Acute anterior uveitis (AAU) describes an inflammation of the anterior uveal tract of the eye. Sudden onset, unilateral, acute, anterior uveitis is the most common form of uveitis. It is the phenotype of uveitis that is associated with HLA-B27 and the spondyloarthritic diseases, such as ankylosing spondylitis and reactive arthritis. However, this form of uveitis may also occur in patients with no other systemic inflammatory diseases. Clinical observations clearly indicate that AAU can be familial. We hypothesize that the genetic susceptibility to AAU is multigenic and that in the context of spondyloarthritis, it will be possible to define the contributions of uveitis-specific genetic mutations. This is a competitive renewal of a study to recruit families with more than one member affected with AAU into a genetic data and DNA bank for the purposes of conducting a genome-wide scan using affected sibling pair linkage analysis methods. During the initial funding period, a genome-wide scan was completed. A locus was identified with strong linkage to AAU, but not to ankylosing spondylitis - i.e. what appears to be a bonafide AAU-specific genetic signal.
The aims of this proposal are as follows:
Specific Aim 1 : To expand the database and DNA bank of families with AAU and repeat the genome-wide scan with a larger cohort. Even though one uveitis-specific locus has been found, a larger cohort will be a more robust test of the hypothesis that multiple genes contribute to the genetic predisposition to AAU.
Specific Aim 2 : To identify candidate genes within the locus identified for susceptibility to AAU by performing functional and positional screening techniques.
Specific Aim 3 : To identify specific candidate gene mutations by using SNP marker analysis, by comparative DNA sequencing and by denaturing HPLC analysis.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013139-08
Application #
7640516
Study Section
Special Emphasis Panel (ZRG1-AED (01))
Program Officer
Chin, Hemin R
Project Start
2000-07-01
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2011-06-30
Support Year
8
Fiscal Year
2009
Total Cost
$504,929
Indirect Cost
Name
Oregon Health and Science University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Robinson, Philip C; Claushuis, Theodora A M; Cortes, Adrian et al. (2015) Genetic dissection of acute anterior uveitis reveals similarities and differences in associations observed with ankylosing spondylitis. Arthritis Rheumatol 67:140-51
Abbasian, Javaneh; Martin, Tammy M; Patel, Sarju et al. (2012) Immunologic and genetic markers in patients with idiopathic ocular inflammation and a family history of inflammatory bowel disease. Am J Ophthalmol 154:72-7
Mackensen, F; David, F; Schwenger, V et al. (2011) HLA-DRB1*0102 is associated with TINU syndrome and bilateral, sudden-onset anterior uveitis but not with interstitial nephritis alone. Br J Ophthalmol 95:971-5
Martin, Tammy M; Rosenbaum, James T (2011) An update on the genetics of HLA B27-associated acute anterior uveitis. Ocul Immunol Inflamm 19:108-14
Kim, Hyun Soo; Choi, Dongseok; Lim, Lyndell L et al. (2011) Association of interleukin 23 receptor gene with sarcoidosis. Dis Markers 31:17-24
Levinson, Ralph D; Martin, Tammy M; Luo, Lihui et al. (2010) Killer cell immunoglobulin-like receptors in HLA-B27-associated acute anterior uveitis, with and without axial spondyloarthropathy. Invest Ophthalmol Vis Sci 51:1505-10
Agnani, S; Choi, D; Martin, T M et al. (2010) Gender and laterality affect recurrences of acute anterior uveitis. Br J Ophthalmol 94:1643-7
Saulsbury, Frank T; Wouters, Carine H; Martin, Tammy M et al. (2009) Incomplete penetrance of the NOD2 E383K substitution among members of a pediatric granulomatous arthritis pedigree. Arthritis Rheum 60:1804-6
Martin, Tammy M; Bye, Louise; Modi, Neil et al. (2009) Genotype analysis of polymorphisms in autoimmune susceptibility genes, CTLA-4 and PTPN22, in an acute anterior uveitis cohort. Mol Vis 15:208-12
Martin, Tammy M; Zhang, Zili; Kurz, Paul et al. (2009) The NOD2 defect in Blau syndrome does not result in excess interleukin-1 activity. Arthritis Rheum 60:611-8

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