Genetic Variants Predicting Sarcoidosis Risk
Strongest Genetic Predictors for General Sarcoidosis
HLA-DRB1*1101 is the most significant genetic risk factor for sarcoidosis across both Black and White populations, with a population attributable risk of 16% in Blacks and 9% in Whites. 1
Primary HLA Class II Associations
HLA-DRB1*1101 demonstrates the strongest association with sarcoidosis susceptibility across ethnic groups, with consistent risk elevation in both African American and European American populations (P<0.01) 1
HLA-DRB1*03:01 (part of the 8.1 ancestral haplotype) is strongly associated with Löfgren's syndrome and predicts better prognosis, including disease remission and reduced need for corticosteroid treatment 2
HLA-DQB1*02:01 shows significant association with Löfgren's syndrome presentation (38% vs 18% in controls, relative risk 2.1) 3
HLA-DRB1*12 and HLA-DRB1*14 are associated with lung-predominant sarcoidosis across populations 4
Protective Alleles
HLA-DRB1*01:01, HLA-DQA1*03:01, and HLA-DQB1*03:02 function as protective factors against sarcoidosis development 2
HLA-DRB1*01 and HLA-DQB1*0501 (which are highly correlated) provide protection against all manifestations of sarcoidosis 4, 5
Novel Susceptibility Loci
rs3129888 near HLA-DRA represents a significant risk variant validated in both European American and African American populations 5
HLA-DQB1*06:02 and HLA-DQB1*06:04 have been identified as novel risk factors in Central European populations 2
HLA-DPB1*0101 (a non-E69-containing allele) contributes independently to sarcoidosis susceptibility, particularly in White populations 1
Genetic Variants Relevant to Cardiac Sarcoidosis
No specific HLA or genetic variants have been definitively associated with cardiac sarcoidosis risk in the available guideline or research evidence. The 2020 American Thoracic Society guidelines acknowledge that cardiac involvement leads to mortality through sudden cardiac death and congestive heart failure but do not identify genetic predictors specific to cardiac manifestations 6
Phenotype-Specific Associations (Non-Cardiac)
While cardiac-specific variants are not established, certain HLA alleles predict other organ involvement patterns:
HLA-DRB1*0401 associates with ocular involvement in both Black and White patients 1
HLA-DQB1*05:03 correlates with extrapulmonary manifestations generally 2
HLA-DRB1*15 relates to restrictive lung pattern and reduced diffusion capacity (relative risk 2.46) 3
HLA-DRB1*11:01 and HLA-DQA1*05:05 associate with more advanced pulmonary disease (chest X-ray stages 2-4) 2
Clinical Implications and Caveats
The 8.1 ancestral haplotype (HLA-A01:01~B08:01C*07:01DRB103:01~DQA105:01~DQB1*02:01) serves as the most clinically useful genetic marker, predicting both Löfgren's syndrome presentation and favorable prognosis. 2
Important Limitations
Genetic testing for sarcoidosis is not recommended in clinical practice for diagnosis or risk stratification, as the 2020 American Thoracic Society guidelines do not include genetic testing in their diagnostic algorithm 6
Environmental and dietary factors shared among family members may contribute to sarcoidosis risk to a similar extent as genetic factors 7
HLA associations differ substantially between ethnic groups due to varying baseline allele frequencies, not necessarily different disease mechanisms 4
The absence of HLA-DRB1*0301 in Japanese populations explains why Löfgren's syndrome is not observed in this ethnic group, despite being common in Dutch and other European populations 4