A common haplotype of the C-C chemokine receptor 2 gene and HLA-DRB1*0301 are independent genetic risk factors for Löfgren's syndrome.
OBJECTIVE
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 Löfgren's syndrome--a clinically and genetically distinct sarcoidosis phenotype--and, importantly, whether this association is independent of the known association with the HLA-DRB1*0301 allele.


METHODS
We investigated 5 CCR2 variants and HLA-DRB1*0301 by sequence-specific primer (SSP) polymerase chain reaction (PCR) in 176 Spanish (76 Löfgren's syndrome, 100 controls) and 387 Swedish subjects (126 Löfgren's syndrome, 77 non-Löfgren sarcoidosis, 184 controls).


RESULTS
One of the deduced haplotypes (CCR2 haplotype 2) was associated with Löfgren'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-Löfgren 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 Löfgren's syndrome (OR: 10.98, P < 0.0001 vs. non-Löfgren 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-Löfgren sarcoidosis, P = 0.001 vs. controls).


CONCLUSIONS
This study confirms that CCR2 haplotype 2 and HLA-DRB1*0301 are independent genetic risk factors for Löfgren's syndrome.
The Clinical Genomic Group, Department of Occupational and Environmental Medicine, National Heart and Lung Institute, Imperial College, London, UK. paolospagnolo@hotmail.com
P
P
Spagnolo
H
H
Sato
J
J
Grunewald
B
B
Brynedal
J
J
Hillert
J
J
Mañá
A U
AU
Wells
A
A
Eklund
K I
KI
Welsh
R M
RM
du Bois
D000208:Acute Disease; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D054390:Receptors, CCR2 / Q000235:genetics*; D012507:Sarcoidosis / Q000235:genetics*; D013030:Spain; D013548:Sweden; D013577:Syndrome; D044465:White People / Q000235:genetics; D055815:Young Adult
D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen; D054390:Receptors, CCR2