An elevated level of interleukin-17A in a Senegalese malaria cohort is associated with rs8193038 IL-17A genetic variant.

Malaria infection is a multifactorial disease partly modulated by host immuno-genetic factors. Recent evidence has demonstrated the importance of Interleukin-17 family proinflammatory cytokines and their genetic variants in host immunity. However, limited knowledge exists about their role in parasitic infections such as malaria. We aimed to investigate IL-17A serum levels in patients with severe and uncomplicated malaria and gene polymorphism's influence on the IL-17A serum levels. In this research, 125 severe (SM) and uncomplicated (UM) malaria patients and 48 free malaria controls were enrolled. IL-17A serum levels were measured with ELISA. PCR and DNA sequencing were used to assess host genetic polymorphisms in IL-17A. We performed a multivariate regression to estimate the impact of human IL-17A variants on IL-17A serum levels and malaria outcomes. Elevated serum IL-17A levels accompanied by increased parasitemia were found in SM patients compared to UM and controls (P < 0.0001). Also, the IL-17A levels were lower in SM patients who were deceased than in those who survived. In addition, the minor allele frequencies (MAF) of two IL-17A polymorphisms (rs3819024 and rs3748067) were more prevalent in SM patients than UM patients, indicating an essential role in SM. Interestingly, the heterozygous rs8193038 AG genotype was significantly associated with higher levels of IL-17A than the homozygous wild type (AA). According to our results, it can be concluded that the IL-17A gene rs8193038 polymorphism significantly affects IL-17A gene expression. Our results fill a gap in the implication of IL-17A gene polymorphisms on the cytokine level in a malaria cohort. IL-17A gene polymorphisms also may influence cytokine production in response to Plasmodium infections and may contribute to the hyperinflammatory responses during severe malaria outcomes.

Gene expression profiling of peripheral blood mononuclear cells from women with cervical lesions reveals new markers of cancer.

Cervical cancer (CC) is a multifactorial disease of which human papillomavirus (HPV) is the main etiological agent. Despite cervical Pap smear screening and anti­HPV vaccination, CC remains a major public health issue. Identification of specific gene expression signatures in the blood could allow better insight into the immune response of CC and could provide valuable information for the development of novel biomarkers. The present study performed a transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) from Senegalese patients with CC (n=31), low­grade cervical intraepithelial neoplasia (CIN1; n=27) and from healthy control (CTR) subjects (n=29). Individuals in the CIN1 and CTR groups exhibited similar patterns in gene expression. A total of 182 genes were revealed to be differentially expressed in patients with CC compared with individuals in the CIN1 and CTR groups. The IL1R2, IL18R1, MMP9 and FKBP5 genes were the most upregulated, whereas the T­cell receptor α gene TRA was the most downregulated in the CC group compared with in the CIN1 and CTR groups. The pathway enrichment analysis of the differentially expressed genes revealed pathways directly and indirectly linked to inflammation. To the best of our knowledge, the present study is the first large transcriptomic study on CC performed using PBMCs from African women; the results revealed the involvement of genes and pathways related to inflammation, most notably the IL­1 pathway, and the involvement of downregulation of the T­cell receptor α, a key component of the immune response. Several of the stated genes have already been reported in other cancer studies as putative blood biomarkers, thus reinforcing the requirement for deeper investigation. These findings may aid in the development of innovative clinical biomarkers for CC prevention and should be further replicated in other populations.

G6PD and HBB polymorphisms in the Senegalese population: prevalence, correlation with clinical malaria.

