title: Leprosy epidemics during history increased protective allele frequency of PARK2/PACRG genes in the population of the Mljet Island, Croatia.
abstract: BACKGROUND
  Two regulatory polymorphisms (rs1040079 and rs9356058) shared by PARK2 and PACRG genes were identified as major risk variants for leprosy susceptibility. The aim of this study was to investigate if allele frequencies of these polymorphisms in the isolated population of the island of Mljet, which served as a quarantine for leprosy patients during past centuries, were different to allele frequencies in two control populations with no history of leprosy.
  
  
  METHODS
  This study included 88 unrelated Caucasian individuals from the island of Mljet while two control groups included 93 individuals from the island of Rab and 160 individuals from the region of Split. Genotyping for rs1040079 and rs9356058 was performed by "real-time" PCR analysis. We also compared the allele frequency of the rs9356058 polymorphism from the population of Mljet with allele frequencies derived from the existing genome wide association scans in two additional island populations, Vis (924 subjects) and Korcula (909 subjects).
  
  
  RESULTS
  We found a significant increase in the frequency of rs9356058 allele C in the population of Mljet when compared to both control groups. We also observed a significant increase in the frequency of rs1040079 allele A in the population of Mljet when compared with the population of Rab, however this increase was not significant when compared with the population of Split. Allele frequencies of both examined polymorphisms did not differ between the two control populations. Protective haplotype rs9356058-rs1040079 CA was also more frequent in the population of Mljet compared with the Rab and Split populations. In addition, an increase of frequency of rs9356058 allele C was also observed in the population of Mljet when compared with the frequency in the Korcula population.
  
  
  CONCLUSIONS
  The results of our study show the association of polymorphisms rs9356058 and rs1040079 in gene PARK2/PACRG with leprosy. The results of our study indicate that exposure to leprosy and mortality in the population caused by leprosy on Mljet resulted in the selection of rs9356058 "protective" C allele in the PARK2 gene, while this was not observed in the two control groups. This is the first study to assess the genetic susceptibility to leprosy in a European population.
authors.affiliation: Clinic for Dermatovenerology Cutis, Vukovarska 22, Dubrovnik, Croatia. ana.bakija-konsuo@du.t-com.hr
authors.forename: A
authors.initials: A
authors.lastname: Bakija-Konsuo
authors.forename: R
authors.initials: R
authors.lastname: Mulić
authors.forename: V
authors.initials: V
authors.lastname: Boraska
authors.forename: M
authors.initials: M
authors.lastname: Pehlic
authors.forename: J E
authors.initials: JE
authors.lastname: Huffman
authors.forename: C
authors.initials: C
authors.lastname: Hayward
authors.forename: M
authors.initials: M
authors.lastname: Marlais
authors.forename: T
authors.initials: T
authors.lastname: Zemunik
authors.forename: I
authors.initials: I
authors.lastname: Rudan
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D017523:Croatia / Q000453:epidemiology; D004252:DNA Mutational Analysis; D058872:Epidemics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D005843:Geography; D006239:Haplotypes; D006801:Humans; D007918:Leprosy / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D015810:Linkage Disequilibrium; D008297:Male; D008840:Microfilament Proteins; D018832:Molecular Chaperones / Q000235:genetics*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D060888:Real-Time Polymerase Chain Reaction; D012641:Selection, Genetic; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D044465:White People
chemical_list: D008840:Microfilament Proteins; D018832:Molecular Chaperones; C471711:PACRG protein, human; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein