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Genetics of exceptional longevity: possible role of GM allotypes
Immunity & Ageing ( IF 5.2 ) Pub Date : 2018-11-06 , DOI: 10.1186/s12979-018-0133-8
Calogero Caruso ₁ , Janardan P Pandey ₂ , Annibale A Puca _{3,

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Affiliation

Many variables contribute to the way we age and the consequent possible achievement of extreme ages. Among these, we can include cultural, anthropological and socio-economic status as well as sex and gender (women live longer than men). Also, ethnic differences (explained by discrepancies in healthcare, environmental and economic status, genetics as well as life occupation) exist in relation to ageing/longevity. In any case, the concrete possibility to manifest a longevity phenotype is strictly related to the stochastic interactions due to accidental events, with environmental and genetic factors having a role in ageing and longevity processes. The genetic component is progressively a major determinant as we evaluate extreme ages to be reached. Indeed, the possibility to inherit longevity increases with age: for long living individuals (LLIs), which are people that belong to the top 5th percentile of life-spans (i.e. 95 years in males and 98 years in female), it reaches up to 33% for women and 48% for men [1,2,3] (https://www.ssa.gov/OACT/STATS/, under “life table”).

Genetics of exceptional longevity has been developed with different approaches depending on the available technologies and on the costs for a single analysis. Although the reduced costs have allowed more comprehensive studies, more is not always better. As an example, given the number of samples available for a given genetic analysis, the power of the study is reduced progressively as we add more hypothesises to test, to the point that the study becomes underpowered in genome-wide association studies (GWAS) [4].

In other words, there is no simple equation, such as more hypotheses = more results. Indeed, APOE ε4 allele was associated with exceptional longevity in 1994 through a candidate gene approach using a small sample size [5]. Since then, many replication attempts were successful, despite the fact that there is a strong gradient in terms of ε4 allele frequency among Northern and Southern European studies (lower in the South) [6]. APOE was so strongly associated that it came up in most GWAS for exceptional longevity, surviving the Bonferroni’s correction of the threshold of significance adopted for GWAS (p < 5 × 10^− 8). This is also true for the FOXO3A locus, while for others replication attempts were not consistent, possibly due to the multiple testing that reduced the threshold of significance [7, 8]. Thus, in the era of candidate gene studies in exceptional longevity, the limitation was not underpowered studies, but the lack of correction for genetic admixture. Indeed, stratification, which is the bias that brings to an enrichment of a specific ethnicity in one of the two arms (cases and controls) of the study, is the main cause of false positive results [4].

In an attempt to reconcile the results of different studies, statistics that included different studies (meta-analysis) was developed. Still, the non-homogeneous criteria adopted to select the two arms of a case-control study could result in conflicting results. Among the criteria that vary among the studies, it is important to mention the ages of LLIs and the young controls and gender distribution, parameters that could influence associations of genetic variants that intervene at extreme ages and with a gender effect [9].

Recently, many studies have been accomplished using chip arrays that interrogated hundreds of thousands of single nucleotide polymorphisms (SNPs,) followed by the imputation of the missing SNPs allowing a comprehensive analysis of the entire genome, with some exceptions where polymorphisms were not well represented at the chip level. Furthermore, the Bonferroni’s correction is a strong killer for genetic risk factors with small effects unless the number of individuals tested is in the tens of thousands. The LLIs are healthy individuals that are not hospitalized and are recruited by home visiting, making it difficult to reach large numbers [4].

Candidate gene studies involving the genomic regions that are not well represented in the SNP arrays are therefore welcome for the discovery of new potential associations with exceptional longevity. It is useful to adopt populations that have already been used for GWAS so as to exclude stratification effects. This is indeed the case for the study presented by Puca et al., [10] which analysed the role of genetic markers of γ chains (GM allotypes), i.e. the hereditary antigenic determinants expressed on immunoglobulin G polypeptide chains, in the attainment of longevity. In this study, the DNA samples from 95 LLIs (mean age 96.7) and 96 young controls (mean age 31.9) from South Italy were typed for GM3/17 and GM23+/− alleles, showing that GM3 allotype is significantly overrepresented in both male and female LLIs. The rs1071803 SNP that codes for the GM 3/17 (arginine/lysine) allotypes is not represented in the commonly employed genotyping platforms. It can be imputed, but the quality of imputation is poor.

