Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Genome-Wide Association Study of African Americans Implicates Multiple Lung and Inflammatory Disease-Associated Loci in Sarcoidosis Susceptibility.
Adrianto1, Indra, Lin1, Chee Paul, Hale1, Jessica J., Levin2, Albert M., Datta2, Indrani, Parker1, Ryan, Adler1, Adam
Oklahoma Medical Research Foundation, Oklahoma City, OK
Henry Ford Health System, Detroit, MI
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation and US Department of Veterans Affairs Medical Center, Oklahoma City, OK
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK
SUNY Upstate Medical University, Syracuse, NY
Sarcoidosis is a systemic inflammatory disease, characterized by the formation of granulomas primarily in the lungs, but the disease can also affect other organ systems including the bones, joints, muscles, spleen, lymph, liver, glands, brain, skin, and heart. While the etiology of this disease remains elusive, the causal chain likely involves a dysregulated immune in response to an environmental agent in a genetically susceptible host. Despite its higher prevalence and morbidity in African Americans (AAs), to date, genome-wide association studies (GWASs) of this disease have focused only on non-African populations. We present here the first GWAS of sarcoidosis in a population of African origin.
We genotyped 1487 AA sarcoidosis cases and 1504 AA family members and independent controls using the Illumina HumanOmni1-Quad platform for 1.1 million single-nucleotide polymorphisms (SNPs) across the genome. After applying sample and SNP quality control, the final set comprised 2,918 samples (1,273 cases and 1,645 controls) including 180 HapMap YRI and ASW controls from the Illumina iControlDB and 887,296 SNPs. We assessed single SNP association to sarcoidosis using the Efficient Mixed-Model Association eXpedited (EMMAX) software that simultaneously controls for both pairwise genetic relatedness between individuals and population stratification under the additive model. Regions associated at a suggestive level of p < 1 × 10-4 were imputed using IMPUTE2 program and the 1000 Genomes Project haplotypes as reference panels.
We identify two novel sarcoidosis effects reaching genome-wide significance (p < 5 × 10-8) at NOTCH4 (p = 4.30 × 10-9) and HLA-DQA1 (p = 1.04 × 10-11). We also replicated previous sarcoidosis Caucasian GWAS hits of RAB23 (p = 9.47 × 10-5) and BTNL2 (p = 6.10 × 10-6) and confirmed association in 12 regions shown to be involved in other lung or inflammatory diseases, including TGM3 (p = 5.60 × 10-6) and DMBT1 (p = 8.70 × 10-5), associated with celiac and Chrohn's disease, respectively. Pathway-based analyses suggested involvement of inflammation regulation and apoptosis (p < 0.001) pathways and an effect-specific heritability estimation analyses suggested the existence of rare genetic effects in sarcoidosis.
We completed the first GWAS for sarcoidosis in AAs. The novel, replication and confirmatory findings of this study highlight both the usefulness of and need for genetic studies of sarcoidosis in the understudied but greatly affected AA population. Future replication and sequencing studies are required to further elucidate the functional variants that may underlie these novel associations.
To cite this abstract, please use the following information:
Adrianto, Indra, Lin, Chee Paul, Hale, Jessica J., Levin, Albert M., Datta, Indrani, Parker, Ryan, et al; Genome-Wide Association Study of African Americans Implicates Multiple Lung and Inflammatory Disease-Associated Loci in Sarcoidosis Susceptibility. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1680