Kim Eun Jin, Kim Kyung Mee, Park Sun Ha, Kim Jong Sik, Lee Won Kee, Cha Sung Ick, Kim Chang Ho, Kang Young Mo, Han Sung Beom, Jung Tae Hoon, Park Jae Yong
Department of Internal Medicine, Kyungpook National University Hospital, Samduk 2 Ga 50, Daegu, 700-412, South Korea.
Biochem Genet. 2008 Aug;46(7-8):506-19. doi: 10.1007/s10528-008-9166-6. Epub 2008 May 27.
The solute carrier family 11 member 1 (SLC11A1) protein plays important roles in macrophage activation and displays pleiotropic effects on various macrophage functions, including the regulation of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and oxidative burst. Considering the important roles of macrophage in the pathogenesis of chronic obstructive pulmonary disease (COPD), we hypothesized that the SLC11A1 gene may act as a low-penetrance susceptibility gene for COPD. To test this hypothesis, we first examined the frequencies of 12 candidate polymorphisms in the SLC11A1 gene in 27 healthy Korean individuals, and then genotyped 3 haplotype-tagging polymorphisms [IVS4 + 14G > C (rs3731865), D543 N (rs17235409), and ()86A > G (rs1059823)] in 83 COPD patients and 203 healthy controls. Individuals with at least one variant allele of the D543 N and ()86A > G polymorphisms were at a significantly increased risk for COPD compared with carriers with each homozygous wild-type allele [adjusted odds ratio (OR) = 2.23, 95% confidence interval (CI) = 1.24-4.02, P = 0.007; and adjusted OR = 1.92, 95% CI = 1.10-3.35, P = 0.022, respectively]. Consistent with the findings of the genotyping analysis, the 122 haplotype carrying both the 543 N and ()86G alleles was associated with a significantly increased risk for COPD compared with the 111 haplotype with the 542D and ()86A alleles (adjusted OR = 2.05, 95% CI = 1.19-3.51, P = 0.009 and Bonferroni corrected P = 0.027). These findings suggest that the SLC11A1 polymorphisms could be used as markers for genetic susceptibility to COPD. However, further studies with large numbers of subjects are needed to confirm our findings.
溶质载体家族11成员1（SLC11A1）蛋白在巨噬细胞激活中发挥重要作用，并对多种巨噬细胞功能表现出多效性影响，包括对肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）的调节以及氧化爆发。鉴于巨噬细胞在慢性阻塞性肺疾病（COPD）发病机制中的重要作用，我们推测SLC11A1基因可能作为COPD的低 penetrance 易感性基因。为了验证这一假设，我们首先检测了27名健康韩国个体中SLC11A1基因12个候选多态性的频率，然后对83名COPD患者和203名健康对照者进行了3个单倍型标签多态性[IVS4 + 14G > C（rs3731865）、D543N（rs17235409）和（）86A > G（rs1059823）]的基因分型。与每个纯合野生型等位基因携带者相比，具有D543N和（）86A > G多态性至少一个变异等位基因的个体患COPD的风险显著增加[调整后的优势比（OR） = 2.23，95%置信区间（CI） = 1.24 - 4.02，P = 0.007；调整后的OR = 1.92，95% CI = 1.10 - 3.35，P = 0.022]。与基因分型分析结果一致，携带543N和（）86G等位基因的122单倍型与携带542D和（）86A等位基因的111单倍型相比，患COPD的风险显著增加（调整后的OR = 2.05，95% CI = 1.19 - 3.51，P = 0.009，Bonferroni校正后P = 0.027）。这些发现表明SLC11A1多态性可作为COPD遗传易感性的标志物。然而，需要更多受试者的进一步研究来证实我们的发现。
