Department of Medicine, McGill Centre for the Study of Host Resistance, Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada.
Hum Genet. 2010 Mar;127(3):337-48. doi: 10.1007/s00439-009-0775-x. Epub 2009 Dec 25.
The chromosomal region 10p13 has been linked to paucibacillary leprosy in two independent studies. The MRC1 gene, encoding the human mannose receptor (MR), is located in the 10p13 region and non-synonymous SNPs in exon 7 of the gene have been suggested as leprosy susceptibility factors. We determined that G396S is the only non-synonymous exon 7-encoded polymorphism in 396 unrelated Vietnamese subjects. This SNP was genotyped in 490 simplex and 90 multiplex leprosy families comprising 704 patients (47% paucibacillary; 53% multibacillary). We observed significant under-transmission of the serine allele of the G396S polymorphism with leprosy per se (P = 0.036) and multibacillary leprosy (P = 0.034). In a sample of 384 Brazilian leprosy cases (51% paucibacillary; 49% multibacillary) and 399 healthy controls, we observed significant association of the glycine allele of the G396S polymorphism with leprosy per se (P = 0.016) and multibacillary leprosy (P = 0.023). In addition, we observed a significant association of exon 7 encoded amino acid haplotypes with leprosy per se (P = 0.012) and multibacillary leprosy (P = 0.004). Next, we tested HEK293 cells over-expressing MR constructs (293-MR) with three exon 7 haplotypes of MRC1 for their ability to bind and internalize ovalbumin and zymosan, two classical MR ligands. No difference in uptake was measured between the variants. In addition, 293-MR failed to bind and internalize viable Mycobacterium leprae and BCG. We propose that the MR-M. leprae interaction is modulated by an accessory host molecule of unknown identity.
10p 染色体区域已在两项独立研究中与少菌型麻风病相关联。MRC1 基因，编码人类甘露糖受体（MR），位于 10p13 区域，该基因外显子 7 中的非同义 SNPs 被认为是麻风病易感性因素。我们确定在 396 个无关越南个体中，G396S 是唯一的外显子 7 编码的非同义多态性。该 SNP 在 490 个单纯和 90 个多发型麻风病家系中进行了基因分型，这些家系包含 704 例患者（47%少菌型；53%多菌型）。我们观察到 G396S 多态性的丝氨酸等位基因与麻风病本身（P = 0.036）和多菌型麻风病（P = 0.034）的传递显著不足。在 384 例巴西麻风病病例（51%少菌型；49%多菌型）和 399 例健康对照中，我们观察到 G396S 多态性的甘氨酸等位基因与麻风病本身（P = 0.016）和多菌型麻风病（P = 0.023）显著相关。此外，我们观察到外显子 7 编码的氨基酸单倍型与麻风病本身（P = 0.012）和多菌型麻风病（P = 0.004）显著相关。接下来，我们用三种 MRC1 外显子 7 单倍型测试了过表达 MR 构建体（293-MR）的 HEK293 细胞，以评估它们结合和内化卵清蛋白和酵母聚糖的能力，这两种是经典的 MR 配体。在变体之间未测量到摄取的差异。此外，293-MR 未能结合和内化活麻风分枝杆菌和卡介苗。我们提出，MR-M. leprae 相互作用受未知身份的辅助宿主分子调节。
