Evidence for an influence of chemokine ligand 3-like 1 (CCL3L1) gene copy number on susceptibility to rheumatoid arthritis.
OBJECTIVE
There is increasing evidence that gene copy-number variation influences phenotypic variation. Chemokine ligand 3-like 1 (CCL3L1) is encoded by a variable copy-number gene, and binds to several pro-inflammatory cytokine receptors, including chemokine receptor 5 (CCR5). Considering lymphocyte recruitment by beta-chemokines is a feature of autoimmunity, and that the CCR5Delta32 variant is associated with protection to rheumatoid arthritis (RA), we hypothesised that CCL3L1 copy-number influences susceptibility to RA and type 1 diabetes (T1D).


METHODS
We measured CCL3L1 copy-number in 1136 RA cases from New Zealand (NZ) and the UK, 252 NZ T1D cases and a total of 1470 controls. All subjects were ancestrally Caucasian.


RESULTS
A copy-number higher than 2 (the most common copy number) was a risk factor for RA in the NZ cohort (odds ratio (OR) 1.34, 95% CI 1.08-1.66, p = 0.009) but not the smaller UK RA cohort (OR 1.09, 95% CI 0.75-1.60, p = 0.643). There was evidence for association in the T1D cohort (OR 1.46, 95% CI 0.98-2.20, p = 0.064) and in the combined RA/T1D cohort (OR 1.30, 95% CI 1.00-1.54, p = 0.003). Genetic interaction between CCL3L1 dosage and CCR5 genotype was found; the increased genetic risk conferred by higher CCL3L1 copy-number was ablated by a dysfunctional CCR5 (CCR5Delta32).


CONCLUSIONS
These data suggest that increased CCL3L1 expression may enhance inflammatory responses and increase the chance of autoimmune disease. Genetic interaction data were consistent with a biologically plausible model; CCR5Delta32 protects against RA and T1D by blocking signalling through the CCR5 pathway, mitigating the pro-inflammatory effects of excess CCL3L1.
McKinney
C
C
Department of Biochemistry, University of Otago, PO Box 56, Dunedin, New Zealand.
Merriman
M E
ME
Chapman
P T
PT
Gow
P J
PJ
Harrison
A A
AA
Highton
J
J
Jones
P B B
PB
McLean
L
L
O'Donnell
J L
JL
Pokorny
V
V
Spellerberg
M
M
Stamp
L K
LK
Willis
J
J
Steer
S
S
Merriman
T R
TR
D001172:Arthritis, Rheumatoid / Q000235:genetics*; D019742:Chemokines, CC / Q000235:genetics*; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D019713:Receptors, CCR5 / Q000235:genetics; D012307:Risk Factors
C492767:CCL3L1 protein, human; D019742:Chemokines, CC; D019713:Receptors, CCR5