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Genetic polymorphisms in the CD14 gene are associated with monocyte activation and carotid intima-media thickness in HIV-infected patients on antiretroviral therapy.

Yong YK, Shankar EM, Westhorpe CL, Maisa A, Spelman T, Kamarulzaman A, Crowe SM, Lewin SR - Medicine (Baltimore) (2016)

Bottom Line: The TT genotype was associated with lower cIMT in HIV-infected patients (n = 47) but not in HIV-uninfected controls (n = 37).The AG genotype for TLR4/+896 was associated with increased CX3CR1 expression on total monocytes among HIV-infected individuals and increased sCCL2 and fibrinogen levels in HIV-uninfected controls.Further investigation on the relationship of these SNPs with a clinical endpoint of CVD is warranted in HIV-infected patients on ART.

View Article: PubMed Central - PubMed

Affiliation: aCentre of Excellence for Research in AIDS (CERiA) bTropical Infectious Diseases Research and Education Centre (TIDREC), Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia cCentre for Biomedical Research dCentre for Population Health, Burnet Institute eDepartment of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia fInfectious Disease Unit, University Malaya Medical Centre, Kuala Lumpur, Malaysia gPeter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Australia hDivision of Infection Biology and Microbiology, Department of Life Sciences, School of Basic and Applied Sciences, Central University of Tamil Nadu (CUTN), Neelakudi Campus, Tiruvarur, India.

ABSTRACT
HIV-infected individuals on antiretroviral therapy (ART) are at increased risk of cardiovascular disease (CVD). Given the relationship between innate immune activation and CVD, we investigated the association of single-nucleotide polymorphisms (SNPs) in TLR4 and CD14 and carotid intima-media thickness (cIMT), a surrogate measurement for CVD, in HIV-infected individuals on ART and HIV-uninfected controls as a cross-sectional, case-control study. We quantified the frequency of monocyte subsets (CD14, CD16), markers of monocyte activation (CD38, HLA-DR), and endothelial adhesion (CCR2, CX3CR1, CD11b) by flow cytometry. Plasma levels of lipopolysaccharide, sCD163, sCD14, sCX3CL1, and sCCL2, were measured by ELISA. Genotyping of TLR4 and CD14 SNPs was also performed. The TT genotype for CD14/-260SNP but not the CC/CT genotype was associated with elevated plasma sCD14, and increased frequency of CD11b+CD14+ monocytes in HIV-infected individuals. The TT genotype was associated with lower cIMT in HIV-infected patients (n = 47) but not in HIV-uninfected controls (n = 37). The AG genotype for TLR4/+896 was associated with increased CX3CR1 expression on total monocytes among HIV-infected individuals and increased sCCL2 and fibrinogen levels in HIV-uninfected controls. SNPs in CD14/-260 and TLR4/+896 were significantly associated with different markers of systemic and monocyte activation and cIMT that differed between HIV-infected participants on ART and HIV-uninfected controls. Further investigation on the relationship of these SNPs with a clinical endpoint of CVD is warranted in HIV-infected patients on ART.

No MeSH data available.


Related in: MedlinePlus

Relationship between the TLR4 (A+896G) genotype and expression of surface markers on monocytes. Expression of various monocytes surface markers were compared between carriers of the TLR4 AA and AG genotypes in HIV-infected and HIV-uninfected (healthy) controls. P < 0.05 by the Mann–Whitney test are indicated, with other comparison P > 0.05; ∗ indicate statistical significant after Benjamin–Hochberg adjustment.
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Figure 2: Relationship between the TLR4 (A+896G) genotype and expression of surface markers on monocytes. Expression of various monocytes surface markers were compared between carriers of the TLR4 AA and AG genotypes in HIV-infected and HIV-uninfected (healthy) controls. P < 0.05 by the Mann–Whitney test are indicated, with other comparison P > 0.05; ∗ indicate statistical significant after Benjamin–Hochberg adjustment.

