Rybicki Benjamin A, Walewski Jose L, Maliarik Mary J, Kian Hamed, Iannuzzi Michael C
Department of Biostatistics and Research Epidemiology, Henry Ford Health System, Detroit, MI, USA.
Am J Hum Genet. 2005 Sep;77(3):491-9. doi: 10.1086/444435. Epub 2005 Jul 20.
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.
BTNL2基因是B7受体家族的成员，可能作为T细胞共刺激分子发挥作用。它位于6号染色体短臂的II类主要组织相容性复合体（MHC）区域，最近在一个德国白人人群中发现其与结节病易感性相关。我们试图在一个非裔美国家庭研究人群（n = 219个核心家庭）以及两个病例对照人群中重复BTNL2基因的关联性研究，其中一个是非裔美国人病例对照人群（n = 295对），另一个是白人病例对照人群（n = 366对）。在跨越BTNL2基因第5外显子/内含子的490bp区域内检测到10个单核苷酸多态性（SNP）。该区域内的单倍型变异在所有三个研究人群中均与结节病显著相关，但在白人中（P = 0.0006）比在非裔美国人病例对照人群（P = 0.02）或家庭研究人群（P = 0.03）中更为明显。先前报道的与结节病关联性最强的BTNL2 SNP，即rs2076530，在我们的白人人群中也是关联性最强的SNP（P < 0.0001）。rs2076530的A等位基因导致外显子剪接位点提前出现，并增加结节病风险（优势比 = 2.03；95%置信区间1.32 - 3.12）。尽管rs2076530在任何一个非裔美国人样本中均与结节病无关，但包含rs2076530的一个三位点单倍型在所有三个研究样本中均与结节病相关。多变量逻辑回归分析表明，在白人中BTNL2基因的作用独立于人类白细胞抗原II类基因，但在非裔美国人中可能存在拮抗相互作用。我们的结果强调了MHC区域引发的结节病遗传风险的复杂性。
