Evaluation of the XXXX gene in a large multi-ancestral lupus cohort.

@entity1 @entity72441 @entity410 @entity16282 @entity72442 @entity72443 @entity56596 @entity75 @entity1252 @entity72440 @entity792
@entity1252 ( @entity1252 ) is a prototypic @entity792 with a complex pathogenesis in which genetic, hormonal and environmental factors have a role. Rare mutations in the @entity56596 gene, the major @entity1 3'-5' exonuclease, have been reported in sporadic @entity1252 cases. Some of these mutations have also been identified in a rare pediatric neurological condition featuring an inflammatory @entity75 known as @entity16282 ( @entity16282 ). We sought to investigate the frequency of these mutations in a large multi-ancestral cohort of @entity1252 cases and controls. A total of 40 single-nucleotide polymorphisms (SNPs), including both common and rare variants, across the @entity56596 gene, were evaluated in    8370 @entity1 with @entity1252 and    7490 control subjects. Stringent quality control procedures were applied, and principal components and admixture proportions were calculated to identify outliers for removal from analysis. Population-based case-control association analyses were performed. P-values, false-discovery rate q values, and odds ratios (OR) with 95% confidence intervals (CI) were calculated. The estimated frequency of @entity56596 mutations in our lupus cohort was 0.5%. Five heterozygous mutations were detected at the @entity72440 polymorphism in European lupus cases but none were observed in European controls. Five African cases incurred heterozygous mutations at the @entity72441 polymorphism and, again, none were observed in the African controls. A rare homozygous @entity72442 mutation was identified in one Asian @entity1252 @entity1 , whereas all genotypes at this mutation in previous reports for @entity1252 were heterozygous. Analysis of common @entity56596 SNPs (minor allele frequency (MAF)>10%) revealed a relatively common risk haplotype in European @entity1252 @entity1 with neurological manifestations, especially @entity410 , with a frequency of 58% in lupus cases compared with 45% in normal controls (P=0.0008, OR=1.73, 95% CI=1.25-2.39). Finally, the presence or absence of specific autoantibodies in certain populations produced significant genetic associations. For example, a strong association with anti-nRNP was observed in the European cohort at a coding synonymous variant @entity72443 (P=2.99E-13, OR=5.2, 95% CI=3.18-8.56). Our data confirm and expand previous reports and provide additional support for the involvement of @entity56596 in lupus pathogenesis.