Literature data show that human longevity may be correlated with optimal functioning of the immune system, so suggesting that genetic determinants of longevity also resides in those polymorphisms for the immune system genes that regulate immune responses, such as human leukocyte antigen (HLA) [11, 12]. Accordingly, several studies have examined the role of HLA antigens in longevity [11, 13]. It has been known since at least 1971 [14] that GM allotypes contribute to the interindividual differences in the magnitude of immune responsiveness, so it is not surprising that GM allotypes are seemingly associated with longevity, it is instead surprising that until now no study was performed on GM allotypes and longevity.

As first suggested by J.B.S. Haldane [15], major infectious diseases have been the principal selective forces in shaping our evolutionary history. GM allotypes have been shown to be associated with immune responsiveness to several major infectious pathogens and with survival from epidemics [16]. One mechanism for how GM determinants could contribute to the outcome of infection with various agents may be through allotype-mediated antibody responses against pathogens, resulting in differential immunity to infectious diseases. Thus, GM allotypes could participate as recognition structures for the pathogenic epitopes on B cell membranes. Additionally, and contrary to the prevalent belief in immunology, these constant-region determinants could directly influence antibody specificity by causing conformational changes in the antigen-binding site in the immunoglobulin variable region. They could also influence the expression of idiotypes involved in immunity to the pathogens. Contribution of both variable and constant regions in the formation of idiotypic determinants was documented many years ago [17].

Human population is very heterogeneous because of the different genetic background and different environmental stimuli, so it has not yet been possible to identify a clear signature of longevity with the exception of APOE and FOXOA. The study of Puca et al., [10] was performed in a very homogeneous population from South Italy, so the observed association of GM with longevity should not depend on population stratification. However, further studies are necessary to confirm this association. GM17/17 (the alternative allele of GM3) has been shown to be associated with the risk of developing HCMV symptomatic infection [18]. Considering the role of HCMV in immunosenescence [19, 20], future studies might evaluate antibodies titers directed versus HCMV in LLIs and young controls, according to GM3 allotype.

APOE:: apolipoprotein E
GM:: genetic markers of γ chains
GWAS:: genome-wide association studies
HCMV:: human cytomegalovirus
HLA:: human leukocyte antigen
LLI:: Long-living individual
SNP:: single nucleotide polymorphism

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Funding

Original work was supported by grant he study was supported by Cariplo Foundation (n.2016–0874) and by Italian Ministry of Health (Ricerca Corrente, RF-2011-02348194) to A.P. and by grant of Italian Ministry of University (PRIN: progetti di ricerca di rilevante interesse nazionale – Bando 2015 Prot 20157ATSLF “Discovery of molecular and genetic/epigenetic signatures underlying resistance to age-related diseases and comorbidities”) to AP, CC.

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Affiliations

Department of Pathobiology and Medical Biotechnologies, Section of General Pathology, University of Palermo, Corso Tukory 211, 90134, Palermo, Italy
- Calogero Caruso
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, 29425, USA
- Janardan P. Pandey
Department of Medicine and Surgery, University of Salerno, Baronissi, Italy
- Annibale A. Puca
IRCCS MultiMedica, Milan, Italy
- Annibale A. Puca

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Calogero CarusoView author publicationsYou can also search for this author in
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All the Authors contributed to write the paper and to edit it. They approved its final version.

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Correspondence to Calogero Caruso.

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Prof. Caruso is the Editor in Chief of Immunity & Ageing. The other authors declare that they have no competing interests.

