title: Association of haplotype combination of serotonin transporter gene polymorphisms with monthly headache days in MOH patients.
abstract: OBJECTIVE
  To evaluate the role of 5-HTTLPR, STin2 VNTR, and rs1042173T>G polymorphisms of the serotonin transporter gene (SLC6A4) as susceptibility factors for medication overuse headache (MOH) and to assess their value as predictors of the number of headache days per month, a potential marker of disease severity.
  
  
  METHODS
  Genotyping was performed by PCR and PCR-RFLP on genomic DNA extracted from peripheral blood of 227 MOH patients and 312 control subjects. Logistic regression analysis was used to evaluate the association between the SL6A4 gene polymorphisms and MOH risk. The association between polymorphic variants and monthly headache days was evaluated by linear regression analysis.
  
  
  RESULTS
  Logistic regression analysis, adjusted for age and gender, revealed a nominal association between rs1042173T>G and MOH risk (TT vs. TG + GG, OR: 1.58 95% CI: 1.05-2.37, P = 0.028). In the linear regression analysis adjusted for age, gender, primary headache diagnosis, acute drug overused and monthly drug number, STin2 VNTR was found nominally associated with monthly headache days (12/12 vs. others, difference: 1.55 days, 95% CI: 0.01-3.08, P = 0.050). When STin2 VNTR and rs1042173T>G were analyzed in haplotypic combination, a global haplotype association emerged with monthly headache days which remained significant after Bonferroni correction for multiple comparisons (global haplotype association P = 0.0056).
  
  
  CONCLUSIONS
  Although a minor contribution of SLC6A4 variants in the genetic liability of MOH cannot be excluded, haplotype-based analysis of STin2 VNTR and rs1042173T>G polymorphisms allowed to identify a subgroup of MOH patients with a higher number of monthly headache and, possibly, with a more severe disease.
authors.affiliation: Università del Piemonte Orientale A. Avogadro, DiSCAFF and Centro di Ricerca Interdipartimentale di Farmacogenetica e Farmacogenomica (CRIFF), Via Bovio, 6, 28100 Novara, Italy. terrazzino@pharm.unipmn.it
authors.forename: S
authors.initials: S
authors.lastname: Terrazzino
authors.forename: C
authors.initials: C
authors.lastname: Tassorelli
authors.forename: G
authors.initials: G
authors.lastname: Sances
authors.forename: M
authors.initials: M
authors.lastname: Allena
authors.forename: M
authors.initials: M
authors.lastname: Viana
authors.forename: F
authors.initials: F
authors.lastname: Monaco
authors.forename: G
authors.initials: G
authors.lastname: Bellomo
authors.forename: G
authors.initials: G
authors.lastname: Nappi
authors.forename: P L
authors.initials: PL
authors.lastname: Canonico
authors.forename: A A
authors.initials: AA
authors.lastname: Genazzani
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000700:Analgesics / Q000009:adverse effects; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D006261:Headache / Q000139:chemically induced* / Q000235:genetics*; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D000700:Analgesics; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins