title: Antiretroviral therapy modifies the genetic effect of known type 2 diabetes-associated risk variants in HIV-infected women.
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's 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's 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 × 10⁻³). 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.
authors.affiliation: aDepartment of Preventive Medicine, University of Southern California bDepartment of Physiology and Biophysics University of Southern California cUSC Diabetes and Obesity Research Institute, University of Southern California, Los Angeles, California dMontefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York eStroger Hospital and Rush University, Chicago, Illinois fJohns Hopkins Bloomberg School of Public Health, Baltimore, Maryland gState University New York - Downstate Medical Center, Brooklyn, New York hGeorgetown University School of Medicine, District of Columbia iUniversity of California San Francisco jDepartment of Veterans Affairs, San Francisco, California, USA. *Wendy J. Mack and Celeste Leigh Pearce contributed equally to the writing of this article.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Frasco
authors.forename: Roksana
authors.initials: R
authors.lastname: Karim
authors.forename: David
authors.initials: D
authors.lastname: Van Den Berg
authors.forename: Richard M
authors.initials: RM
authors.lastname: Watanabe
authors.forename: Kathryn
authors.initials: K
authors.lastname: Anastos
authors.forename: Mardge
authors.initials: M
authors.lastname: Cohen
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Gange
authors.forename: Deborah R
authors.initials: DR
authors.lastname: Gustafson
authors.forename: Chenglong
authors.initials: C
authors.lastname: Liu
authors.forename: Phyllis C
authors.initials: PC
authors.lastname: Tien
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Mack
authors.forename: Celeste L
authors.initials: CL
authors.lastname: Pearce
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044966:Anti-Retroviral Agents / Q000009:adverse effects* / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects* / Q000379:methods; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000235:genetics*; D005006:Ethnicity; D005260:Female; D020022:Genetic Predisposition to Disease; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy*; D006801:Humans; D008875:Middle Aged; D011446:Prospective Studies; D018570:Risk Assessment; D055815:Young Adult
chemical_list: D044966:Anti-Retroviral Agents