Homozygosity for DNASE2 single nucleotide polymorphisms in the 5'-regulatory region is associated with rheumatoid arthritis.
OBJECTIVE
To analyse the distribution of single nucleotide polymorphisms (SNPs) in the 5'-regulatory region of the DNASE2 gene, in patients with rheumatoid arthritis (RA) and healthy controls.


METHODS
A total of 906 patients with RA and 878 healthy controls were genotyped. All subjects were of German Caucasian origin. Genotyping was performed by real-time polymerase chain reaction technology, using a TaqMan 5'-allele discrimination assay.


RESULTS
In the initial analysis of unrelated case-control samples, three DNASE2 SNP alleles in the 5'-regulatory region were significantly more frequent in patients with RA than in healthy controls. The strongest association was found for the -1066G allele (33.5% vs 27.2%, p = 0.007, odds ratio (OR) = 1.34). Homozygosity for this allele (genotype GG) resulted in an additional increase in disease susceptibility (12.5% vs 6.2%, OR = 2.17). The association was replicated in a second case-control series of 483 patients with RA from two German multicentre studies and 474 controls. The association of DNASE2 -1066 GG homozygosity with RA was limited to rheumatoid factor-positive disease, but was not influenced by the presence of anti-cyclic citrullinated peptide or antinuclear antibodies. Similarly, the presence or absence of the HLA-DRB1 shared epitope or the RA-associated PTPN22 allele had no influence on this association.


CONCLUSIONS
The association of SNPs in the 5'-regulatory region of the DNA degrading enzyme DNASE2 with RA implies a role for this enzyme in the pathogenesis of this autoimmune disease.
Rossol
M
M
Division of Rheumatology, Department of Internal Medicine II, University of Leipzig, Johannisallee 30, Leipzig 04103, Germany. manuela.rossol@medizin.uni-leipzig.de
Pierer
M
M
Arnold
S
S
Keysser
G
G
Burkhardt
H
H
Baerwald
C
C
Wagner
U
U
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000974:Antibodies, Antinuclear / Q000097:blood; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D004706:Endodeoxyribonucleases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D012217:Rheumatoid Factor / Q000097:blood; D055815:Young Adult
D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D015415:Biomarkers; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide; D012217:Rheumatoid Factor; D004706:Endodeoxyribonucleases; C019329:deoxyribonuclease II