Background and aims ANA are one of the earliest features of lupus, preceding the onset of clinical symptoms. The genetic risk factors that underlie the development of serological autoimmunity are unknown. A genome-wide association study was undertaken to understand the genetics of ANA development.

Methods Serum and DNA were collected from 2635 healthy individuals with no personal history of autoimmunity. Sera from 724 individuals (ANA-, ANA+, and SLE) were assayed by protein microarray quantifying IgM and IgG responses to 96 human autoantigens. A nested cohort of subjects consisting of all the ANA+ Caucasian individuals and matched ANA- controls were genotyped.

Results In healthy individuals, 16.2% had moderate and 8.0% had high levels of IgG antinuclear antibodies. ANA+ healthy individuals had a high prevalence of antibodies to non-nuclear and cytoplasmic antigens, while subjects with SLE predictably produced antibodies to a variety of nuclear antigens. A quantitative genetic association test with ANA identified genomic loci associated with high ANA phenotype. HLA was second strongest signal (p=6.2x10^-6). The frequencies of SLE risk haplotypes at several loci were significantly increased in the ANA high positive group compared to ANA negative subjects. However, SLE risk haplotypes at other loci were only high in the SLE group, suggesting their main role in a transition to clinical disease.

Conclusions The genetic risk for the development of ANA includes many of the previously documented SLE risk haplotypes. However, other genetic associations are specific for SLE, suggesting distinct risk factors for ANA and for lupus.