severity of cSSSIs as assessed by the lesion size of major abscesses and DFIs. ClinicalTrial.gov Identifier: NCT00402727.

SUBMITTER: D'Onofrio V

PROVIDER: S-EPMC7010613 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Lesion size is associated with genetic polymorphisms in TLR1, TLR6, and TIRAP genes in patients with major abscesses and diabetic foot infections.

D'Onofrio Valentino V Monnier Annelie A AA Kremer Cécile C Stappers Mark H T MHT Netea Mihai G MG Gyssens Inge C IC

European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology 20191130 2

Genetic variation in Toll-like receptors (TLRs) has previously been associated with susceptibility to complicated skin and skin structure infections (cSSSIs). The aim of this study was to investigate associations between the severity of cSSSIs, i.e., major abscesses and diabetic foot infections (DFIs), and a set of genetic polymorphisms in the Toll-like receptor pathway. A total of 121 patients with major abscesses and 132 with DFIs participating in a randomized clinical trial were genotyped for ...[more]

PMID: 31786695

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Project description:ObjectiveThe purpose of this study was to evaluate the disparities in the outcomes of White, African American (AA) and non-AA minority (Hispanics and Native Americans (NA)), patients admitted in the hospitals with diabetic foot infections (DFIs).Research design and methodsThe HCUP-Nationwide Inpatient Sample (2002 to 2015) was queried to identify patients who were admitted to the hospital for management of DFI using ICD-9 codes. Outcomes evaluated included minor and major amputations, open or endovascular revascularization, and hospital length of stay (LOS). Incidence for amputation and open or endovascular revascularization were evaluated over the study period. Multivariable regression analyses were performed to assess the association between race/ethnicity and outcomes.ResultsThere were 150,701 admissions for DFI, including 98,361 Whites, 24,583 AAs, 24,472 Hispanics, and 1,654 Native Americans (NAs) in the study cohort. Overall, 45,278 (30%) underwent a minor amputation, 9,039 (6%) underwent a major amputation, 3,151 underwent an open bypass, and 8,689 had an endovascular procedure. There was a decreasing incidence in major amputations and an increasing incidence of minor amputations over the study period (P < .05). The risks for major amputation were significantly higher (all p<0.05) for AA (OR 1.4, 95%CI 1.4,1.5), Hispanic (OR 1.3, 95%CI 1.3,1.4), and NA (OR 1.5, 95%CI 1.2,1.8) patients with DFIs compared to White patients. Hispanics (OR 1.3, 95%CI 1.2,1.5) and AAs (OR 1.2, 95%CI 1.1,1.4) were more likely to receive endovascular intervention or open bypass than Whites (all p<0.05). NA patients with DFI were less likely to receive a revascularization procedure (OR 0.6, 95%CI 0.3, 0.9, p = 0.03) than Whites. The mean hospital length of stay (LOS) was significantly longer for AAs (9.2 days) and Hispanics (8.6 days) with DFIs compared to Whites (8.1 days, p<0.001).ConclusionDespite a consistent incidence reduction of amputation over the past decade, racial and ethnic minorities including African American, Hispanic, and Native American patients admitted to hospitals with DFIs have a consistently significantly higher risk of major amputation and longer hospital length of stay than their White counterparts. Native Americans were less likely to receive revascularization procedures compared to other minorities despite exhibiting an elevated risk of an amputation. Further study is required to address and limit racial and ethnic disparities and to further promote equity in the treatment and outcomes of these at-risk patients.

Project description:BackgroundToll-like receptors (TLRs) play important roles in building innate immune and inducing adaptive immune responses. Associations of the TLR genes polymorphisms with disease susceptibility, which are the basis of molecular breeding for disease resistant animals, have been reported extensively. Retrotransposon insertion polymorphisms (RIPs), as a new type of molecular markers developed recently, have great potential in population genetics and quantitative trait locus mapping. In this study, bioinformatic prediction combined with PCR-based amplification was employed to screen for RIPs in porcine TLR genes. Their population distribution was examined, and for one RIP the impact on gene activity and phenotype was further evaluated.ResultsFive RIPs, located at the 3' flank of TLR3, 5' flank of TLR5, intron 1 of TLR6, intron 1 of TLR7, and 3' flank of TLR8 respectively, were identified. These RIPs were detected in different breeds with an uneven distribution among them. By using the dual luciferase activity assay a 192 bp endogenous retrovirus (ERV) in the intron 1 of TLR6 was shown to act as an enhancer increasing the activities of TLR6 putative promoter and two mini-promoters. Furthermore, real-time quantitative polymerase chain reaction (qPCR) analysis revealed significant association (p < 0.05) of the ERV insertion with increased mRNA expression of TLR6, the neighboring gene TLR1, and genes downstream in the TLR signaling pathway such as MyD88 (Myeloid differentiation factor 88), Rac1 (Rac family small GTPase 1), TIRAP (TIR domain containing adaptor protein), Tollip (Toll interacting protein) as well as the inflammatory factors IL6 (Interleukin 6), IL8 (Interleukin 8), and TNFα (Tumor necrosis factor alpha) in tissues of 30 day-old piglet. In addition, serum IL6 and TNFα concentrations were also significantly upregulated by the ERV insertion (p < 0.05).ConclusionsA total of five RIPs were identified in five different TLR loci. The 192 bp ERV insertion in the first intron of TLR6 was associated with higher expression of TLR6, TLR1, and several genes downstream in the signaling cascade. Thus, the ERV insertion may act as an enhancer affecting regulation of the TLR signaling pathways, and can be potentially applied in breeding of disease resistant animals.

Dataset Information

Lesion size is associated with genetic polymorphisms in TLR1, TLR6, and TIRAP genes in patients with major abscesses and diabetic foot infections.

Publications

Lesion size is associated with genetic polymorphisms in TLR1, TLR6, and TIRAP genes in patients with major abscesses and diabetic foot infections.

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