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Caruso, C., Pandey, J.P. & Puca, A.A. Genetics of exceptional longevity: possible role of GM allotypes. Immun Ageing 15, 25 (2018). https://doi.org/10.1186/s12979-018-0133-8

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Received: 14 August 2018
Accepted: 19 October 2018
Published: 06 November 2018
DOI: https://doi.org/10.1186/s12979-018-0133-8

Keywords

Case control studies
GM allotypes
GWAS
Immune response
Longevity

中文翻译：

超长寿命的遗传学：转基因同种异型的可能作用

许多变量都会影响我们的衰老方式以及最终可能达到的极端年龄。其中，我们可以包括文化、人类学和社会经济地位以及性别（女性比男性寿命更长）。此外，种族差异（通过医疗保健、环境和经济状况、遗传学以及生活职业的差异来解释）也与衰老/寿命有关。无论如何，表现出长寿表型的具体可能性与偶然事件引起的随机相互作用密切相关，环境和遗传因素在衰老和长寿过程中发挥着作用。当我们评估要达到的极限年龄时，遗传因素逐渐成为一个主要的决定因素。事实上，遗传长寿的可能性随着年龄的增长而增加：对于长寿个体（LLI），即属于寿命前 5 个百分位的人（即男性 95 岁，女性 98 岁），它可以达到女性为 33%，男性为 48% [1,2,3]（https://www.ssa.gov/OACT/STATS/，“生命表”下）。

根据可用技术和单次分析的成本，人们采用不同的方法开发了超长寿遗传学。尽管成本的降低使得研究更加全面，但研究并不总是越多越好。举个例子，考虑到可用于给定遗传分析的样本数量，随着我们添加更多的假设来测试，研究的功效逐渐降低，以至于该研究在全基因组关联研究（GWAS）中变得动力不足[ 4]。

换句话说，不存在简单的等式，例如更多的假设=更多的结果。事实上，1994 年，通过使用小样本量的候选基因方法，APOE ε4 等位基因与异常长寿相关[5]。从那时起，尽管北欧和南欧研究中 ε4 等位基因频率存在很大梯度（南部较低），但许多复制尝试都取得了成功[6]。APOE 的相关性如此之强，以至于它在大多数 GWAS 中出现，具有超长的寿命，在 Bonferroni 对 GWAS 所采用的显着性阈值的校正中幸存下来 ( p < 5 × 10 ^{− 8} )。FOXO3A 基因座也是如此，而对于其他基因座，复制尝试并不一致，可能是由于多次测试降低了显着性阈值 [7, 8]。因此，在超长寿候选基因研究时代，其局限性并不是研究动力不足，而是缺乏对基因混合的校正。事实上，分层是导致假阳性结果的主要原因[4]，分层是导致研究的两个组（病例和对照）之一中特定种族丰富的偏见。

为了协调不同研究的结果，开发了包含不同研究的统计数据（荟萃分析）。尽管如此，选择病例对照研究的两个组时采用的非同质标准可能会导致相互矛盾的结果。在不同研究的标准中，重要的是要提及 LLI 的年龄和年轻对照以及性别分布，这些参数可能影响在极端年龄干预并具有性别效应的遗传变异的关联[9]。

最近，许多研究已经使用芯片阵列完成，该芯片询问了数十万个单核苷酸多态性（SNP），然后对缺失的 SNP 进行插补，从而可以对整个基因组进行全面分析，但也有一些例外，其中多态性在芯片级别。此外，Bonferroni 的校正对于遗传风险因素来说是一个强有力的杀手，而且影响很小，除非测试的人数达到数万人。LLI 是健康个体，没有住院，是通过家访招募的，因此很难接触到大量[4]。

因此，涉及 SNP 阵列中未充分代表的基因组区域的候选基因研究受到欢迎，以发现与超长寿命的新潜在关联。采用已经用于 GWAS 的人群很有用，可以排除分层效应。Puca 等人的研究确实属于这种情况，[10] 该研究分析了 γ 链（GM 同种异型）遗传标记（即免疫球蛋白 G 多肽链上表达的遗传性抗原决定簇）在实现长寿中的作用。在这项研究中，对来自意大利南部 95 名 LLI（平均年龄 96.7 岁）和 96 名年轻对照者（平均年龄 31.9 岁）的 DNA 样本进行了 GM3/17 和 GM23+/- 等位基因分型，表明 GM3 同种异型在男性和女性中均显着过高。女性 LLI。编码 GM 3/17（精氨酸/赖氨酸）同种异型的 rs1071803 SNP 并未出现在常用的基因分型平台中。它可以被估算，但估算的质量很差。