Mentions: We compared the expression levels of monocyte activation markers between theCD14/−260 TT versus CC/CT genotypes in both HIV-infected and HIV-uninfected individuals (Supplementary Figure 2). Details of the gating strategy used in this study have been previously described.[26] The TT genotype compared to the CC/CT genotype in HIV-infected individuals was associated with reduced expression (percentage) of CCR2 on the total monocyte population (TT = 50% vs CC/CT = 71.8%) and CD14+CD16- monocytes (TT = 56% vs CC/CT = 76.5%) (Fig. 1A) and an increased expression of CD11b on total monocytes (TT = 54.4 vs CC/CT = 37.9%) (measured as mean fluorescence intensity, MFI), CD14+CD16- monocytes (TT = 52 vs CC/CT = 36) and CD16+monocyte (TT = 54.6 vs CC/CT = 41.4) (Fig. 1E). In the HIV-uninfected controls, the TT genotype was only associated with higher expression of CX3CR1 on CD14+CD16- monocytes (TT = 18.9 vs CC/CT 14.3) (Fig. 1D). After Benjamin–Hochberg adjustment for multiple comparisons, only expression of CD11b in total monocytes and CD14+CD16- monocytes in HIV-infected participants and CX3CR1 (MFI) in CD14+CD16- monocytes in healthy controls remained significantly associated with CD14 −260 SNP. In addition, as CD14/−260 SNP can influence the expression of CD14, we also examined the surface levels of CD14 on monocytes and found no significant difference between the genotypes (Supplementary Figure 3). The TLR4/+896 AG genotype, compared to the AA genotype in HIV-infected participants, was associated with increased expression (MFI) of CX3CR1 in total monocytes (AG = 15 vs AA = 9.3) (Fig. 2D) and a trend toward reduction in expression of CD11b on total monocytes and CD14+ monocytes (Fig. 2E). After Benjamin–Hochberg adjustment, only CX3CR1 (MFI) in total monocytes of HIV-infected participants was associated with TLR4/+896 SNP. The percentage of CCR2 was not associated with TLR4/+896 SNP and the percentage of CX3CR1 (Fig. 2A) and expression of CCR2, HLA-DR, and CD38 were not associated with both CD14/−260 and TLR4/+896 SNPS (Fig. 1B, C, F, G and Fig. 2B, C, F, and 2G).


Genetic polymorphisms in the CD14 gene are associated with monocyte activation and carotid intima-media thickness in HIV-infected patients on antiretroviral therapy.

Yong YK, Shankar EM, Westhorpe CL, Maisa A, Spelman T, Kamarulzaman A, Crowe SM, Lewin SR - Medicine (Baltimore) (2016)

Relationship between the TLR4 (A+896G) genotype and expression of surface markers on monocytes. Expression of various monocytes surface markers were compared between carriers of the TLR4 AA and AG genotypes in HIV-infected and HIV-uninfected (healthy) controls. P < 0.05 by the Mann–Whitney test are indicated, with other comparison P > 0.05; ∗ indicate statistical significant after Benjamin–Hochberg adjustment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4979844&req=5

