Antiretroviral therapy modifies the genetic effect of known type 2 diabetes-associated risk variants in HIV-infected women

Melissa A. Frasco, Roksana Karim, David Van Den Berg, Richard M. Watanabe, Kathryn Anastos, Mardge Cohen, Stephen J. Gange, Deborah R. Gustafson, Chenglong Liu, Phyllis C. Tien, Wendy J. MacK, Celeste L. Pearce

Research output: Contribution to journalArticle

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Abstract

OBJECTIVE:: Type 2 diabetes mellitus incidence is increased in HIV-infected persons. We examined the associations of diabetes mellitus with known diabetes mellitus-risk alleles from the general population in the context of HIV infection, and explored effect modification by combination antiretroviral therapy (cART). METHODS:: The WomenÊ1/4s Interagency HIV Study is a prospective cohort of HIV-infected women. Seventeen European-derived diabetes mellitus-risk polymorphisms were genotyped in the eligible participants of the WomenÊ1/4s Interagency HIV Study. Analyses were run separately for non-African Americans (Whites, Hispanics, Asians, and other; n=378, 49 with incident diabetes mellitus) and African Americans (n=591, 49 with incident diabetes mellitus). Cox proportional-hazards models were fit to estimate hazard ratios for diabetes mellitus overall and within strata of cART. RESULTS:: In non-African Americans, heterogeneity across cART regimen was observed for nine of the 14 polymorphisms (phet<0.05). One polymorphism was statistically significantly inversely associated with diabetes mellitus risk among women taking two nucleotide reverse transcriptase inhibitors (NRTIs) + non-nucleotide reverse transcriptase inhibitor (NNRTI). Five polymorphisms were statistically significantly associated with diabetes mellitus among women treated with at least two NRTIs+at least one protease inhibitor and one polymorphism was associated with diabetes mellitus among those treated with at least three NRTIs±NNRTI. The hazard ratio per risk allele for IGF2BP2 rs1470579 was 2.67 (95% confidence interval 1.67-4.31) for women taking cART with at least two NRTIs+at least one protease inhibitor and 2.45 (95% confidence interval 1.08-5.53) in women taking at least three NRTIs±NNRTI (phet=2.50×10). No such associations were observed in the African Americans. CONCLUSIONS:: Genetic susceptibility to diabetes mellitus, based on the variants studied, is substantially elevated among HIV-infected women using cART containing three or more NRTI/protease inhibitor components. A personalized medicine approach to cART selection may be indicated for HIV-infected persons carrying these diabetes mellitus-risk variants.

Original languageEnglish (US)
Pages (from-to)1815-1823
Number of pages9
JournalAIDS
Volume28
Issue number12
DOIs
StatePublished - Jul 31 2014

Fingerprint

Genetic Therapy
Type 2 Diabetes Mellitus
Diabetes Mellitus
HIV
Reverse Transcriptase Inhibitors
Nucleotides
Protease Inhibitors
African Americans
Therapeutics
Alleles
Confidence Intervals
Precision Medicine
Genetic Predisposition to Disease
Hispanic Americans
Proportional Hazards Models
HIV Infections
Odds Ratio
Incidence

Keywords

  • antiretroviral therapy
  • genetics
  • HIV
  • type 2 diabetes
  • women

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Antiretroviral therapy modifies the genetic effect of known type 2 diabetes-associated risk variants in HIV-infected women. / Frasco, Melissa A.; Karim, Roksana; Van Den Berg, David; Watanabe, Richard M.; Anastos, Kathryn; Cohen, Mardge; Gange, Stephen J.; Gustafson, Deborah R.; Liu, Chenglong; Tien, Phyllis C.; MacK, Wendy J.; Pearce, Celeste L.

In: AIDS, Vol. 28, No. 12, 31.07.2014, p. 1815-1823.

Research output: Contribution to journalArticle

Frasco, MA, Karim, R, Van Den Berg, D, Watanabe, RM, Anastos, K, Cohen, M, Gange, SJ, Gustafson, DR, Liu, C, Tien, PC, MacK, WJ & Pearce, CL 2014, 'Antiretroviral therapy modifies the genetic effect of known type 2 diabetes-associated risk variants in HIV-infected women', AIDS, vol. 28, no. 12, pp. 1815-1823. https://doi.org/10.1097/QAD.0000000000000366
Frasco, Melissa A. ; Karim, Roksana ; Van Den Berg, David ; Watanabe, Richard M. ; Anastos, Kathryn ; Cohen, Mardge ; Gange, Stephen J. ; Gustafson, Deborah R. ; Liu, Chenglong ; Tien, Phyllis C. ; MacK, Wendy J. ; Pearce, Celeste L. / Antiretroviral therapy modifies the genetic effect of known type 2 diabetes-associated risk variants in HIV-infected women. In: AIDS. 2014 ; Vol. 28, No. 12. pp. 1815-1823.
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abstract = "OBJECTIVE:: Type 2 diabetes mellitus incidence is increased in HIV-infected persons. We examined the associations of diabetes mellitus with known diabetes mellitus-risk alleles from the general population in the context of HIV infection, and explored effect modification by combination antiretroviral therapy (cART). METHODS:: The Women{\^E}1/4s Interagency HIV Study is a prospective cohort of HIV-infected women. Seventeen European-derived diabetes mellitus-risk polymorphisms were genotyped in the eligible participants of the Women{\^E}1/4s Interagency HIV Study. Analyses were run separately for non-African Americans (Whites, Hispanics, Asians, and other; n=378, 49 with incident diabetes mellitus) and African Americans (n=591, 49 with incident diabetes mellitus). Cox proportional-hazards models were fit to estimate hazard ratios for diabetes mellitus overall and within strata of cART. RESULTS:: In non-African Americans, heterogeneity across cART regimen was observed for nine of the 14 polymorphisms (phet<0.05). One polymorphism was statistically significantly inversely associated with diabetes mellitus risk among women taking two nucleotide reverse transcriptase inhibitors (NRTIs) + non-nucleotide reverse transcriptase inhibitor (NNRTI). Five polymorphisms were statistically significantly associated with diabetes mellitus among women treated with at least two NRTIs+at least one protease inhibitor and one polymorphism was associated with diabetes mellitus among those treated with at least three NRTIs±NNRTI. The hazard ratio per risk allele for IGF2BP2 rs1470579 was 2.67 (95{\%} confidence interval 1.67-4.31) for women taking cART with at least two NRTIs+at least one protease inhibitor and 2.45 (95{\%} confidence interval 1.08-5.53) in women taking at least three NRTIs±NNRTI (phet=2.50×10). No such associations were observed in the African Americans. CONCLUSIONS:: Genetic susceptibility to diabetes mellitus, based on the variants studied, is substantially elevated among HIV-infected women using cART containing three or more NRTI/protease inhibitor components. A personalized medicine approach to cART selection may be indicated for HIV-infected persons carrying these diabetes mellitus-risk variants.",
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AU - Karim, Roksana

