Lymphocyte Count Derived Polygenic Score and Interindividual Variability in CD4 T-cell Recovery in Response to Antiretroviral Therapy
Access to safe and effective antiretroviral therapy (ART) is a cornerstone in the global response to the HIV pandemic. Among people living with HIV, there is considerable interindividual variability in absolute CD4 T-cell recovery following initiation of virally suppressive ART. The contribution of host genetics to this variability is not well understood. We explored the contribution of a polygenic score which was derived from large, publicly available summary statistics for absolute lymphocyte count from individuals in the general population (PGSlymph) due to a lack of publicly available summary statistics for CD4 T-cell count. We explored associations with baseline CD4 T-cell count prior to ART initiation (n=4959) and change from baseline to week 48 on ART (n=3274) among treatment-naïve participants in prospective, randomized ART studies of the AIDS Clinical Trials Group. We separately examined an African-ancestry-derived and a European-ancestry-derived PGSlymph, and evaluated their performance across all participants, and also in the African and European ancestral groups separately. Multivariate models that included PGSlymph, baseline plasma HIV-1 RNA, age, sex, and 15 principal components (PCs) of genetic similarity explained ∼26-27% of variability in baseline CD4 T-cell count, but PGSlymph accounted for <1% of this variability. Models that also included baseline CD4 T-cell count explained ∼7-9% of variability in CD4 T-cell count increase on ART, but PGSlymph accounted for <1% of this variability. In univariate analyses, PGSlymph was not significantly associated with baseline or change in CD4 T-cell count. Among individuals of African ancestry, the African PGSlymph term in the multivariate model was significantly associated with change in CD4 T-cell count while not significant in the univariate model. When applied to lymphocyte count in a general medical biobank population (Penn Medicine BioBank), PGSlymph explained ∼6-10% of variability in multivariate models (including age, sex, and PCs) but only ∼1% in univariate models. In summary, a lymphocyte count PGS derived from the general population was not consistently associated with CD4 T-cell recovery on ART. Nonetheless, adjusting for clinical covariates is quite important when estimating such polygenic effects.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:29 |
|---|---|
| Enthalten in: |
Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing - 29(2024) vom: 08., Seite 594-610 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Cardone, Kathleen M [VerfasserIn] |
|---|
| Themen: |
|---|
| Anmerkungen: |
Date Completed 03.01.2024 Date Revised 25.04.2024 published: Print Citation Status MEDLINE |
|---|
| Förderinstitution / Projekttitel: |
|
|---|
| PPN (Katalog-ID): |
NLM366509489 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM366509489 | ||
| 003 | DE-627 | ||
| 005 | 20240425232630.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240108s2024 xx |||||o 00| ||eng c | ||
| 028 | 5 | 2 | |a pubmed24n1386.xml |
| 035 | |a (DE-627)NLM366509489 | ||
| 035 | |a (NLM)38160309 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Cardone, Kathleen M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Lymphocyte Count Derived Polygenic Score and Interindividual Variability in CD4 T-cell Recovery in Response to Antiretroviral Therapy |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 03.01.2024 | ||
| 500 | |a Date Revised 25.04.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Access to safe and effective antiretroviral therapy (ART) is a cornerstone in the global response to the HIV pandemic. Among people living with HIV, there is considerable interindividual variability in absolute CD4 T-cell recovery following initiation of virally suppressive ART. The contribution of host genetics to this variability is not well understood. We explored the contribution of a polygenic score which was derived from large, publicly available summary statistics for absolute lymphocyte count from individuals in the general population (PGSlymph) due to a lack of publicly available summary statistics for CD4 T-cell count. We explored associations with baseline CD4 T-cell count prior to ART initiation (n=4959) and change from baseline to week 48 on ART (n=3274) among treatment-naïve participants in prospective, randomized ART studies of the AIDS Clinical Trials Group. We separately examined an African-ancestry-derived and a European-ancestry-derived PGSlymph, and evaluated their performance across all participants, and also in the African and European ancestral groups separately. Multivariate models that included PGSlymph, baseline plasma HIV-1 RNA, age, sex, and 15 principal components (PCs) of genetic similarity explained ∼26-27% of variability in baseline CD4 T-cell count, but PGSlymph accounted for <1% of this variability. Models that also included baseline CD4 T-cell count explained ∼7-9% of variability in CD4 T-cell count increase on ART, but PGSlymph accounted for <1% of this variability. In univariate analyses, PGSlymph was not significantly associated with baseline or change in CD4 T-cell count. Among individuals of African ancestry, the African PGSlymph term in the multivariate model was significantly associated with change in CD4 T-cell count while not significant in the univariate model. When applied to lymphocyte count in a general medical biobank population (Penn Medicine BioBank), PGSlymph explained ∼6-10% of variability in multivariate models (including age, sex, and PCs) but only ∼1% in univariate models. In summary, a lymphocyte count PGS derived from the general population was not consistently associated with CD4 T-cell recovery on ART. Nonetheless, adjusting for clinical covariates is quite important when estimating such polygenic effects | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Anti-HIV Agents |2 NLM | |
| 700 | 1 | |a Dudek, Scott |e verfasserin |4 aut | |
| 700 | 1 | |a Keat, Karl |e verfasserin |4 aut | |
| 700 | 1 | |a Bradford, Yuki |e verfasserin |4 aut | |
| 700 | 1 | |a Cindi, Zinhle |e verfasserin |4 aut | |
| 700 | 1 | |a Daar, Eric S |e verfasserin |4 aut | |
| 700 | 1 | |a Gulick, Roy |e verfasserin |4 aut | |
| 700 | 1 | |a Riddler, Sharon A |e verfasserin |4 aut | |
| 700 | 1 | |a Lennox, Jeffrey L |e verfasserin |4 aut | |
| 700 | 1 | |a Sinxadi, Phumla |e verfasserin |4 aut | |
| 700 | 1 | |a Haas, David W |e verfasserin |4 aut | |
| 700 | 1 | |a Ritchie, Marylyn D |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing |d 1998 |g 29(2024) vom: 08., Seite 594-610 |w (DE-627)NLM093340621 |x 2335-6936 |7 nnns |
| 773 | 1 | 8 | |g volume:29 |g year:2024 |g day:08 |g pages:594-610 |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 29 |j 2024 |b 08 |h 594-610 | ||