Objective
Several confirmed genetic susceptibility loci for lupus have been described. To date, no clear evidence for genetic epistasis in lupus has been established. The aim of this study was to ...test for gene–gene interactions in a number of known lupus susceptibility loci.
Methods
Eighteen single‐nucleotide polymorphisms tagging independent and confirmed lupus susceptibility loci were genotyped in a set of 4,248 patients with lupus and 3,818 normal healthy control subjects of European descent. Epistasis was tested by a 2‐step approach using both parametric and nonparametric methods. The false discovery rate (FDR) method was used to correct for multiple testing.
Results
We detected and confirmed gene–gene interactions between the HLA region and CTLA4, IRF5, and ITGAM and between PDCD1 and IL21 in patients with lupus. The most significant interaction detected by parametric analysis was between rs3131379 in the HLA region and rs231775 in CTLA4 (interaction odds ratio 1.19, Z = 3.95, P = 7.8 × 10−5 FDR ≤0.05, P for multifactor dimensionality reduction = 5.9 × 10−45). Importantly, our data suggest that in patients with lupus, the presence of the HLA lupus risk alleles in rs1270942 and rs3131379 increases the odds of also carrying the lupus risk allele in IRF5 (rs2070197) by 17% and 16%, respectively (P = 0.0028 and P = 0.0047, respectively).
Conclusion
We provide evidence for gene–gene epistasis in systemic lupus erythematosus. These findings support a role for genetic interaction contributing to the complexity of lupus heritability.
En France, la Loi sur « l’Égalité des Droits et des Chances, la Participation et la Citoyenneté des Personnes Handicapée » (loi n° 2005-102) repose sur deux idées clés : (1) l’enfant présentant un ...handicap doit être scolarisé autant que possible en milieu ordinaire et (2) l’école a pour mission de s’adapter à ses besoins et non l’inverse. Cette façon d’envisager la scolarisation selon un paradigme inclusif (Ebersold, 2009 ; Thomazet, 2006) résulte d’une construction sociale et de l’aboutissem...
Objective
Maternal–fetal cell transfer during pregnancy can lead to long‐lasting microchimerism, which raises the question of whether microchimerism sometimes contributes to autoimmune disease later ...in life. In an experimental model, transfusion of parental lymphocytes homozygous for major histocompatibility complex alleles results in systemic lupus erythematosus (SLE). We identified male patients with SLE and healthy male subjects and their mothers in order to investigate the mother–son HLA relationship in SLE risk. Male subjects were selected in order to avoid confounding due to fetal microchimerism, which may occur in women.
Methods
HLA genotyping for DRB1, DQA1, and DQB1 was conducted for sons and their mothers. Thirty men with SLE and their mothers were compared with 76 healthy men and their mothers.
Results
Sons with SLE were HLA‐identical with their mothers (bidirectionally compatible) for the basic HLA–DRB1 groups encoded by DRB1*01 through DRB1*14 more often than were healthy sons (odds ratio OR 5.0, P = 0.006). Each DRB1 group contains multiple allelic variants; male patients with SLE and their mothers often were identical for both DRB1 allelic variants (OR 3.2, P = 0.08). For DQA1 and DQB1, the ORs were 2.3 (P = 0.08) and 2.0 (P = 0.21), respectively. When analysis was limited to male subjects with SLE‐associated HLA genes (encoding HLA–DR2 or HLA–DR3), the differences further increased for DRB1 basic groups (OR 7.2, P = 0.01), DRB1 alleles (OR 15.0, P = 0.018), DQA1 6.4 (P = 0.006), and DQB1 (OR 5.7, P = 0.027). No increase in (unidirectional) compatibility of the mother from the son's perspective was observed at any locus.
Conclusion
We observed increased bidirectional HLA class II compatibility of male SLE patients and their mothers compared with healthy men and their mothers. This observation implies that maternal microchimerism could sometimes be involved in SLE and therefore merits further investigation.
Objective
T cells from patients with systemic lupus erythematosus (SLE) express increased amounts of PP2Ac, which contributes to decreased production of interleukin‐2 (IL‐2). Because IL‐2 is ...important in the regulation of several aspects of the immune response, it has been proposed that PP2Ac contributes to the expression of SLE. This study was designed to determine whether genetic variants of PPP2AC are linked to the expression of SLE and specific clinical manifestations and account for the increased expression of PP2Ac.
Methods
We conducted a trans‐ethnic study of 8,695 SLE cases and 7,308 controls of 4 different ancestries. Eighteen single‐nucleotide polymorphisms (SNPs) across PPP2CA were genotyped using an Illumina custom array. PPP2CA expression in SLE and control T cells was analyzed by real‐time polymerase chain reaction.
Results
A 32‐kb haplotype comprising multiple SNPs of PPP2CA showed significant association with SLE in Hispanic Americans, European Americans, and Asians, but not in African Americans. Conditional analyses revealed that SNP rs7704116 in intron 1 showed consistently strong association with SLE across Asian, European American, and Hispanic American populations (odds ratio 1.3 95% confidence interval 1.14‐1.31, meta‐analysis P = 3.8 × 10−7). In European Americans, the largest ethnic data set studied, the risk A allele of rs7704116 was associated with the presence of renal disease, anti–double‐stranded DNA, and anti‐RNP antibodies. PPP2CA expression was ∼2‐fold higher in SLE patients carrying the rs7704116 AG genotype than those carrying the GG genotype (P = 0.007).
Conclusion
Our data provide the first evidence of an association between PPP2CA polymorphisms and elevated PP2Ac transcript levels in T cells, which implicates a new molecular pathway for SLE susceptibility in European Americans, Hispanic Americans, and Asians.
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