A common haplotype of the C-C chemokine receptor 2 gene and HLA-DRB1*0301 are independent genetic risk factors for Löfgren’s syndrome

Aim. Sarcoidosis is a heterogeneous disorder with a
strong genetic influence. Genetic factors are also
thought to influence disease severity and outcome.
We sought to determine whether polymorphisms
within CCR2 gene predispose to Lo¨fgren’s syndrome
– a clinically and genetically distinct sarcoidosis phenotype
– and, importantly, whether this association is
independent of the known association with the HLADRB1*
0301 allele.
Methods. We investigated 5 CCR2 variants and HLADRB1*
0301 by sequence-specific primer (SSP)
polymerase chain reaction (PCR) in 176 Spanish (76
Lo¨fgren’s syndrome, 100 controls) and 387 Swedish
subjects (126 Lo¨fgren’s syndrome, 77 non-Lo¨fgren
sarcoidosis, 184 controls).
Results. One of the deduced haplotypes (CCR2 haplotype
2) was associated with Lo¨fgren’s syndrome in
both Spanish (OR: 2.03, uncorrected P = 0.02; permuted
P = 0.041 vs. controls) and Swedish patients
(OR: 3.02, uncorrected P = 0.0007; permuted
P = 0.0027 vs. non-Lo¨fgren sarcoidosis; OR: 2.46,
uncorrected P = 0.0005; permuted P = 0.0031 vs.
controls). HLA-DRB1*0301 allele frequency was also
increased in Spanish (OR: 3.52, P = 0.0004 vs. controls)
and Swedish patients with Lo¨fgren’s syndrome
(OR: 10.98, P < 0.0001 vs. non-Lo¨fgren sarcoidosis,
OR: 7.71, P < 0.0001 vs. controls). Finally, multivariate
analysis revealed that the CCR2 association was
independent of HLA-DRB1*0301 in both Spanish
(P = 0.02 vs. controls) and Swedish cohorts
(P = 0.002 vs. non-Lo¨fgren sarcoidosis, P = 0.001 vs.
controls).
Conclusions. This study confirms that CCR2 haplotype
2 and HLA-DRB1*0301 are independent genetic risk
factors for Lo¨fgren’s syndrome