Background: Host genetic factors contribute to the variability of malaria phenotypes and can allow a better understanding of mechanisms involved in susceptibility and/or resistance to Plasmodium falciparum infection outcomes. Several genetic polymorphisms were reported to be prevalent among populations living in tropical malaria-endemic regions and induce protection against malaria. The present study aims to investigate the prevalence of HBB (chr11) and G6PD (chrX) deficiencies polymorphisms among Senegalese populations and their associations with the risk for severe Plasmodium falciparum malaria occurrence. Methods: We performed a retrospective study with 437 samples, 323 patients recruited in hospitals located in three different endemic areas where malaria episodes were confirmed and 114 free malaria controls. The patients enrolled were classified into two groups: severe malaria (SM) (153 patients) and uncomplicated malaria (UM) (170 patients). PCR and DNA sequencing assessed host genetic polymorphisms in HBB and G6PD. Using a multivariate regression and additive model, estimates of the impact of human HBB and G6PD polymorphisms on malaria incidence were performed. Results: Six frequent SNPs with minor allele frequencies (MAF) > 3% were detected in the HBB gene (rs7946748, rs7480526, rs10768683, rs35209591, HbS (rs334) and rs713040) and two in the G6PD gene (rs762515 and rs1050828 (G6PD-202 G > A). Analysis of selected HbS polymorphism showed significant association with protective effect against severe malaria with a significant p-value = 0.033 (OR 0.38, 95% CI [0.16-0.91]) for SM vs. UM comparison. Surprisingly, our study did not identify the protective effect of variant HbC polymorphism against severe malaria. Finally, we found some of the polymorphisms, like HbS (rs334), are associated with age and biological parameters like eosinophils, basophils, lymphocytes etc. Conclusion: Our data report HBB and G6PD polymorphisms in the Senegalese population and their correlation with severe/mild malaria and outcome. The G6PD and HBB deficiencies are widespread in West Africa endemic malaria regions such as The Gambia, Mali, and Burkina Faso. The study shows the critical role of genetic factors in malaria outcomes. Indeed, genetic markers could be good tools for malaria endemicity prognosis.

Identification of New Biological Pathways Involved in Skin Aging From the Analysis of French Women Genome-Wide Data.

Skin aging is an ineluctable process leading to the progressive loss of tissue integrity and is characterized by various outcomes such as wrinkling and sagging. Researchers have identified impacting environmental factors (sun exposure, smoking, etc.) and several molecular mechanisms leading to skin aging. We have previously performed genome-wide association studies (GWAS) in 502 very-well characterized French women, looking for associations with four major outcomes of skin aging, namely, photoaging, solar lentigines, wrinkling, and sagging, and this has led to new insights into the molecular mechanisms of skin aging. Since individual SNP associations in GWAS explain only a small fraction of the genetic impact in complex polygenic phenotypes, we have made the integration of these genotypes into the reference Kegg biological pathways and looked for associations by the gene set enrichment analysis (GSEA) approach. 106 pathways were tested for association with the four outcomes of skin aging. This biological pathway analysis revealed new relevant pathways and genes, some likely specific of skin aging such as the WNT7B and PRKCA genes in the "melanogenesis" pathway and some likely involved in global aging such as the DDB1 gene in the "nucleotide excision repair" pathway, not picked up in the previously published GWAS. Overall, our results suggest that the four outcomes of skin aging possess specific molecular mechanisms such as the "proteasome" and "mTOR signaling pathway" but may also share common molecular mechanisms such as "nucleotide excision repair."

Wasl is crucial to maintain microglial core activities during glioblastoma initiation stages.

Microglia actively promotes the growth of high-grade gliomas. Within the glioma microenvironment an amoeboid microglial morphology has been observed, however the underlying causes and the related impact on microglia functions and their tumor promoting activities is unclear. Using the advantages of the larval zebrafish model, we identified the underlying mechanism and show that microglial morphology and functions are already impaired during glioma initiation stages. The presence of pre-neoplastic HRasV12 expressing cells induces an amoeboid morphology of microglia, increases microglial numbers and decreases their motility and phagocytic activity. RNA sequencing analysis revealed lower expression levels of the actin nucleation promoting factor wasla in microglia. Importantly, a microglia specific rescue of wasla expression restores microglial morphology and functions. This results in increased phagocytosis of pre-neoplastic cells and slows down tumor progression. In conclusion, we identified a mechanism that de-activates core microglial functions within the emerging glioma microenvironment. Restoration of this mechanism might provide a way to impair glioma growth.

Gene expression profiling reveals a conserved microglia signature in larval zebrafish.

