Sarcoidosis HLA class II genotyping distinguishes differences of clinical phenotype across ethnic groups

Abstract

The HLA class II (DRB1 and DQB1) associations with sarcoidosis have been studied by several groups but often without consistent results. In this paper, we consider the hypothesis that observed inconsistencies relate to distinct, genetically encoded disease phenotypes which differ in prevalence between centres. We therefore typed HLA-DRB1 and DQB1 in 340 UK, 139 Dutch and 163 Japanese sarcoidosis patients and, respectively, 354, 218 and 168 healthy controls from these populations. We applied consistent phenotyping and genotyping and investigated associations between HLA class II alleles and distinct disease phenotypes within and between ethnic groups. DRB1*01 and DQB1*0501 are protective against all manifestations of sarcoidosis. Lung-predominant sarcoidosis is associated with DRB1*12 and *14. Löfgren's syndrome is a common sarcoidosis phenotype in the Dutch and is strongly associated with the DRB1*0301 allele. This phenotype is not seen among the Japanese in whom DRB1*0301 is absent. The same allele is protective for UK uveitis. Sarcoid uveitis is common in Japan. The DRB1*04-DQB1*0301 haplotype is a risk factor for this disease manifestation in Japanese and UK subjects but protective for sarcoidosis overall. We show that distinct sarcoidosis phenotypes have similar genetic associations across ethnic groups. The disease case mix differs between centres and may be explained by different ethnic allelic frequencies.

Figure 1.

Associations between HLA-DRB1 alleles and overall sarcoidosis in UK, Dutch and Japanese populations. In all three groups, DRB1*12 shows a positive association and DRB1*01 a negative association. DRB1*0301, DRB1*1401/02 and DRB1*0401–DQB1*0301 show different associations in the three groups.

Figure 2.

Associations between HLA-DRB1 alleles and lung-predominant sarcoidosis in UK, Dutch and Japanese populations. DRB1*1401/2 shows a positive association and DRB1*01 a negative association in all three groups. DRB1*12 shows a positive association in UK and Japanese populations. None of these groups had an association with DRB1*11.

Figure 3.

Carriage frequencies of DRB1*0301 in UK and Dutch sarcoidosis patients and controls. In the Dutch cohort, overall sarcoidosis (P < 0.001) and Löfgren's syndrome (P < 0.0001) were significantly increased compared with controls. In the UK cohort, sarcoidosis with uveitis was significantly less common than in the control groups (P < 0.001). However, after excluding Löfgren's syndrome and uveitis, there were no significant differences between lung-predominant sarcoidosis and controls in both the UK and Dutch cohorts.

Figure 4.

A proposed schema for the genetic subtypes of sarcoidosis. DRB1*01 and DQB1*0501 are protective for overall sarcoidosis. The DRB1*0401–DQB1*0301 haplotype is protective for sarcoidosis overall but a risk factor for uveitis as shown. Within sarcoidosis, DRB1*0301–DQB1*0201 is associated with Löfgren's syndrome. Lung sarcoidosis is associated with both DRB1*12 and *1401/2. DRB1*0803 is a risk factor not only for uveitis, but also for neurological and cardiac sarcoidosis. Splenomegaly is associated with DRB1*0602 (45).