title: Genetic variation in iron metabolism is associated with neuropathic pain and pain severity in HIV-infected patients on antiretroviral therapy.
abstract: HIV sensory neuropathy and distal neuropathic pain (DNP) are common, disabling complications associated with combination antiretroviral therapy (cART). We previously associated iron-regulatory genetic polymorphisms with a reduced risk of HIV sensory neuropathy during more neurotoxic types of cART. We here evaluated the impact of polymorphisms in 19 iron-regulatory genes on DNP in 560 HIV-infected subjects from a prospective, observational study, who underwent neurological examinations to ascertain peripheral neuropathy and structured interviews to ascertain DNP. Genotype-DNP associations were explored by logistic regression and permutation-based analytical methods. Among 559 evaluable subjects, 331 (59%) developed HIV-SN, and 168 (30%) reported DNP. Fifteen polymorphisms in 8 genes (p<0.05) and 5 variants in 4 genes (p<0.01) were nominally associated with DNP: polymorphisms in TF, TFRC, BMP6, ACO1, SLC11A2, and FXN conferred reduced risk (adjusted odds ratios [ORs] ranging from 0.2 to 0.7, all p<0.05); other variants in TF, CP, ACO1, BMP6, and B2M conferred increased risk (ORs ranging from 1.3 to 3.1, all p<0.05). Risks associated with some variants were statistically significant either in black or white subgroups but were consistent in direction. ACO1 rs2026739 remained significantly associated with DNP in whites (permutation p<0.0001) after correction for multiple tests. Several of the same iron-regulatory-gene polymorphisms, including ACO1 rs2026739, were also associated with severity of DNP (all p<0.05). Common polymorphisms in iron-management genes are associated with DNP and with DNP severity in HIV-infected persons receiving cART. Consistent risk estimates across population subgroups and persistence of the ACO1 rs2026739 association after adjustment for multiple testing suggest that genetic variation in iron-regulation and transport modulates susceptibility to DNP.
authors.affiliation: Department of Genomic Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States of America; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Asha R
authors.initials: AR
authors.lastname: Kallianpur
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Peilin
authors.initials: P
authors.lastname: Jia
authors.affiliation: Department of Neurology, University of California San Diego, San Diego, California, United States of America.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Ellis
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Scripps Genomic Medicine, Scripps Translational Science Institute, and Scripps Health, La Jolla, California, United States of America.
authors.forename: Cinnamon
authors.initials: C
authors.lastname: Bloss
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Wanqing
authors.initials: W
authors.lastname: Wen
authors.affiliation: Department of Neurology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Marra
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Todd
authors.initials: T
authors.lastname: Hulgan
authors.affiliation: Department of Neurology, Icahn School of Medicine of Mt. Sinai, New York, New York, United States of America.
authors.forename: David M
authors.initials: DM
authors.lastname: Simpson
authors.affiliation: Department of Neurology, Icahn School of Medicine of Mt. Sinai, New York, New York, United States of America.
authors.forename: Susan
authors.initials: S
authors.lastname: Morgello
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Justin C
authors.initials: JC
authors.lastname: McArthur
authors.affiliation: Department of Neurology, Washington University, St. Louis, Missouri, United States of America.
authors.forename: David B
authors.initials: DB
authors.lastname: Clifford
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Ann C
authors.initials: AC
authors.lastname: Collier
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Gelman
authors.affiliation: Department of Medicine, University of California San Diego, San Diego, California, United States of America.
authors.forename: J Allen
authors.initials: JA
authors.lastname: McCutchan
authors.affiliation: HIV Neurobehavioral Research Center & CHARTER Center, University of California San Diego, San Diego, California, United States of America.
authors.forename: Donald
authors.initials: D
authors.lastname: Franklin
authors.affiliation: Department of Molecular Physiology and Biophysics and Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: David C
authors.initials: DC
authors.lastname: Samuels
authors.affiliation: HIV Neurobehavioral Research Center & CHARTER Center, University of California San Diego, San Diego, California, United States of America.
authors.forename: Debralee
authors.initials: D
authors.lastname: Rosario
authors.affiliation: Department of Molecular Physiology and Biophysics and Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Emily
authors.initials: E
authors.lastname: Holzinger
authors.affiliation: Department of Molecular Physiology and Biophysics and Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Deborah G
authors.initials: DG
authors.lastname: Murdock
authors.affiliation: Department of Medicine, University of California San Diego, San Diego, California, United States of America.
authors.forename: Scott
authors.initials: S
authors.lastname: Letendre
authors.affiliation: Department of Psychiatry, University of California San Diego, San Diego, California, United States of America.
authors.forename: Igor
authors.initials: I
authors.lastname: Grant
mesh_terms: D000328:Adult; D000368:Aged; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000235:genetics; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009437:Neuralgia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D055815:Young Adult
chemical_list: D044966:Anti-Retroviral Agents; D007501:Iron; D035941:Iron Regulatory Protein 1