Microglia are the resident macrophages of the brain. Over the past decade, our understanding of the function of these cells has significantly improved. Microglia do not only play important roles in the healthy brain but are involved in almost every brain pathology. Gene expression profiling allowed to distinguish microglia from other macrophages and revealed that the full microglia signature can only be observed in vivo. Thus, animal models are irreplaceable to understand the function of these cells. One of the popular models to study microglia is the zebrafish larva. Due to their optical transparency and genetic accessibility, zebrafish larvae have been employed to understand a variety of microglia functions in the living brain. Here, we performed RNA sequencing of larval zebrafish microglia at different developmental time points: 3, 5, and 7 days post fertilization (dpf). Our analysis reveals that larval zebrafish microglia rapidly acquire the core microglia signature and many typical microglia genes are expressed from 3 dpf onwards. The majority of changes in gene expression happened between 3 and 5 dpf, suggesting that differentiation mainly takes place during these days. Furthermore, we compared the larval microglia transcriptome to published data sets of adult zebrafish microglia, mouse microglia, and human microglia. Larval microglia shared a significant number of expressed genes with their adult counterparts in zebrafish as well as with mouse and human microglia. In conclusion, our results show that larval zebrafish microglia mature rapidly and express the core microglia gene signature that seems to be conserved across species.

A genome wide association study identifies new genes potentially associated with eyelid sagging.

Sagging eyelid is considered as an outward of skin ageing and may cause medical issues. However, little is known about the factors involved in sagging eyelid. The study, which aims at determining genetic risk factors for eyelid sagging, was conducted in a cohort of 502 unrelated Caucasian women living in the Paris region. All included participants were aged between 44 and 70 years old (mean age, 57.6 years old). The severity of sagging eyelid was graded in 6 categories by a dermatologist using standardized photographs of the face. A genome wide association study adjusted on potential risk factors (including age and smoking habits) was conducted to identify genetic associations. Two single nucleotide polymorphisms in total linkage disequilibrium on chromosome 10, rs16927253 (P = 7.07 × 10-10 ) and rs4746957 (P = 1.06 × 10-8 ), were significantly associated with eyelid sagging severity. The rs16927253-T and rs4746957-A alleles showed a dominant protective effect towards eyelid sagging. These polymorphisms are located in intronic parts of the H2AFY2 gene which encodes a member of the H2A histone family and very close to the AIFM2 gene that induces apoptosis. Additionally, single nucleotide polymorphisms with a false discovery rate below 0.25 were located nearby the type XIII collagen COL13A1 gene on chromosome 10 and in the ADAMTS18 gene on chromosome 16. Several relevant genes were identified by the genome wide association study for their potential role in the sagging eyelid severity.

HLA-check: evaluating HLA data from SNP information.

BACKGROUND: The major histocompatibility complex (MHC) region of the human genome, and specifically the human leukocyte antigen (HLA) genes, play a major role in numerous human diseases. With the recent progress of sequencing methods (eg, Next-Generation Sequencing, NGS), the accurate genotyping of this region has become possible but remains relatively costly. In order to obtain the HLA information for the millions of samples already genotyped by chips in the past ten years, efficient bioinformatics tools, such as SNP2HLA or HIBAG, have been developed that infer HLA information from the linkage disequilibrium existing between HLA alleles and SNP markers in the MHC region. RESULTS: In this study, we first used ShapeIT and Impute2 to implement an imputation method akin to SNP2HLA and found a comparable quality of imputation on a European dataset. More importantly, we developed a new tool, HLA-check, that allows for the detection of aberrant HLA allele calling with regard to the SNP genotypes in the region. Adding this tool to the HLA imputation software increases dramatically their accuracy, especially for HLA class I genes. CONCLUSION: Overall, HLA-check was able to identify a limited number of implausible HLA typings (less than 10%) in a population, and these samples can then either be removed or be retyped by NGS for HLA association analysis.

A new 3p25 locus is associated with liver fibrosis progression in human immunodeficiency virus/hepatitis C virus-coinfected patients.

