title: 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.
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.
authors.affiliation: Institute of Transfusion Medicine, Campus Virchow Klinikum, Charité, Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany. berthold.hoppe@charite.de
authors.forename: Berthold
authors.initials: B
authors.lastname: Hoppe
authors.forename: Guido A
authors.initials: GA
authors.lastname: Heymann
authors.forename: Farzaneh
authors.initials: F
authors.lastname: Tolou
authors.forename: Holger
authors.initials: H
authors.lastname: Kiesewetter
authors.forename: Thomas
authors.initials: T
authors.lastname: Doerner
authors.forename: Abdulgabar
authors.initials: A
authors.lastname: Salama
mesh_terms: D005091:Exons; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D006867:Hydrolases / Q000235:genetics*; D007527:Isoenzymes / Q000235:genetics; D008969:Molecular Sequence Data; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D017422:Sequence Analysis, DNA
chemical_list: D007527:Isoenzymes; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases