title: Adipogenic gene variants in patients with HIV-associated lipodystrophy.
abstract: OBJECTIVE
  Although highly active antiretroviral therapy (HAART) has been hugely beneficial in the treatment of HIV, HIV lipodystrophy (HIVLD) associated with HAART is a serious adverse effect, with long-term consequences including metabolic disturbances and an increased risk of atherosclerotic disease. Although HIVLD is clearly related to the drug regimen, individual susceptibility also plays a role. We hypothesized that variation in genes regulating adipogenesis, and in those implicated in inherited forms of lipodystrophy, may predispose to the development of HIVLD.
  
  
  METHODS
  DNA samples were obtained from 180 HAART-treatedHIV+ patients: 124 with HIVLD (HIVLD+) and 56 without HIVLD (HIVLD-). Diagnosis of HIVLD was carried out by clinician's confirmation of patient self-report. High-throughput genotyping using Sequenom was used to screen 62 single nucleotide polymorphisms (SNPs) in eight genes involved in adipogenesis and inherited forms of lipodystrophy. Statistical analysis was performed using Haploview. Multivariate analysis (logistic regression) was used to identify independent predictors of HIVLD development in HAART-treated patients.
  
  
  RESULTS
  SNPs in two adipogenesis regulators, LPIN1 and CEBPα, showed a significant association with HIVLD whereas a SNP in ZMPSTE24, a zinc metalloproteinase involved in prelamin A processing, showed a trend toward significance. Multivariate analysis identified time since HIV diagnosis (P=0.001) and carriage of more than one associated allele (P=0.008) to be the most significant independent predictors for the development of HIVLD.
  
  
  CONCLUSIONS
  Genetic variation in key regulators of adipogenesis could interfere with fat storage and metabolism contributing to the development of HIVLD in HAART-treated HIV patients. These results need replication in other cohorts.
authors.affiliation: NIHR Biomedical Research Centre, Royal Liverpool Hospital, Liverpool, UK. sudeepp@liv.ac.uk
authors.forename: Sudeep P
authors.initials: SP
authors.lastname: Pushpakom
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Vilar
authors.forename: Hannah
authors.initials: H
authors.lastname: Castro
authors.forename: David T
authors.initials: DT
authors.lastname: Dunn
authors.forename: David J
authors.initials: DJ
authors.lastname: Back
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
mesh_terms: D050156:Adipogenesis / Q000235:genetics*; D000328:Adult; D000368:Aged; D000483:Alleles; D015331:Cohort Studies; D003710:Demography; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D039682:HIV-Associated Lipodystrophy Syndrome / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012044:Regression Analysis; D055815:Young Adult