AU - Van Den Berg, David

AU - Watanabe, Richard M.

AU - Anastos, Kathryn

AU - Cohen, Mardge

AU - Gange, Stephen J.

AU - Gustafson, Deborah R.

AU - Liu, Chenglong

AU - Tien, Phyllis C.

AU - MacK, Wendy J.

AU - Pearce, Celeste L.

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N2 - OBJECTIVE:: Type 2 diabetes mellitus incidence is increased in HIV-infected persons. We examined the associations of diabetes mellitus with known diabetes mellitus-risk alleles from the general population in the context of HIV infection, and explored effect modification by combination antiretroviral therapy (cART). METHODS:: The WomenÊ1/4s Interagency HIV Study is a prospective cohort of HIV-infected women. Seventeen European-derived diabetes mellitus-risk polymorphisms were genotyped in the eligible participants of the WomenÊ1/4s Interagency HIV Study. Analyses were run separately for non-African Americans (Whites, Hispanics, Asians, and other; n=378, 49 with incident diabetes mellitus) and African Americans (n=591, 49 with incident diabetes mellitus). Cox proportional-hazards models were fit to estimate hazard ratios for diabetes mellitus overall and within strata of cART. RESULTS:: In non-African Americans, heterogeneity across cART regimen was observed for nine of the 14 polymorphisms (phet<0.05). One polymorphism was statistically significantly inversely associated with diabetes mellitus risk among women taking two nucleotide reverse transcriptase inhibitors (NRTIs) + non-nucleotide reverse transcriptase inhibitor (NNRTI). Five polymorphisms were statistically significantly associated with diabetes mellitus among women treated with at least two NRTIs+at least one protease inhibitor and one polymorphism was associated with diabetes mellitus among those treated with at least three NRTIs±NNRTI. The hazard ratio per risk allele for IGF2BP2 rs1470579 was 2.67 (95% confidence interval 1.67-4.31) for women taking cART with at least two NRTIs+at least one protease inhibitor and 2.45 (95% confidence interval 1.08-5.53) in women taking at least three NRTIs±NNRTI (phet=2.50×10). No such associations were observed in the African Americans. CONCLUSIONS:: Genetic susceptibility to diabetes mellitus, based on the variants studied, is substantially elevated among HIV-infected women using cART containing three or more NRTI/protease inhibitor components. A personalized medicine approach to cART selection may be indicated for HIV-infected persons carrying these diabetes mellitus-risk variants.

AB - OBJECTIVE:: Type 2 diabetes mellitus incidence is increased in HIV-infected persons. We examined the associations of diabetes mellitus with known diabetes mellitus-risk alleles from the general population in the context of HIV infection, and explored effect modification by combination antiretroviral therapy (cART). METHODS:: The WomenÊ1/4s Interagency HIV Study is a prospective cohort of HIV-infected women. Seventeen European-derived diabetes mellitus-risk polymorphisms were genotyped in the eligible participants of the WomenÊ1/4s Interagency HIV Study. Analyses were run separately for non-African Americans (Whites, Hispanics, Asians, and other; n=378, 49 with incident diabetes mellitus) and African Americans (n=591, 49 with incident diabetes mellitus). Cox proportional-hazards models were fit to estimate hazard ratios for diabetes mellitus overall and within strata of cART. RESULTS:: In non-African Americans, heterogeneity across cART regimen was observed for nine of the 14 polymorphisms (phet<0.05). One polymorphism was statistically significantly inversely associated with diabetes mellitus risk among women taking two nucleotide reverse transcriptase inhibitors (NRTIs) + non-nucleotide reverse transcriptase inhibitor (NNRTI). Five polymorphisms were statistically significantly associated with diabetes mellitus among women treated with at least two NRTIs+at least one protease inhibitor and one polymorphism was associated with diabetes mellitus among those treated with at least three NRTIs±NNRTI. The hazard ratio per risk allele for IGF2BP2 rs1470579 was 2.67 (95% confidence interval 1.67-4.31) for women taking cART with at least two NRTIs+at least one protease inhibitor and 2.45 (95% confidence interval 1.08-5.53) in women taking at least three NRTIs±NNRTI (phet=2.50×10). No such associations were observed in the African Americans. CONCLUSIONS:: Genetic susceptibility to diabetes mellitus, based on the variants studied, is substantially elevated among HIV-infected women using cART containing three or more NRTI/protease inhibitor components. A personalized medicine approach to cART selection may be indicated for HIV-infected persons carrying these diabetes mellitus-risk variants.

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