Figure 2: Relationship between the TLR4 (A+896G) genotype and expression of surface markers on monocytes. Expression of various monocytes surface markers were compared between carriers of the TLR4 AA and AG genotypes in HIV-infected and HIV-uninfected (healthy) controls. P < 0.05 by the Mann–Whitney test are indicated, with other comparison P > 0.05; ∗ indicate statistical significant after Benjamin–Hochberg adjustment.
Mentions: We compared the expression levels of monocyte activation markers between theCD14/−260 TT versus CC/CT genotypes in both HIV-infected and HIV-uninfected individuals (Supplementary Figure 2). Details of the gating strategy used in this study have been previously described.[26] The TT genotype compared to the CC/CT genotype in HIV-infected individuals was associated with reduced expression (percentage) of CCR2 on the total monocyte population (TT = 50% vs CC/CT = 71.8%) and CD14+CD16- monocytes (TT = 56% vs CC/CT = 76.5%) (Fig. 1A) and an increased expression of CD11b on total monocytes (TT = 54.4 vs CC/CT = 37.9%) (measured as mean fluorescence intensity, MFI), CD14+CD16- monocytes (TT = 52 vs CC/CT = 36) and CD16+monocyte (TT = 54.6 vs CC/CT = 41.4) (Fig. 1E). In the HIV-uninfected controls, the TT genotype was only associated with higher expression of CX3CR1 on CD14+CD16- monocytes (TT = 18.9 vs CC/CT 14.3) (Fig. 1D). After Benjamin–Hochberg adjustment for multiple comparisons, only expression of CD11b in total monocytes and CD14+CD16- monocytes in HIV-infected participants and CX3CR1 (MFI) in CD14+CD16- monocytes in healthy controls remained significantly associated with CD14 −260 SNP. In addition, as CD14/−260 SNP can influence the expression of CD14, we also examined the surface levels of CD14 on monocytes and found no significant difference between the genotypes (Supplementary Figure 3). The TLR4/+896 AG genotype, compared to the AA genotype in HIV-infected participants, was associated with increased expression (MFI) of CX3CR1 in total monocytes (AG = 15 vs AA = 9.3) (Fig. 2D) and a trend toward reduction in expression of CD11b on total monocytes and CD14+ monocytes (Fig. 2E). After Benjamin–Hochberg adjustment, only CX3CR1 (MFI) in total monocytes of HIV-infected participants was associated with TLR4/+896 SNP. The percentage of CCR2 was not associated with TLR4/+896 SNP and the percentage of CX3CR1 (Fig. 2A) and expression of CCR2, HLA-DR, and CD38 were not associated with both CD14/−260 and TLR4/+896 SNPS (Fig. 1B, C, F, G and Fig. 2B, C, F, and 2G).

Bottom Line: The TT genotype was associated with lower cIMT in HIV-infected patients (n = 47) but not in HIV-uninfected controls (n = 37).The AG genotype for TLR4/+896 was associated with increased CX3CR1 expression on total monocytes among HIV-infected individuals and increased sCCL2 and fibrinogen levels in HIV-uninfected controls.Further investigation on the relationship of these SNPs with a clinical endpoint of CVD is warranted in HIV-infected patients on ART.

View Article: PubMed Central - PubMed

Affiliation: aCentre of Excellence for Research in AIDS (CERiA) bTropical Infectious Diseases Research and Education Centre (TIDREC), Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia cCentre for Biomedical Research dCentre for Population Health, Burnet Institute eDepartment of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia fInfectious Disease Unit, University Malaya Medical Centre, Kuala Lumpur, Malaysia gPeter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Australia hDivision of Infection Biology and Microbiology, Department of Life Sciences, School of Basic and Applied Sciences, Central University of Tamil Nadu (CUTN), Neelakudi Campus, Tiruvarur, India.

ABSTRACT
HIV-infected individuals on antiretroviral therapy (ART) are at increased risk of cardiovascular disease (CVD). Given the relationship between innate immune activation and CVD, we investigated the association of single-nucleotide polymorphisms (SNPs) in TLR4 and CD14 and carotid intima-media thickness (cIMT), a surrogate measurement for CVD, in HIV-infected individuals on ART and HIV-uninfected controls as a cross-sectional, case-control study. We quantified the frequency of monocyte subsets (CD14, CD16), markers of monocyte activation (CD38, HLA-DR), and endothelial adhesion (CCR2, CX3CR1, CD11b) by flow cytometry. Plasma levels of lipopolysaccharide, sCD163, sCD14, sCX3CL1, and sCCL2, were measured by ELISA. Genotyping of TLR4 and CD14 SNPs was also performed. The TT genotype for CD14/-260SNP but not the CC/CT genotype was associated with elevated plasma sCD14, and increased frequency of CD11b+CD14+ monocytes in HIV-infected individuals. The TT genotype was associated with lower cIMT in HIV-infected patients (n = 47) but not in HIV-uninfected controls (n = 37). The AG genotype for TLR4/+896 was associated with increased CX3CR1 expression on total monocytes among HIV-infected individuals and increased sCCL2 and fibrinogen levels in HIV-uninfected controls. SNPs in CD14/-260 and TLR4/+896 were significantly associated with different markers of systemic and monocyte activation and cIMT that differed between HIV-infected participants on ART and HIV-uninfected controls. Further investigation on the relationship of these SNPs with a clinical endpoint of CVD is warranted in HIV-infected patients on ART.

No MeSH data available.


Related in: MedlinePlus