title: Association analysis of PON2 genetic variants with serum paraoxonase activity and systemic lupus erythematosus.
abstract: BACKGROUND
  Low serum paraoxonase (PON) activity is associated with the risk of coronary artery disease, diabetes and systemic lupus erythematosus (SLE). Our prior studies have shown that the PON1/rs662 (p.Gln192Arg), PON1/rs854560 (p.Leu55Met), PON3/rs17884563 and PON3/rs740264 SNPs (single nucleotide polymorphisms) significantly affect serum PON activity. Since PON1, PON2 and PON3 share high degree of structural and functional properties, in this study, we examined the role of PON2 genetic variation on serum PON activity, risk of SLE and SLE-related clinical manifestations in a Caucasian case-control sample.
  
  
  METHODS
  PON2 SNPs were selected from HapMap and SeattleSNPs databases by including at least one tagSNP from each bin defined in these resources. A total of nineteen PON2 SNPs were successfully genotyped in 411 SLE cases and 511 healthy controls using pyrosequencing, restriction fragment length polymorphism (RFLP) or TaqMan allelic discrimination methods.
  
  
  RESULTS
  Our pair-wise linkage disequilibrium (LD) analysis, using an r² cutoff of 0.7, identified 14 PON2 tagSNPs that captured all 19 PON2 variants in our sample, 12 of which were not in high LD with known PON1 and PON3 SNP modifiers of PON activity. Stepwise regression analysis of PON activity, including the known modifiers, identified five PON2 SNPs [rs6954345 (p.Ser311Cys), rs13306702, rs987539, rs11982486, and rs4729189; P = 0.005 to 2.1 × 10⁻⁶] that were significantly associated with PON activity. We found no association of PON2 SNPs with SLE risk but modest associations were observed with lupus nephritis (rs11981433, rs17876205, rs17876183) and immunologic disorder (rs11981433) in SLE patients (P = 0.013 to 0.042).
  
  
  CONCLUSIONS
  Our data indicate that PON2 genetic variants significantly affect variation in serum PON activity and have modest effects on risk of lupus nephritis and SLE-related immunologic disorder.
authors.affiliation: Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Sudeshna
authors.initials: S
authors.lastname: Dasgupta
authors.forename: F Yesim
authors.initials: FY
authors.lastname: Demirci
authors.forename: Amy S
authors.initials: AS
authors.lastname: Dressen
authors.forename: Amy H
authors.initials: AH
authors.lastname: Kao
authors.forename: Elisa Y
authors.initials: EY
authors.lastname: Rhew
authors.forename: Rosalind
authors.initials: R
authors.lastname: Ramsey-Goldman
authors.forename: Susan
authors.initials: S
authors.lastname: Manzi
authors.forename: Candace M
authors.initials: CM
authors.lastname: Kammerer
authors.forename: M Ilyas
authors.initials: MI
authors.lastname: Kamboh
mesh_terms: D000328:Adult; D000483:Alleles; D043303:Aryldialkylphosphatase / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: D043303:Aryldialkylphosphatase; C468411:PON2 protein, human