There is growing evidence that human genetic variants contribute to liver fibrosis in subjects with hepatitis C virus (HCV) monoinfection, but this aspect has been little investigated in patients coinfected with HCV and human immunodeficiency virus (HIV). We performed the first genome-wide association study of liver fibrosis progression in patients coinfected with HCV and HIV, using the well-characterized French National Agency for Research on AIDS and Viral Hepatitis CO13 HEPAVIH cohort. Liver fibrosis was assessed by elastography (FibroScan), providing a quantitative fibrosis score. After quality control, a genome-wide association study was conducted on 289 Caucasian patients, for a total of 8,426,597 genotyped (Illumina Omni2.5 BeadChip) or reliably imputed single-nucleotide polymorphisms. Single-nucleotide polymorphisms with P values <10-6 were investigated in two independent replication cohorts of European patients infected with HCV alone. Two signals of genome-wide significance (P < 5 × 10-8 ) were obtained. The first, on chromosome 3p25 and corresponding to rs61183828 (P = 3.8 × 10-9 ), was replicated in the two independent cohorts of patients with HCV monoinfection. The cluster of single-nucleotide polymorphisms in linkage disequilibrium with rs61183828 was located close to two genes involved in mechanisms affecting both cell signaling and cell structure (CAV3) or HCV replication (RAD18). The second signal, obtained with rs11790131 (P = 9.3 × 10-9 ) on chromosome region 9p22, was not replicated. CONCLUSION: This genome-wide association study identified a new locus associated with liver fibrosis severity in patients with HIV/HCV coinfection, on chromosome 3p25, a finding that was replicated in patients with HCV monoinfection; these results provide new relevant hypotheses for the pathogenesis of liver fibrosis in patients with HIV/HCV coinfection that may help define new targets for drug development or new prognostic tests, to improve patient care. (Hepatology 2016;64:1462-1472).

A genome-wide association study in Caucasian women suggests the involvement of HLA genes in the severity of facial solar lentigines.

Solar lentigines are a common feature of sun-induced skin ageing. Little is known, however, about the genetic factors contributing to their development. In this genome-wide association study, we aimed to identify genetic loci associated with solar lentigines on the face in 502 middle-aged French women. Nine SNPs, gathered in two independent blocks on chromosome 6, exhibited a false discovery rate below 25% when looking for associations with the facial lentigine score. The first block, in the 6p22 region, corresponded to intergenic SNPs and also exhibited a significant association with forehead lentigines (P = 1.37 × 10(-8) ). The second block, within the 6p21 HLA region, was associated with decreased HLA-C expression according to several eQTL databases. Interestingly, these SNPs were also in high linkage disequilibrium with the HLA-C*0701 allele (r(2)  = 0.95). We replicated an association recently found by GWAS in the IRF4 gene. Finally, a complementary study on 44 selected candidate SNPs revealed novel associations in the MITF gene. Overall, our results point to several mechanisms involved in the severity of facial lentigines, including HLA/immunity and the melanogenesis pathway.

Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load.

Previous genome-wide association studies (GWAS) of HIV-1-infected populations have been underpowered to detect common variants with moderate impact on disease outcome and have not assessed the phenotypic variance explained by genome-wide additive effects. By combining the majority of available genome-wide genotyping data in HIV-infected populations, we tested for association between ∼8 million variants and viral load (HIV RNA copies per milliliter of plasma) in 6,315 individuals of European ancestry. The strongest signal of association was observed in the HLA class I region that was fully explained by independent effects mapping to five variable amino acid positions in the peptide binding grooves of the HLA-B and HLA-A proteins. We observed a second genome-wide significant association signal in the chemokine (C-C motif) receptor (CCR) gene cluster on chromosome 3. Conditional analysis showed that this signal could not be fully attributed to the known protective CCR5Δ32 allele and the risk P1 haplotype, suggesting further causal variants in this region. Heritability analysis demonstrated that common human genetic variation-mostly in the HLA and CCR5 regions-explains 25% of the variability in viral load. This study suggests that analyses in non-European populations and of variant classes not assessed by GWAS should be priorities for the field going forward.

Identification of Genes Whose Expression Profile Is Associated with Non-Progression towards AIDS Using eQTLs.

