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Genome-wide association study identifies single nucleotide polymorphism in DYRK1A associated with replication of HIV-1 in monocyte-derived macrophages.

Bol SM, Moerland PD, Limou S, van Remmerden Y, Coulonges C, van Manen D, Herbeck JT, Fellay J, Sieberer M, Sietzema JG, van 't Slot R, Martinson J, Zagury JF, Schuitemaker H, van 't Wout AB - PLoS ONE (2011)

Bottom Line: We found a strong association between in vitro HIV-1 replication in monocyte-derived macrophages and SNP rs12483205 in DYRK1A (p = 2.16 × 10(-5)).In addition, we found this SNP to be associated with HIV-1 disease progression in vivo in two independent cohort studies (p = 0.035 and p = 0.0048).These findings suggest that the kinase DYRK1A is involved in the replication of HIV-1, in vitro in macrophages as well as in vivo.

View Article: PubMed Central - PubMed

Affiliation: Landsteiner Laboratory, Sanquin Research, Department of Experimental Immunology, and Center for Infection and Immunity Amsterdam, Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands.

ABSTRACT

Background: HIV-1 infected macrophages play an important role in rendering resting T cells permissive for infection, in spreading HIV-1 to T cells, and in the pathogenesis of AIDS dementia. During highly active anti-retroviral treatment (HAART), macrophages keep producing virus because tissue penetration of antiretrovirals is suboptimal and the efficacy of some is reduced. Thus, to cure HIV-1 infection with antiretrovirals we will also need to efficiently inhibit viral replication in macrophages. The majority of the current drugs block the action of viral enzymes, whereas there is an abundance of yet unidentified host factors that could be targeted. We here present results from a genome-wide association study identifying novel genetic polymorphisms that affect in vitro HIV-1 replication in macrophages.

Methodology/principal findings: Monocyte-derived macrophages from 393 blood donors were infected with HIV-1 and viral replication was determined using Gag p24 antigen levels. Genomic DNA from individuals with macrophages that had relatively low (n = 96) or high (n = 96) p24 production was used for SNP genotyping with the Illumina 610 Quad beadchip. A total of 494,656 SNPs that passed quality control were tested for association with HIV-1 replication in macrophages, using linear regression. We found a strong association between in vitro HIV-1 replication in monocyte-derived macrophages and SNP rs12483205 in DYRK1A (p = 2.16 × 10(-5)). While the association was not genome-wide significant (p<1 × 10(-7)), we could replicate this association using monocyte-derived macrophages from an independent group of 31 individuals (p = 0.0034). Combined analysis of the initial and replication cohort increased the strength of the association (p = 4.84 × 10(-6)). In addition, we found this SNP to be associated with HIV-1 disease progression in vivo in two independent cohort studies (p = 0.035 and p = 0.0048).

Conclusions/significance: These findings suggest that the kinase DYRK1A is involved in the replication of HIV-1, in vitro in macrophages as well as in vivo.

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Related in: MedlinePlus

Association between HIV-1 replication in monocyte-derived macrophages (MDM) and the genotypes for the SNPs rs12483205 in DYRK1A, rs2304418 in PDE8A, rs2905 in UBR7, rs1046099 and rs1270629 in MOAP1, and rs17519417 in SPOCK3.Only donors with MDM with low (n = 95) or high (n = 96) HIV-1 replication in vitro were included in the genome-wide SNP analysis. This selection of donors with a more extreme phenotype explains the absence of circles in the middle section of the graphs. MAJ, homozygous for the major allele; HZ, heterozygote; MIN, homozygous for the minor allele.
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pone-0017190-g001: Association between HIV-1 replication in monocyte-derived macrophages (MDM) and the genotypes for the SNPs rs12483205 in DYRK1A, rs2304418 in PDE8A, rs2905 in UBR7, rs1046099 and rs1270629 in MOAP1, and rs17519417 in SPOCK3.Only donors with MDM with low (n = 95) or high (n = 96) HIV-1 replication in vitro were included in the genome-wide SNP analysis. This selection of donors with a more extreme phenotype explains the absence of circles in the middle section of the graphs. MAJ, homozygous for the major allele; HZ, heterozygote; MIN, homozygous for the minor allele.

Mentions: A total of 494,656 SNPs passing quality control were tested for association with levels of HIV-1 replication in monocyte-derived macrophages (MDM) using linear regression. With data from 191 healthy blood donors whose MDM ranked in the bottom quartile with lowest (n = 95 donors) or top quartile with highest (n = 96 donors) Gag p24 production 14 days post infection with HIV-1 [39] (Table 1), we found strongest associations for SNPs in the genes PDE8A (rs2304418, p = 2.4×10−6 and rs12909130, p = 8.3×10−6), UBR7 (rs2905, p = 7.0×10−6), MOAP1 (rs1046099, p = 9.9×10−6 and rs1270629, p = 1.09×10−5), DYRK1A (rs12483205, p = 2.2×10−5) and SPOCK3 (rs17519417, p = 2.5×10−5) (Figure 1, Table S1). The two SNPs in PDE8A were found to be in high linkage disequilibrium (LD; r2 = 0.97), whereas only a moderate degree of LD was found between rs1046099 and rs1270629 in MOAP1 (r2 = 0.54) (Table 2). Table 2 shows all other SNPs associated with HIV-1 replication in MDM (cutoff p value = 5×10−5; n = 16), and includes information about LD, location, number of donors homozygous for the minor allele (MIN) and empirical p values after permutation testing. Genotyping results for none of these 16 SNPs violated Hardy-Weinberg equilibrium.


