Haplotype-based identification of a microsomal transfer protein marker associated with the human lifespan
Haplotype-based identification of a microsomal transfer protein marker associated with the human lifespan
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DOI：
10.1073/pnas.1936249100
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发表时间：
2003-11-25
影响因子：
11.1
通讯作者：
Puca, AA
中科院分区：
文献类型：
--
作者：
Geesaman, BJ;Benson, E;Puca, AA
我们以前报道了一个全基因组的人类长寿连锁研究，使用308长寿的个人（LLI）（百岁老人或近百岁老人）在137个同胞，并确定了4号染色体内的微卫星D4 S1564附近的统计学显着的连锁。这一区间跨越1200万bp，包含大约50个推定基因。为了确定影响寿命的特定基因和基因变异，我们对该区间进行了基于单体型的精细定位研究。由此产生的遗传关联研究确定了微粒体转移蛋白中的单倍型标记作为人类寿命的修饰剂。在法国的第二个LLI队列中测试了相同的变体，尽管这种关联没有被复制，但有证据表明Hardy-Weinberg不平衡形式的统计失真。微粒体转移蛋白已被确定为脂蛋白合成的限速步骤，并可能通过微妙地调节这一途径影响寿命。这项研究为使用LLI的基因组来鉴定影响寿命的基因的可行性提供了概念证明。
We previously reported a genomewide linkage study for human longevity using 308 long-lived individuals (LLI) (centenarians or near-centenarians) in 137 sibships and identified statistically significant linkage within chromosome 4 near microsatellite D4S1564. This interval spans 12 million bp and contains approximate to50 putative genes. To identify the specific gene and gene variants impacting lifespan, we performed a haplotype-based fine-mapping study of the interval. The resulting genetic association study identified a haplotype marker within microsomal transfer protein as a modifier of human lifespan. This same variant was tested in a second cohort of LLI from France, and although the association was not replicated, there was evidence for statistical distortion in the form of Hardy-Weinberg disequilibrium. Microsomal transfer protein has been identified as the rate-limiting step in lipoprotein synthesis and may affect longevity by subtly modulating this pathway. This study provides proof of concept for the feasibility of using the genomes of LLI to identify genes impacting longevity.