Association of two functional polymorphisms in the CCR5 gene with juvenile rheumatoid arthritis.
Juvenile rheumatoid arthritis (JRA) is mediated by Th1-immune responses. In children with JRA, synovial T cells express high levels of the Th1-chemokine receptor CC chemokine receptor 5 (CCR5), which has been implicated in susceptibility to rheumatoid arthritis. To test the hypothesis that genetic variation in CCR5 is associated with susceptibility to JRA, we analyzed patterns of variation in the 5'cis-regulatory region of CCR5 in 124 multiplex families from a JRA-affected sibpair registry. After sequencing the upstream region of CCR5, variants were tested for association with JRA by transmission disequilibrium testing. A single nucleotide polymorphism, C-1835T, was significantly undertransmitted to children with early-onset JRA (P<0.01). C-1835T was genotyped in 424 additional simplex and multiplex families. CCR5-1835T allele was undertransmitted in the cohort of all probands with JRA (P<0.02), as well as in those with early-onset (P<0.01) or pauciarticular JRA (P<0.05). Another variant, a 32-bp deletion in the open reading frame of CCR5 (CCR5-Delta32) was also tested in approximately 700 simplex and multiplex families. CCR5-Delta32 was also significantly undertransmitted to probands with early-onset JRA (P<0.05). Both variants are in regions under natural selection, and result in functional consequences. Our results suggest these CCR5 variants are protective against early-onset JRA.
Prahalad
S
S
Division of Immunology and Rheumatology, Department of Pediatrics, University of Utah, Salt Lake City, UT 84132-2206, USA. prahal@genetics.utah.edu
Bohnsack
J F
JF
Jorde
L B
LB
Whiting
A
A
Clifford
B
B
Dunn
D
D
Weiss
R
R
Moroldo
M
M
Thompson
S D
SD
Glass
D N
DN
Bamshad
M J
MJ
D001171:Arthritis, Juvenile / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D019713:Receptors, CCR5 / Q000235:genetics*
D019713:Receptors, CCR5