Genome-wide association study identifies single nucleotide polymorphism in DYRK1A associated with replication of HIV-1 in monocyte-derived macrophages.

Bol SM, Moerland PD, Limou S, van Remmerden Y, Coulonges C, van Manen D, Herbeck JT, Fellay J, Sieberer M, Sietzema JG, van 't Slot R, Martinson J, Zagury JF, Schuitemaker H, van 't Wout AB - PLoS ONE (2011)

Association between HIV-1 replication in monocyte-derived macrophages (MDM) and the genotypes for the SNPs rs12483205 in DYRK1A, rs2304418 in PDE8A, rs2905 in UBR7, rs1046099 and rs1270629 in MOAP1, and rs17519417 in SPOCK3.Only donors with MDM with low (n = 95) or high (n = 96) HIV-1 replication in vitro were included in the genome-wide SNP analysis. This selection of donors with a more extreme phenotype explains the absence of circles in the middle section of the graphs. MAJ, homozygous for the major allele; HZ, heterozygote; MIN, homozygous for the minor allele.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3045405&req=5

pone-0017190-g001: Association between HIV-1 replication in monocyte-derived macrophages (MDM) and the genotypes for the SNPs rs12483205 in DYRK1A, rs2304418 in PDE8A, rs2905 in UBR7, rs1046099 and rs1270629 in MOAP1, and rs17519417 in SPOCK3.Only donors with MDM with low (n = 95) or high (n = 96) HIV-1 replication in vitro were included in the genome-wide SNP analysis. This selection of donors with a more extreme phenotype explains the absence of circles in the middle section of the graphs. MAJ, homozygous for the major allele; HZ, heterozygote; MIN, homozygous for the minor allele.
Mentions: A total of 494,656 SNPs passing quality control were tested for association with levels of HIV-1 replication in monocyte-derived macrophages (MDM) using linear regression. With data from 191 healthy blood donors whose MDM ranked in the bottom quartile with lowest (n = 95 donors) or top quartile with highest (n = 96 donors) Gag p24 production 14 days post infection with HIV-1 [39] (Table 1), we found strongest associations for SNPs in the genes PDE8A (rs2304418, p = 2.4×10−6 and rs12909130, p = 8.3×10−6), UBR7 (rs2905, p = 7.0×10−6), MOAP1 (rs1046099, p = 9.9×10−6 and rs1270629, p = 1.09×10−5), DYRK1A (rs12483205, p = 2.2×10−5) and SPOCK3 (rs17519417, p = 2.5×10−5) (Figure 1, Table S1). The two SNPs in PDE8A were found to be in high linkage disequilibrium (LD; r2 = 0.97), whereas only a moderate degree of LD was found between rs1046099 and rs1270629 in MOAP1 (r2 = 0.54) (Table 2). Table 2 shows all other SNPs associated with HIV-1 replication in MDM (cutoff p value = 5×10−5; n = 16), and includes information about LD, location, number of donors homozygous for the minor allele (MIN) and empirical p values after permutation testing. Genotyping results for none of these 16 SNPs violated Hardy-Weinberg equilibrium.

Bottom Line: We found a strong association between in vitro HIV-1 replication in monocyte-derived macrophages and SNP rs12483205 in DYRK1A (p = 2.16 × 10(-5)).In addition, we found this SNP to be associated with HIV-1 disease progression in vivo in two independent cohort studies (p = 0.035 and p = 0.0048).These findings suggest that the kinase DYRK1A is involved in the replication of HIV-1, in vitro in macrophages as well as in vivo.

View Article: PubMed Central - PubMed

Affiliation: Landsteiner Laboratory, Sanquin Research, Department of Experimental Immunology, and Center for Infection and Immunity Amsterdam, Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands.

ABSTRACT

Background: HIV-1 infected macrophages play an important role in rendering resting T cells permissive for infection, in spreading HIV-1 to T cells, and in the pathogenesis of AIDS dementia. During highly active anti-retroviral treatment (HAART), macrophages keep producing virus because tissue penetration of antiretrovirals is suboptimal and the efficacy of some is reduced. Thus, to cure HIV-1 infection with antiretrovirals we will also need to efficiently inhibit viral replication in macrophages. The majority of the current drugs block the action of viral enzymes, whereas there is an abundance of yet unidentified host factors that could be targeted. We here present results from a genome-wide association study identifying novel genetic polymorphisms that affect in vitro HIV-1 replication in macrophages.

Methodology/principal findings: Monocyte-derived macrophages from 393 blood donors were infected with HIV-1 and viral replication was determined using Gag p24 antigen levels. Genomic DNA from individuals with macrophages that had relatively low (n = 96) or high (n = 96) p24 production was used for SNP genotyping with the Illumina 610 Quad beadchip. A total of 494,656 SNPs that passed quality control were tested for association with HIV-1 replication in macrophages, using linear regression. We found a strong association between in vitro HIV-1 replication in monocyte-derived macrophages and SNP rs12483205 in DYRK1A (p = 2.16 × 10(-5)). While the association was not genome-wide significant (p<1 × 10(-7)), we could replicate this association using monocyte-derived macrophages from an independent group of 31 individuals (p = 0.0034). Combined analysis of the initial and replication cohort increased the strength of the association (p = 4.84 × 10(-6)). In addition, we found this SNP to be associated with HIV-1 disease progression in vivo in two independent cohort studies (p = 0.035 and p = 0.0048).

Conclusions/significance: These findings suggest that the kinase DYRK1A is involved in the replication of HIV-1, in vitro in macrophages as well as in vivo.

Show MeSH
Related in: MedlinePlus