Polymorphisms in NACHT-LRR (NLR) genes in atopic dermatitis.
Atopic dermatitis (AD) is a chronic skin disease affecting up to 15% of children in industrialized countries. AD belongs to the group of atopic disorders characterized by excessive immune reactions to ubiquitous antigens. Complex interactions between genetic and environmental factors have been suggested for atopic disorders. Dysregulation of the innate immune system appears crucial for the pathogenesis of AD. The NACHT-LRRs (NLRs) represent a group of innate immune receptors with special relevance for inflammatory processes. In order to investigate the role of variation in NLR genes for AD, we genotyped 23 single nucleotide polymorphisms (SNPs) in seven selected NLR genes (CARD4, CARD15, CARD12, NALP1, NALP3, NALP12, MHC2TA) in 392 AD patients and 297 controls by restriction enzyme digestion or TaqMan assays. Single-SNP analysis demonstrated significant associations of the CARD15_R702W variation and the NALP12_In9 T-allele with AD (P = 0.008 and P = 0.03, resp.; insignificant after Bonferroni correction). In the CARD4 gene, a rare haplotype was more frequent in AD patients than in controls. Interactions between all pairs of SNPs in the seven genes were analysed by logistic regression. Significant interactions comprised SNPs in the CARD4 gene (CARD4_In1 and CARD4_Ex6, P = 6.56 x 10(-7); CARD4_Prom und CARD4_Ex6, P = 2.45 x 10(-4)) and promoter polymorphisms in the CARD12 and NALP1 genes (P = 4.31 x 10(-4)). In conclusion, variation in individual genes from the NLR family as well as interactions within this group of innate immune receptor genes could play a role in AD pathogenesis. Investigations in other populations and functional studies are warranted to clarify contributions of NLR variation for this frequent skin disease.
Macaluso
Filippina
F
Department of Human Genetics, Ruhr-University Bochum, Bochum, Germany.
Nothnagel
Michael
M
Parwez
Qumar
Q
Petrasch-Parwez
Elisabeth
E
Bechara
Falk Georges
FG
Epplen
Joerg Thomas
JT
Hoffjan
Sabine
S
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D003876:Dermatitis, Atopic / Q000235:genetics*; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D016015:Logistic Models; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000070576:NLR Proteins; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015534:Trans-Activators / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C083728:MHC class II transactivator protein; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000070576:NLR Proteins; C435692:NLRC4 protein, human; C427903:NLRP1 protein, human; C476731:NLRP12 protein, human; C453881:NLRP3 protein, human; C119067:NOD1 protein, human; C429018:NOD2 protein, human; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D009687:Nuclear Proteins; D015534:Trans-Activators