文献数据显示，人类长寿可能与免疫系统的最佳功能相关，因此表明长寿的遗传决定因素也存在于调节免疫反应的免疫系统基因的多态性中，例如人类白细胞抗原（HLA）[11， 12]。因此，多项研究探讨了 HLA 抗原在长寿中的作用 [11, 13]。至少从 1971 年起人们就知道 GM 同种异型会导致个体间免疫反应程度的差异，因此 GM 同种异型似乎与长寿相关并不奇怪，但令人惊讶的是，到目前为止还没有研究表明 GM 同种异型与长寿有关。对转基因同种异型和寿命进行了研究。

正如 JBS Haldane [15] 首次提出的那样，主要传染病一直是塑造我们进化史的主要选择力量。转基因同种异型已被证明与对几种主要传染性病原体的免疫反应以及流行病的生存有关[16]。转基因决定因素如何影响各种病原体感染的结果的一种机制可能是通过同种异型介导的针对病原体的抗体反应，从而导致对传染病的差异免疫。因此，转基因同种异型可以作为 B 细胞膜上致病表位的识别结构。此外，与免疫学中普遍认为的相反，这些恒定区决定簇可以通过引起免疫球蛋白可变区中抗原结合位点的构象变化来直接影响抗体特异性。它们还可以影响与病原体免疫有关的独特型的表达。许多年前就记录了可变区和恒定区在独特型决定簇形成中的贡献[17]。

由于不同的遗传背景和不同的环境刺激，人类群体具有很大的异质性，因此除了APOE和FOXOA之外，目前还不可能鉴定出明确的长寿特征。Puca 等人的研究 [10] 是在意大利南部的一个非常同质的人群中进行的，因此观察到的 GM 与长寿的关联不应依赖于人群分层。然而，需要进一步的研究来证实这种关联。GM17/17（GM3 的替代等位基因）已被证明与发生 HCMV 有症状感染的风险相关[18]。考虑到 HCMV 在免疫衰老中的作用 [19, 20]，未来的研究可能会根据 GM3 同种异型评估 LLI 和年轻对照中针对 HCMV 的抗体滴度。

载脂蛋白：: 载脂蛋白E
总经理：: γ链遗传标记
GWAS：: 全基因组关联研究
巨细胞病毒：: 人类巨细胞病毒
人类白细胞抗原：: 人类白细胞抗原
LLI:: 长寿个体
单核苷酸多态性：: 单核苷酸多态性

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下载参考资料

没有任何。

资金

原始工作得到了资助，他的研究得到了 Cariplo 基金会 (n.2016-0874) 和意大利卫生部 (Ricerca Corrente, RF-2011-02348194) 的资助，并得到了意大利大学部 (PRIN: progetti) 的资助di Ricerca di rilevante interesse nazionale – Bando 2015 Prot 20157ATSLF“发现抵抗年龄相关疾病和合并症的分子和遗传/表观遗传特征”）至 AP、CC。

数据和材料的可用性

不适用。

隶属关系

巴勒莫大学病理生物学和医学生物技术系普通病理科，Corso Tukory 211, 90134，巴勒莫，意大利
- 卡洛杰罗·卡鲁索
南卡罗来纳医科大学微生物学和免疫学系，查尔斯顿，SC，29425，美国
- 贾纳丹·P·潘迪
萨莱诺大学医学和外科系，巴罗尼西意大利
- 安尼巴莱·普卡
IRCCS MultiMedica，米兰，意大利
- 安尼巴莱·普卡

作者

Calogero Caruso查看作者出版物您还可以在以下位置搜索该作者：
- 考研
- 谷歌学术
Janardan P. Pandey查看作者出版物您还可以在以下位置搜索该作者：
- 考研
- 谷歌学术
Annibale A. Puca查看作者出版物您还可以在以下位置搜索该作者：
- 考研
- 谷歌学术

贡献

所有作者都为撰写和编辑这篇论文做出了贡献。他们批准了最终版本。

通讯作者

通讯作者：卡洛杰罗·卡鲁索。

道德批准并同意参与

不适用。

同意发表

不适用。

利益争夺

卡鲁索教授是《免疫与衰老》杂志的主编。其他作者声明他们没有利益冲突。

出版商备注

施普林格·自然对于已出版的地图和机构隶属关系中的管辖权主张保持中立。

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