Trivedi Neil N, Tamraz Bani, Chu Catherine, Kwok Pui-Yan, Caughey George H
Cardiovascular Research Institute, University of California at San Francisco, San Francisco, Calif, USA.
J Allergy Clin Immunol. 2009 Nov;124(5):1099-105.e1-4. doi: 10.1016/j.jaci.2009.07.026. Epub 2009 Sep 12.
Mast cell tryptases have proposed roles in allergic inflammation and host defense against infection. Tryptase gene loci TPSAB1 and TPSB2 are known to be polymorphic, but the nature and extent of diversity at these loci have not been fully explored.
We sought to compare functional and nonfunctional tryptase allele frequencies and establish haplotypes in human populations.
Tryptase allele frequencies were determined by means of direct sequencing in 270 individuals from HapMap populations of European, African, Chinese, and Japanese ancestry. Haplotypes were predicted, validated in parent-child trios, and compared between populations.
We identify a new frame-shifted tryptase allele (betaIII(FS)) carried by 23% and 19% of individuals of European and African ancestry but 0% of Asian subjects. Homology models predict that betaIII(FS) is functionless. Our genotyping assay shows that allele and haplotype distributions in each population are unique. Strong linkage disequilibrium between TPSAB1 and TPSB2 (r(2)=0.83, D'=0.85) yields 2 major and 5 minor tryptase haplotypes.
Tryptase deficiency alleles (alpha and the newly discovered betaIII(FS)) are common, causing the number of inherited active genes to range from a minimum of 2 to a maximum of 4, with major differences between populations in the proportion of individuals inheriting 2 versus 4 active alleles. African and Asian populations are especially enriched in genes encoding functional and nonfunctional tryptases, respectively. Strong linkage of TPSAB1 and TPSB2 and pairing of deficiency alleles with functional alleles in observed haplotypes protect human subjects from "knockout" genomes and indeed from inheritance of fewer than 2 active alleles.
肥大细胞类胰蛋白酶在过敏性炎症和宿主抗感染防御中发挥作用。已知类胰蛋白酶基因座TPSAB1和TPSB2具有多态性，但这些基因座的多样性本质和程度尚未得到充分研究。
我们试图比较功能性和非功能性类胰蛋白酶等位基因频率，并在人群中建立单倍型。
通过直接测序确定了来自欧洲、非洲、中国和日本血统的HapMap人群的270名个体的类胰蛋白酶等位基因频率。预测单倍型，在亲子三联体中进行验证，并在人群之间进行比较。
我们鉴定出一种新的移码类胰蛋白酶等位基因（βIII(FS)），欧洲和非洲血统个体中分别有23%和19%携带该等位基因，而亚洲受试者中为0%。同源性模型预测βIII(FS)无功能。我们的基因分型分析表明，每个群体中的等位基因和单倍型分布都是独特的。TPSAB1和TPSB2之间存在强连锁不平衡（r(2)=0.83，D'=0.85），产生2种主要和5种次要类胰蛋白酶单倍型。
类胰蛋白酶缺陷等位基因（α和新发现的βIII(FS)）很常见，导致遗传的活性基因数量范围从最少2个到最多4个，不同人群中继承2个与4个活性等位基因的个体比例存在重大差异。非洲和亚洲人群分别尤其富含编码功能性和非功能性类胰蛋白酶的基因。TPSAB1和TPSB2的强连锁以及观察到的单倍型中缺陷等位基因与功能性等位基因的配对保护人类受试者免受“敲除”基因组的影响，实际上也免受少于2个活性等位基因的遗传影响。
