The BTNL2 gene and sarcoidosis susceptibility in African Americans and Whites

Abstract

The BTNL2 gene is a member of the B7 receptor family that probably functions as a T-cell costimulatory molecule. It resides in the class II major histocompatibility complex (MHC) region of chromosome 6p and has recently been associated with sarcoidosis susceptibility in a white German population. We sought to replicate the BTNL2 association in an African American family-based study population (n=219 nuclear families) and two case-control populations--one African American (n=295 pairs) and one white (n=366 pairs). Ten SNPs were detected within a 490-bp region spanning exon/intron 5 of BTNL2. Haplotype variation within this region was significantly associated with sarcoidosis in all three study populations but more so in whites (P=.0006) than in the African American case-control (P=.02) or family-based (P=.03) samples. The previously reported BTNL2 SNP with the strongest sarcoidosis association, rs2076530, was also the SNP with the strongest association in our white population (P<.0001). The A allele of rs2076530 results in a premature exon-splice site and increases risk for sarcoidosis (odds ratio=2.03; 95% confidence interval 1.32-3.12). Although rs2076530 was not associated with sarcoidosis in either African American sample, a three-locus haplotype that included rs2076530 was associated with sarcoidosis across all three study samples. Multivariable logistic regression analyses showed that BTNL2 effects are independent of human leukocyte antigen class II genes in whites but may interact antagonistically in African Americans. Our results underscore the complexity of genetic risk for sarcoidosis emanating from the MHC region.

Figure 1

Level of association between sarcoidosis and variation in the exon/intron 5 region of BTNL2 on the basis of the three-SNP haplotype window moving across the region. The three study samples analyzed include 219 African American nuclear families (blackened circles), 295 African American case-control pairs (unblackened circles), and 366 white case-control pairs (unblackened squares).

Figure 2

A, Incomplete disequilibrium (as measured by 1-D^′) between allele pairs of HLA-DRB1 and the four BTNL2 exon/intron 5 haplotype-tagging SNPs (G16043A [rs9268480], A16071G [rs2076530], G16113T, and T16165C) in whites with sarcoidosis and matched controls (n=260 pairs). B, Incomplete disequilibrium (as measured by 1-D^′) between allele pairs of HLA-DRB1 and the four BTNL2 exon/intron 5 haplotype-tagging SNPs (G16043A [rs9268480], A16071G [rs2076530], G16113T, and T16165C) in African Americans with sarcoidosis and matched controls (n=187 pairs).