BACKGROUND: Many genome-wide association studies have been performed on progression towards the acquired immune deficiency syndrome (AIDS) and they mainly identified associations within the HLA loci. In this study, we demonstrate that the integration of biological information, namely gene expression data, can enhance the sensitivity of genetic studies to unravel new genetic associations relevant to AIDS. METHODS: We collated the biological information compiled from three databases of expression quantitative trait loci (eQTLs) involved in cells of the immune system. We derived a list of single nucleotide polymorphisms (SNPs) that are functional in that they correlate with differential expression of genes in at least two of the databases. We tested the association of those SNPs with AIDS progression in two cohorts, GRIV and ACS. Tests on permuted phenotypes of the GRIV and ACS cohorts or on randomised sets of equivalent SNPs allowed us to assess the statistical robustness of this method and to estimate the true positive rate. RESULTS: Eight genes were identified with high confidence (p = 0.001, rate of true positives 75%). Some of those genes had previously been linked with HIV infection. Notably, ENTPD4 belongs to the same family as CD39, whose expression has already been associated with AIDS progression; while DNAJB12 is part of the HSP90 pathway, which is involved in the control of HIV latency. Our study also drew our attention to lesser-known functions such as mitochondrial ribosomal proteins and a zinc finger protein, ZFP57, which could be central to the effectiveness of HIV infection. Interestingly, for six out of those eight genes, down-regulation is associated with non-progression, which makes them appealing targets to develop drugs against HIV.

Evidence after imputation for a role of MICA variants in nonprogression and elite control of HIV type 1 infection.

Past genome-wide association studies (GWAS) involving individuals with AIDS have mainly identified associations in the HLA region. Using the latest software, we imputed 7 million single-nucleotide polymorphisms (SNPs)/indels of the 1000 Genomes Project from the GWAS-determined genotypes of individuals in the Genomics of Resistance to Immunodeficiency Virus AIDS nonprogression cohort and compared them with those of control cohorts. The strongest signals were in MICA, the gene encoding major histocompatibility class I polypeptide-related sequence A (P = 3.31 × 10(-12)), with a particular exonic deletion (P = 1.59 × 10(-8)) in full linkage disequilibrium with the reference HCP5 rs2395029 SNP. Haplotype analysis also revealed an additive effect between HLA-C, HLA-B, and MICA variants. These data suggest a role for MICA in progression and elite control of human immunodeficiency virus type 1 infection.

Association study of common genetic variants and HIV-1 acquisition in 6,300 infected cases and 7,200 controls.

Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6 × 10⁻¹¹). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size.

A genome-wide association study in Caucasian women points out a putative role of the STXBP5L gene in facial photoaging.

A genome-wide association study (GWAS) was conducted on 502 French middle-aged Caucasian women to identify genetic factors that may affect skin aging severity. A high-throughput Illumina Human Omni1-Quad beadchip was used. After single-nucleotide polymorphism (SNP) quality controls, 795,063 SNPs remained for analysis purposes. Possible stratification was first examined using the Eigenstrat method, and then the relationships between genotypes and four skin aging indicators (global photoaging, lentigines, wrinkles, and sagging) were investigated separately by linear regressions adjusted on age, smoking habits, lifetime sun exposure, hormonal status, and the two main Eigen vectors. One signal passed the Bonferroni threshold (P=1.53 × 10(-8)) and was significantly associated with global photoaging. It was also correlated with the wrinkling score and the sagging score. According to HapMap, this SNP, rs322458, was in linkage disequilibrium (LD) with intronic SNPs of the STXBP5L gene, which is expressed in the skin. In addition, it was also in LD with another SNP that increases the expression of the FBXO40 gene in the skin. These two genes, which were not previously described in the context of aging, may constitute good candidates for the investigation of molecular mechanisms of skin photoaging.

Multicohort genomewide association study reveals a new signal of protection against HIV-1 acquisition.

