A locus on chromosome 9p predisposes to a specific disease manifestation, acute anterior uveitis, in ankylosing spondylitis, a genetically complex, multisystem, inflammatory disease.
OBJECTIVE
Uveitis or intraocular inflammation is a major cause of visual loss. Acute anterior uveitis (AAU) affects approximately 40% of patients with ankylosing spondylitis (AS) but also affects patients with no evidence of spondylarthritis. We sought to determine whether a unique genetic region could be implicated in a specific manifestation-AAU-of a multisystem, inflammatory, genetically complex disease, AS.


METHODS
Individuals from families multiplex for AAU were genotyped at 400 markers representing the ABI PRISM linkage map MD-10, and at the HLA-B, DRB1, DQA1, DQB1, and DPB1 alleles. Among the family members with AAU, 76 affected sibpairs were analyzed (6 without concomitant AS, 12 discordant for AS, and 58 concordant for AS). Two-point and multipoint nonparametric linkage analyses were performed, and 1-parameter allele-sharing model logarithm of odds (LOD) scores were determined.


RESULTS
As previously reported for AS, linkage at the major histocompatibility complex region (chromosome 6p21) was evident, exhibiting the highest multipoint LOD score (4.96 at marker HLA-B). Strong linkage was seen at a region on chromosome 9p21-9p24, with a LOD score of 3.72 at marker D9S157. When compared with a companion cohort of AS families, the linkage at this region was found in association with AAU but not with AS. A third region on chromosome 1q23-1q31 was observed to have suggestive linkage (LOD 2.05 at marker D1S238), which overlaps with a region associated with AS.


CONCLUSIONS
This is the first study in which a genetic region for AAU has been identified by genome-wide scan. Even though AS was highly prevalent in this cohort of families, a locus at chromosome 9p21-9p24 was identified that uniquely associates with AAU. Identifying the genetic perturbation at this region may advance our understanding of the mechanisms involved in tissue-specific pathology of complex inflammatory diseases.
Martin
Tammy M
TM
Casey Eye Institute, CE-RES, Oregon Health & Science University, 3375 SW Terwilliger Boulevard, Portland, OR 97239, USA. martint@ohsu.edu
Zhang
Ge
G
Luo
Jingchun
J
Jin
Li
L
Doyle
Trudy M
TM
Rajska
Barbara M
BM
Coffman
Jessica E
JE
Smith
Justine R
JR
Becker
Matthias D
MD
Mackensen
Friederike
F
Khan
Muhammad A
MA
Levinson
Ralph D
RD
Schumacher
H Ralph
HR
Wade
N Kevin
NK
Rosenbaum
James T
JT
Reveille
John D
JD
D000208:Acute Disease; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D002896:Chromosomes, Human, Pair 6; D002899:Chromosomes, Human, Pair 9; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015235:HLA-B Antigens / Q000235:genetics; D006801:Humans; D008126:Lod Score; D008285:Major Histocompatibility Complex / Q000235:genetics; D013167:Spondylitis, Ankylosing / Q000235:genetics*; D014606:Uveitis, Anterior / Q000235:genetics*
D015235:HLA-B Antigens