Whole genome sequencing of extreme phenotypes identifies variants in CD101 and UBE2V1 associated with increased risk of sexually acquired HIV-1.
Whole genome sequencing of extreme phenotypes identifies variants in CD101 and UBE2V1 associated with increased risk of sexually acquired HIV-1.
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DOI：
10.1371/journal.ppat.1006703
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发表时间：
2017-11
期刊：
影响因子：
6.7
通讯作者：
Partners in Prevention HSV/HIV Transmission Study and the Partners PrEP Study Teams
中科院分区：
文献类型：
--
作者：
Mackelprang RD;Bamshad MJ;Chong JX;Hou X;Buckingham KJ;Shively K;deBruyn G;Mugo NR;Mullins JI;McElrath MJ;Baeten JM;Celum C;Emond MJ;Lingappa JR;Partners in Prevention HSV/HIV Transmission Study and the Partners PrEP Study Teams
Host genetic variation modifying HIV-1 acquisition risk can inform development of HIV-1 prevention strategies. However, associations between rare or intermediate-frequency variants and HIV-1 acquisition are not well studied. We tested for the association between variation in genic regions and extreme HIV-1 acquisition phenotypes in 100 sub-Saharan Africans with whole genome sequencing data. Missense variants in immunoglobulin-like regions of CD101 and, among women, one missense/5’ UTR variant in UBE2V1, were associated with increased HIV-1 acquisition risk (p = 1.9x10-4 and p = 3.7x10-3, respectively, for replication). Both of these genes are known to impact host inflammatory pathways. Effect sizes increased with exposure to HIV-1 after adjusting for the independent effect of increasing exposure on acquisition risk. Trial registration: ClinicalTrials.gov NCT00194519; NCT00557245 Antiretroviral drugs for pre-exposure prophylaxis (PrEP) or treatment significantly reduce risk of HIV-1 acquisition and transmission, but face challenges of increasing access, maintaining high adherence, and selecting viral resistance. Improved understanding of the molecular determinants of HIV-1 sexual transmission could provide new public health HIV-1 prevention interventions. Factors proven to impact sexual HIV-1 transmission risk include epidemiologic exposure (e.g., level of virus in the transmitting partner and frequency of unprotected sex), presence of genital inflammation, and host genetic variants common in the population. Rare or intermediate frequency genetic variants are an increasingly recognized reservoir of complex human disease-causing factors, but are not well studied in HIV-1 infection. However, the low frequency of these variants reduces statistical power to detect disease associations. Aggregating variants in a common biological domain (e.g., a gene) can increase power for identifying variants with a common direction of effect. We report comparison of whole genome sequences from HIV-1 exposure extremes—highly-HIV-exposed individuals who remained HIV-uninfected and lower-exposed individuals who became HIV-infected. We discover and replicate associations between HIV-1 risk and aggregate variation in two genes, CD101 and UBE2V1 that increase directly with the level of HIV-1 exposure. These genes may modulate host inflammation thereby identifying molecular mechanisms linking genital inflammation to HIV-1 infection, possibly leading to novel candidate host-directed HIV-1 prevention interventions.
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来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
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通讯作者：
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作者：
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通讯作者：
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