BACKGROUND: To date, only mutations in CCR5 have been shown to confer resistance to human immunodeficiency virus type 1 (HIV-1) infection, and these explain only a small fraction of the observed variability in HIV susceptibility. METHODS: We performed a meta-analysis between 2 independent European genomewide association studies, each comparing HIV-1 seropositive cases with normal population controls known to be HIV uninfected, to identify single-nucleotide polymorphisms (SNPs) associated with the HIV-1 acquisition phenotype. SNPs exhibiting P < 10(-5) in this first stage underwent second-stage analysis in 2 independent US cohorts of European descent. RESULTS: After the first stage, a single highly significant association was revealed for the chromosome 8 rs6996198 with HIV-1 acquisition and was replicated in both second-stage cohorts. Across the 4 groups, the rs6996198-T allele was consistently associated with a significant reduced risk of HIV-1 infection, and the global meta-analysis reached genomewide significance: P(combined) = 7.76 × 10(-8). CONCLUSIONS: We provide strong evidence of association for a common variant with HIV-1 acquisition in populations of European ancestry. This protective signal against HIV-1 infection is the first identified outside the CCR5 nexus. First clues point to a potential functional role for a nearby candidate gene, CYP7B1, but this locus warrants further investigation.

Identification of IL7RA risk alleles for rapid progression during HIV-1 infection: a comprehensive study in the GRIV cohort.

Interleukin 7 (IL7) is a critical factor for lymphocyte homeostasis. A dysfunction of the IL7/IL7R pathway has previously been described in HIV-1 infection, and promising results were observed in recent analyses of IL7 for therapeutic use in HIV infected individuals. However, further investigations are still warranted to understand the possible roles of this cytokine. Here, we explored whether the IL7 and IL7RA genetic polymorphisms were associated with the progression of HIV infection. We extensively genotyped the IL7 and IL7RA genes in the GRIV (Genomics of Resistance to Immunodeficiency Virus) cohort, composed of patients with extreme progression profiles - long-term non (LTNP) and rapid (RP) progressors--, and in a healthy control group (CTR). Statistical case-control analyses were performed using the Fisher's exact test, comparing either LTNP vs CTR or RP vs CTR. Three IL7RA SNPs (single nucleotide polymorphisms--rs7701176, rs987106 and rs10491434), but no IL7 SNPs, were significantly associated with rapid disease progression (P < 0.01). In a multi-marker analysis focusing on functional variants, a strong association between an IL7RA haplotype and rapid progression was observed (P = 5.59 x 10(-3)). In summary, our comprehensive genetic study revealed three SNPs and a risk of haplotype associated with rapid progression to AIDS in the IL7RA gene. Interestingly, the haplotype is composed of SNPs previously identified in other inflammatory diseases (e.g., multiple sclerosis) by GWAS and by functional studies. Our results contribute to the growing understanding of the role of IL7/IL7R in HIV disease progression, and more widely, in CD4+ T cell homeostasis.

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

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.

Screening low-frequency SNPS from genome-wide association study reveals a new risk allele for progression to AIDS.

BACKGROUND: Seven genome-wide association studies (GWAS) have been published in AIDS, and only associations in the HLA region on chromosome 6 and CXCR6 have passed genome-wide significance. METHODS: We reanalyzed the data from 3 previously published GWAS, targeting specifically low-frequency SNPs (minor allele frequency <5%). Two groups composed of 365 slow progressors and 147 rapid progressors from Europe and the United States were compared with a control group of 1394 seronegative individuals using Eigenstrat corrections. RESULTS: Of the 8584 SNPs with minor allele frequency <5% in cases and controls (Bonferroni threshold = 5.8 × 10⁻6), 4 SNPs showed statistical evidence of association with the slow progressor phenotype. The best result was for HCP5 rs2395029 [P = 8.54 × 10⁻¹5, odds ratio (OR) = 3.41] in the HLA locus, in partial linkage disequilibrium with 2 additional chromosome 6 associations in C6orf48 (P = 3.03 × 10⁻¹°, OR = 2.9) and NOTCH4 (9.08 × 10⁻°7, OR = 2.32). The fourth association corresponded to rs2072255 located in RICH2 (P = 3.30 × 10⁻°6, OR = 0.43) in chromosome 17. Using HCP5 rs2395029 as a covariate, the C6orf48 and NOTCH4 signals disappeared, but the RICH2 signal still remained significant. CONCLUSIONS: Besides the already known chromosome 6 associations, the analysis of low-frequency SNPs brought up a new association in the RICH2 gene. Interestingly, RICH2 interacts with BST-2 known to be a major restriction factor for HIV-1 infection. Our study has thus identified a new candidate gene for AIDS molecular etiology and confirms the interest of singling out low-frequency SNPs to exploit GWAS data.