Journal of Molecular Medicine

, Volume 82, Issue 11, pp 762–767

High variability of peptidylarginine deiminase 4 (PADI4) in a healthy white population: characterization of six new variants of PADI4 exons 2–4 by a novel haplotype-specific sequencing-based approach

  • Berthold Hoppe
  • Guido A. Heymann
  • Farzaneh Tolou
  • Holger Kiesewetter
  • Thomas Doerner
  • Abdulgabar Salama
Original Article

Abstract

Seven single nucleotide polymorphisms (SNPs) of the peptidylarginine deiminase 4 (PADI4) gene have recently been reported to be strongly associated with rheumatoid arthritis in Japanese individuals. These SNPs are located in or close to exons 2–4 of PADI4 and are organized in at least four different haplotypes. However, a detailed sequencing-based characterization of the PADI4 gene in other populations is still lacking. We therefore analyzed exons 2–4 of the PADI4 gene in 102 healthy white Germans individuals by DNA sequencing and characterized new variants and haplotypes by a novel haplotype-specific sequencing-based approach. The haplotypes 2/3 (padi4_89*G, padi4_90*T, padi4_92*G, padi4_94*T, padi4_104*T, padi4_95*C, padi4_96*C), and haplotype 4 (padi4_89*G, padi4_90*T, padi4_92*G, padi4_94*T, padi4_104*C, padi4_95*G, padi4_96*T) conferring susceptibility to rheumatoid arthritis were detected at frequencies of 30.9% and 7.8%, respectively. In addition, three novel coding SNPs in exons 2, 3, and 4, and three SNPs in introns 2 and 3 located near the exon-intron boundaries were identified in 11 individuals (10.8%). The so-called nonsusceptibility haplotype 1 (padi4_89*A, padi4_90*C, padi4_92*C, padi4_94*C, padi4_104*C, padi4_95*G, padi4_96*T) occurred at a frequency of 58.3%. Additionally, we identified a closely related novel haplotype, haplotype 1B (2.9%), that differs from haplotype 1 only by padi4_92*G/padi4_96*C. This haplotype was not described in the Japanese population. Our results indicate that the PADI4 gene exhibits a remarkable variability and a rather complex haplotypic organization. Further studies on disease association of PADI4 should be performed by haplotype-specific sequencing-based approaches to identify the exact genotype of the PADI4 fragment of interest.

Keywords

PADI4 Haplotype Sequencing Single nucleotide polymorphism Rheumatoid arthritis 

Abbreviations

PAD

Peptidylarginine deiminase

nPADI

Nonsusceptibility haplotype

sPADI

Susceptibility haplotype

PCR

Polymerase chain reaction

RA

Rheumatoid arthritis

SNP

Single nucleotide polymorphism

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Berthold Hoppe
    • 1
  • Guido A. Heymann
    • 1
  • Farzaneh Tolou
    • 1
  • Holger Kiesewetter
    • 1
  • Thomas Doerner
    • 1
  • Abdulgabar Salama
    • 1
  1. 1.Institute of Transfusion Medicine, Campus Virchow Klinikum, CharitéUniversitätsmedizin BerlinBerlinGermany

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