Which genetic variants are associated with increased susceptibility to sarcoidosis in individuals of Nordic ancestry?

Genetic Susceptibility to Sarcoidosis in Nordic Ancestry

The HLA-DRB1 gene region on chromosome 6 is the strongest genetic determinant of sarcoidosis susceptibility in Nordic populations, with specific alleles (particularly DRB103, DRB101, DRB115, and DRB107) conferring either increased risk or protection depending on clinical subtype. 1, 2, 3

Primary Genetic Associations in Nordic/Scandinavian Populations

HLA Class II Genes (Strongest Evidence)

• HLA-DRB1 alleles represent the most consistently replicated genetic risk factor across multiple Scandinavian cohorts, with the MHC class II region showing the strongest association with disease susceptibility 1, 4, 3

• DRB1*03 is strongly associated with Löfgren's syndrome (the acute, self-resolving form common in Scandinavians) and paradoxically protects against chronic/persistent disease 3

• DRB1*15 significantly increases risk for persistent (non-resolving) sarcoidosis, particularly when combined with specific class I alleles 2, 3

• DRB1*01 protects against non-resolving disease across clinical subtypes 3

• DRB1*14 associates with non-resolving disease course 3

HLA Class I Genes (Independent Effects)

• HLA-B*07 independently increases risk for both persistent disease (OR 1.9) and resolving disease (OR 2.7), suggesting it influences fundamental disease susceptibility rather than just prognosis 2

• The combination A03, B07, DRB1*15 confers the highest risk for persistent disease (OR 4.7), found in 25.3% of persistent disease patients versus only 7.1% of healthy Nordic controls 2

• HLA-B*08 shows weaker associations with both resolving (OR 2.4) and persistent disease (OR 2.2), though these effects are partially secondary to linkage with DRB1 alleles 2

Additional MHC Region Variants

• SNPs in the BTNL2 and HLA-DRA regions show independent associations with sarcoidosis that are not entirely explained by linkage disequilibrium with HLA-DRB1 1

• rs3177928 (near BTNL2/HLA-DRA) associates with non-Löfgren sarcoidosis (P = 1.79E-07, OR 1.9) and disease activity (P = 0.003, OR 1.9) across four European populations including Swedish and Finnish cohorts 1

• rs3129843 shows the strongest association with Löfgren's syndrome (P = 3.44E-12, OR 3.4) in joint European analysis 1

• These SNPs function as expression quantitative trait loci (eQTL) for HLA-DRB1 and HLA-DRB5, suggesting they regulate gene expression rather than directly altering protein structure 1

Clinical Implications for Risk Assessment

Family History Evaluation

• Comprehensive three-generation family history should be obtained to identify clustering of sarcoidosis or related inflammatory conditions, as both genetic and shared environmental factors contribute to familial risk 5

• Environmental and dietary factors shared among family members may contribute to risk similarly to genetic factors, making it essential to document shared occupational and environmental exposures (beryllium, aluminum, mold, air pollution) 5

Prognostic Value of HLA Typing

• HLA typing has prognostic utility in Nordic patients: DRB103 predicts favorable outcomes even when other high-risk alleles are present, while DRB115 combinations predict chronic disease requiring long-term immunosuppression 2, 3

• The clinical influence of DRB103 dominates over DRB115, meaning patients carrying both alleles tend toward better prognosis 3

• HLA class I and class II alleles should both be evaluated for optimal risk stratification, as class I effects are more pronounced than previously recognized 2

Important Caveats

• Polygenic risk scores incorporating MUC5B and other variants show promise for interstitial lung disease risk but have not been validated specifically for sarcoidosis and should not be used in routine clinical practice 5

• The specific genetic architecture differs dramatically between Löfgren's syndrome and non-Löfgren's sarcoidosis (p = 4 × 10^-36), emphasizing that these should be considered genetically distinct entities 3

• Most of the genetic etiology remains unknown—identified variants explain only a portion of heritability, and gene-environment interactions are poorly characterized 4

• HLA associations vary substantially across ethnic groups; these Nordic-specific associations may not apply to African, Asian, or other populations 6