Sequence Variants in Three Loci Influence Monocyte Counts and Erythrocyte Volume
Sequence Variants in Three Loci Influence Monocyte Counts and Erythrocyte Volume
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DOI：
10.1016/j.ajhg.2009.10.005
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发表时间：
2009-11-13
影响因子：
9.8
通讯作者：
Boomsma, Dorret I.
中科院分区：
文献类型：
--
作者：
Ferreira, Manuel A. R.;Hottenga, Jouke-Jan;Boomsma, Dorret I.
血细胞参与重要的生理过程，它们的数量受到严格的调节，以维持体内平衡。关键调节机制的破坏是许多血液相关的孟德尔疾病的基础，但也有助于更常见的疾病，包括动脉粥样硬化。我们通过全基因组关联研究寻找血液性状的数量性状位点（QTL），因为这些可以为造血和疾病机制提供新的见解。我们测试了180万个变异与来自澳大利亚和荷兰人群的6015名个体中测量的13个血液学性状的关联。这些特征包括血红蛋白组成、血小板计数以及红细胞和白色细胞指数。我们确定了三个强关联的区域，据我们所知，以前没有在文献中报道。第一个位于染色体9 q31靠近LRAR 1的基因间区域，解释单核细胞计数变异的1.5%（最佳SNP rs7023923，p = 8.9 x 10（-14））。第二个位点位于染色体6p 21上，与平均细胞红细胞体积相关（rs 12661667，p = 1.2 × 10（-9），解释0.7%方差），该区域跨越5个基因，包括CCND 3，一个参与造血干细胞扩增的D-细胞周期蛋白基因家族成员。第三个区域也与红细胞体积相关，位于染色体6 q24上的基因间区域（rs 592423，p = 5.3 x 10（-9），解释0.60%方差）。所有三个基因座在1543个个体的独立小组中复制（p值分别= 0.001、9.9 x 10（-5）和7 x 10（-5））。这些QTL的鉴定为我们进一步了解造血细胞命运的调控机制提供了新的机会。
Blood cells participate in vital physiological processes, and their numbers are tightly regulated so that homeostasis is maintained. Disruption of key regulatory mechanisms underlies many blood-related Mendelian diseases but also contributes to more common disorders, including atherosclerosis. We searched for quantitative trait loci (QTL) for hematology traits through a whole-genome association study, because these could provide new insights into both hemopoeitic and disease mechanisms. We tested 1.8 million variants for association with 13 hematology traits measured in 6015 individuals from the Australian and Dutch populations. These traits included hemoglobin composition, platelet counts, and red blood cell and white blood cell indices. We identified three regions of strong association that, to our knowledge, have not been previously reported in the literature. The first was located in an intergenic region of chromosome 9q31 near LRAR1, explaining 1.5% of the variation in monocyte counts (best SNP rs7023923, p = 8.9 x 10(-14)). The second locus was located on chromosome 6p21 and associated with mean cell erythrocyte volume (rs12661667, p = 1.2 x 10(-9), 0.7% variance explained) in a region that spanned five genes, including CCND3, a member of the D-cyclin gene family that is involved in hematopoietic stem cell expansion. The third region was also associated with erythrocyte volume and was located in an intergenic region on chromosome 6q24 (rs592423, p = 5.3 x 10(-9), 0.60% variance explained). All three loci replicated in an independent panel of 1543 individuals (p values = 0.001, 9.9 x 10(-5), and 7 x 10(-5), respectively). The identification of these QTL provides new opportunities for furthering our understanding of the mechanisms regulating hemopoietic cell fate.