Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Aging Cell. 2012 Jun;11(3):475-81. doi: 10.1111/j.1474-9726.2012.00808.x. Epub 2012 Mar 27.
A mutation in the LMNA gene is responsible for the most dramatic form of premature aging, Hutchinson-Gilford progeria syndrome (HGPS). Several recent studies have suggested that protein products of this gene might have a role in normal physiological cellular senescence. To explore further LMNA's possible role in normal aging, we genotyped 16 SNPs over a span of 75.4 kb of the LMNA gene on a sample of long-lived individuals (LLI) (US Caucasians with age ≥ 95 years, N=873) and genetically matched younger controls (N=443). We tested all common nonredundant haplotypes (frequency ≥ 0.05) based on subgroups of these 16 SNPs for association with longevity. The most significant haplotype, based on four SNPs, remained significant after adjustment for multiple testing (OR=1.56, P=2.5 × 10(-5) , multiple-testing-adjusted P=0.0045). To attempt to replicate these results, we genotyped 3619 subjects from four independent samples of LLI and control subjects from (i) the New England Centenarian Study (NECS) (N=738), (ii) the Southern Italian Centenarian Study (SICS) (N=905), (iii) France (N=1103), and (iv) the Einstein Ashkenazi Longevity Study (N= 702). We replicated the association with the most significant haplotype from our initial analysis in the NECS sample (OR=1.60, P=0.0023), but not in the other three samples (P > 0.15). In a meta-analysis combining all five samples, the best haplotype remained significantly associated with longevity after adjustment for multiple testing in the initial and follow-up samples (OR=1.18, P=7.5 × 10(-4) , multiple-testing-adjusted P=0.037). These results suggest that LMNA variants may play a role in human lifespan.
LMNA 基因突变是导致最显著的早老症形式——哈钦森-吉尔福德早衰综合征（HGPS）的原因。最近的几项研究表明，该基因的蛋白质产物可能在正常生理细胞衰老中发挥作用。为了进一步探索 LMNA 在正常衰老中的可能作用，我们在一个长寿个体样本（LLI）（美国白种人，年龄≥95 岁，N=873）和遗传匹配的年轻对照组（N=443）上对 LMNA 基因的 16 个 SNP 进行了基因分型，跨度为 75.4 kb。我们根据这 16 个 SNP 的亚组测试了所有常见的非冗余单倍型（频率≥0.05）与长寿的相关性。基于这四个 SNP 的最显著单倍型，在经过多重检验调整后仍然显著（OR=1.56，P=2.5×10(-5)，多重检验调整 P=0.0045）。为了尝试复制这些结果，我们对来自四个独立的 LLI 和对照组样本的 3619 名受试者进行了基因分型，这些样本来自（i）新英格兰百岁老人研究（NECS）（N=738），（ii）意大利南部百岁老人研究（SICS）（N=905），（iii）法国（N=1103），和（iv）爱因斯坦阿什肯纳兹长寿研究（N=702）。我们在最初的分析中复制了与最显著单倍型的关联，该单倍型与 NECS 样本中的关联（OR=1.60，P=0.0023），但在其他三个样本中没有关联（P>0.15）。在一项结合了所有五个样本的荟萃分析中，在最初和随访样本中经过多重检验调整后，最佳单倍型仍然与长寿显著相关（OR=1.18，P=7.5×10(-4)，多重检验调整 P=0.037）。这些结果表明，LMNA 变体可能在人类寿命中发挥作用。
