title: Effect of TNF-alpha genetic variants and CCR5 Delta 32 on the vulnerability to HIV-1 infection and disease progression in Caucasian Spaniards.
abstract: BACKGROUND
  Tumor necrosis factor alpha (TNF-alpha) is thought to be involved in the various immunogenetic events that influence HIV-1 infection.
  
  
  METHODS
  We aimed to determine whether carriage of the TNF-alpha-238G>A, -308G>A and -863 C>A gene promoter single nucleotide polymorphisms (SNP) and the CCR5 Delta 32 variant allele influence the risk of HIV-1 infection and disease progression in Caucasian Spaniards. The study group consisted of 423 individuals. Of these, 239 were uninfected (36 heavily exposed but uninfected [EU] and 203 healthy controls [HC]) and 184 were HIV-1-infected (109 typical progressors [TP] and 75 long-term nonprogressors [LTNP] of over 16 years' duration). TNF-alpha SNP and the CCR5 Delta 32 allele were assessed using PCR-RFLP and automatic sequencing analysis methods on white blood cell DNA. Genotype and allele frequencies were compared using the chi 2 test and the Fisher exact test. Haplotypes were compared by logistic regression analysis.
  
  
  RESULTS
  The distribution of TNF-alpha-238G>A, -308G>A and -863 C>A genetic variants was non-significantly different in HIV-1-infected patients compared with uninfected individuals: -238G>A, p = 0.7 and p = 0.3; -308G>A, p = 0.05 and p = 0.07; -863 C>A, p = 0.7 and p = 0.4, for genotype and allele comparisons, respectively. Haplotype analyses, however, indicated that carriers of the haplotype H3 were significantly more common among uninfected subjects (p = 0.04). Among the infected patients, the distribution of the three TNF-alpha genetic variants assessed was non-significantly different between TP and LTNP: -238G>A, p = 0.35 and p = 0.7; -308G>A, p = 0.7 and p = 0.6: -863 C>A, p = 0.2 and p = 0.2, for genotype and allele comparisons, respectively. Haplotype analyses also indicated non-significant associations. Subanalyses in the LTNP subset indicated that the TNF-alpha-238A variant allele was significantly overrepresented in patients who spontaneously controlled plasma viremia compared with those who had a detectable plasma viral load (genotype comparisons, p = 0.02; allele comparisons, p = 0.03). The CCR5 Delta 32 distribution was non-significantly different in HIV-1-infected patients with respect to the uninfected population (p = 0.15 and p = 0.2 for genotype and allele comparisons, respectively) and in LTNP vs TP (p = 0.4 and p = 0.5 for genotype and allele comparisons, respectively).
  
  
  CONCLUSIONS
  In our cohort of Caucasian Spaniards, TNF-alpha genetic variants could be involved in the vulnerability to HIV-1 infection. TNF-alpha genetic variants were unrelated to disease progression in infected subjects. The -238G>A SNP may modulate the control of viremia in LTNP. Carriage of the CCR5 Delta 32 variant allele had no effect on the risk of infection and disease progression.
authors.affiliation: Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain.
authors.forename: Sergi
authors.initials: S
authors.lastname: Veloso
authors.forename: Montserrat
authors.initials: M
authors.lastname: Olona
authors.forename: Felipe
authors.initials: F
authors.lastname: García
authors.forename: Pere
authors.initials: P
authors.lastname: Domingo
authors.forename: Carlos
authors.initials: C
authors.lastname: Alonso-Villaverde
authors.forename: Montserrat
authors.initials: M
authors.lastname: Broch
authors.forename: Joaquim
authors.initials: J
authors.lastname: Peraire
authors.forename: Consuelo
authors.initials: C
authors.lastname: Viladés
authors.forename: Montserrat
authors.initials: M
authors.lastname: Plana
authors.forename: Enric
authors.initials: E
authors.lastname: Pedrol
authors.forename: Miguel
authors.initials: M
authors.lastname: López-Dupla
authors.forename: Carmen
authors.initials: C
authors.lastname: Aguilar
authors.forename: Mar
authors.initials: M
authors.lastname: Gutiérrez
authors.forename: Agathe
authors.initials: A
authors.lastname: Leon
authors.forename: Mariona
authors.initials: M
authors.lastname: Tasias
authors.forename: Josep Ma
authors.initials: JM
authors.lastname: Gatell
authors.forename: Cristóbal
authors.initials: C
authors.lastname: Richart
authors.forename: Francesc
authors.initials: F
authors.lastname: Vidal
mesh_terms: D000328:Adult; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D015658:HIV Infections / Q000235:genetics*; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D019713:Receptors, CCR5 / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D035862:Vulnerable Populations; D044465:White People
chemical_list: D019713:Receptors, CCR5; D014409:Tumor Necrosis Factor-alpha