Whole Exome Sequencing Identified Two Single Nucleotide Polymorphisms of Human Leukocyte Antigen-DRB5 in Familial Sarcoidosis in China.

BACKGROUND

Sarcoidosis is a multisystem granulomatous disorder whose etiology is related to genetic and immunological factors. Familial aggregation and ethnic prevalence suggest a genetic predisposition and inherited susceptibility to sarcoidosis.

OBJECTIVE

This study aimed to identify suspected risk loci for familial sarcoidosis patients.

METHODS

We conducted whole exome sequencing on two sarcoidosis patients and five healthy family members in a Chinese family for a case-control study. The two sarcoidosis patients were siblings who showed chronic disease.

RESULTS

The Gene Ontology results showed single nucleotide polymorphisms in three genes, including human leukocyte antigen (, associated with both 'antigen processing and presentation' and 'regulation of immune response.' Sanger sequencing verified two nonsynonymous mutations in (rs696318 and rs115817940) located on 6p21.3 in the major histocompatibility complex (MHC) class II beta 1 region. The structural model simulated on Prot- Param protein analysis by the Expert Protein Analysis System predicted that the hydropathy index changed at two mutation sites (rs696318: p.F96L, -1.844 to -1.656 and rs115817940: p.T106N, -0.322 to -0.633), which indicated the probability of changes in peptide-binding selectivity.

CONCLUSION

Our results indicated that two nonsynonymous mutations of have been identified in two sarcoidosis siblings, while their healthy family members do not have the mutations. The two alleles may influence genetic susceptibility and chronic disease progression through peptide mutations on the MHC class II molecule among the two affected family members.