Identification of a variant associated with adult-type hypolactasia
Identification of a variant associated with adult-type hypolactasia
复制标题
DOI：
10.1038/ng826
复制
发表时间：
2002-02-01
期刊：
影响因子：
30.8
通讯作者：
Järvelä, I
中科院分区：
文献类型：
--
作者：
Enattah, NS;Sahi, T;Järvelä, I
成人型乳糖缺乏症，也称为乳糖酶不持久性（乳糖不耐受），是一种常见的常染色体隐性疾病，由断奶后肠细胞中乳糖酶-根皮苷水解酶（LPH）活性的生理下降引起。LPH将乳糖水解成葡萄糖和半乳糖。LCT（编码LPH的基因）的编码区和启动子区的序列分析显示，没有与乳糖酶不持久性相关的DNA变异（1，2）。相关的单倍型跨越LCT，以及在杂合子中“非持久性”和“持久性”等位基因的转录水平的明显差异，表明顺式作用元件促成乳糖酶非持久性表型（3，4）。使用连锁不平衡（LD）和单倍型分析的9个扩展的芬兰家庭，我们限制了2 q21上的一个47-kb的间隔的位点。完整区域的序列分析和随后的关联分析显示，一个DNA变异体，C/T-13910，大约14 kb的LCT位点上游，完全与生化验证的乳糖酶非持久性在芬兰家庭和样本集236个人从四个不同的人群。第二个变异体，G/A（-22018），位于C/T-13910端粒的8 kb，也与236例中的229例的性状相关。1,047份DNA样本中C/T-13910变异的患病率与4个不同人群中成人型低乳症的报告患病率一致。变异体（C/T-13910）出现在远亲群体中表明它非常古老。
Adult-type hypolactasia, also known as lactase non-persistence (lactose intolerance), is a common autosomal recessive condition resulting from the physiological decline in activity of the lactase-phlorizin hydrolase (LPH) in intestinal cells after weaning. LPH hydrolyzes lactose into glucose and galactose. Sequence analyses of the coding and promoter regions of LCT, the gene encoding LPH, has revealed no DNA variations correlating with lactase nonpersistence(1,2). An associated haplotype spanning LCT, as well as a distinct difference in the transcript levels of 'non-persistence' and 'persistence' alleles in heterozygotes, suggest that a cis-acting element contributes to the lactase non-persistence phenotype(3,4). Using linkage disequilibrium (LD) and haplotype analysis of nine extended Finnish families, we restricted the locus to a 47-kb interval on 2q21. Sequence analysis of the complete region and subsequent association analyses revealed that a DNA variant, C/T-13910, roughly 14 kb upstream from the LCT locus, completely associates with biochemically verified lactase non-persistence in Finnish families and a sample set of 236 individuals from four different populations. A second variant, G/A(-22018), 8 kb telomeric to C/T-13910, is also associated with the trait in 229 of 236 cases. Prevalence of the C/T-13910 variant in 1,047 DNA samples is consistent with the reported prevalence of adult-type hypolactasla in four different populations. That the variant (C/T-13910) occurs in distantly related populations indicates that it is very old.