NALP1 in vitiligo-associated multiple autoimmune disease.
BACKGROUND
Autoimmune and autoinflammatory diseases involve interactions between genetic risk factors and environmental triggers. We searched for a gene on chromosome 17p13 that contributes to a group of epidemiologically associated autoimmune and autoinflammatory diseases. The group includes various combinations of generalized vitiligo, autoimmune thyroid disease, latent autoimmune diabetes in adults, rheumatoid arthritis, psoriasis, pernicious anemia, systemic lupus erythematosus, and Addison's disease.


METHODS
We tested 177 single-nucleotide polymorphisms (SNPs) spanning the 17p13 linkage peak for association with disease and identified a strong candidate gene. We then sequenced DNA in and around the gene to identify additional SNPs. We carried out a second round of tests of association using some of these additional SNPs, thus elucidating the association with disease in the gene and its extended promoter region in fine detail.


RESULTS
Association analyses resulted in our identifying as a candidate gene NALP1, which encodes NACHT leucine-rich-repeat protein 1, a regulator of the innate immune system. Fine-scale association mapping with the use of DNA from affected families and additional SNPs in and around NALP1 showed an association of specific variants with vitiligo alone, with an extended autoimmune and autoinflammatory disease phenotype, or with both. Conditional logistic-regression analysis of NALP1 SNPs indicated that at least two variants contribute independently to the risk of disease.


CONCLUSIONS
DNA sequence variants in the NALP1 region are associated with the risk of several epidemiologically associated autoimmune and autoinflammatory diseases, implicating the innate immune system in the pathogenesis of these disorders.
Jin
Ying
Y
Human Medical Genetics Program, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045, USA.
Mailloux
Christina M
CM
Gowan
Katherine
K
Riccardi
Sheri L
SL
LaBerge
Greggory
G
Bennett
Dorothy C
DC
Fain
Pamela R
PR
Spritz
Richard A
RA
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D001327:Autoimmune Diseases / Q000235:genetics*; D002886:Chromosomes, Human, Pair 17; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D040582:Inheritance Patterns; D016015:Logistic Models; D008969:Molecular Sequence Data; D000070576:NLR Proteins; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D014820:Vitiligo / Q000235:genetics* / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000070576:NLR Proteins; C427903:NLRP1 protein, human