不安定なDNA 02


1. Introduction.

Fibromyalgia (FM), which affects at least 10 million American adults [1], is a multisymptom condition resulting in not only widespread chronic pain, but also fatigue, sleep disturbances, and morning stiffness.
線維筋痛症 (FM) はアメリカの成人の少なくとも1000万人が罹患しており、広範囲で慢性的な痛みだけでなく、疲労、睡眠障害、朝のこわばりなど多くの症状を伴う。

In addition, many patients experience depression, anxiety, and dyscognition [2, 3].

FM has a significant adverse impact on many individuals' physical and mental health [4, 5] and also leads to reduced workplace productivity and increased health care/disability expenses, with the estimated cost of FM on the US economy being reported to be 12–14 billion dollars [1, 6].

While the adverse impact of this condition is indisputable, its etiology remains enigmatic.

Due to the lack of clarity for the underlying cause(s) of FM, it poses a diagnostic challenge, often requiring multiple visits by specialists to render a diagnosis [7].
FMの原因 (複数かもしれない) の理解に明確さを欠くために診断には困難が伴い、診断を下すためにしばしば何人もの専門家が訪れる必要がある。

The lack of understanding of the biological basis of this condition also confounds our ability to develop effective interventions and/or monitor disease progression.

FM has been suggested to be a complex, multifactorial trait that is influenced by age, gender (frequency is the highest in middle-aged females), and stress/trauma.
FMは複雑で多因性であることが示唆されており、年齢、性別 (頻度は中年の女性で最も高い)、ストレス/精神的外傷に影響される。

Despite showing a strong familial aggregation [8–10], attempts to identify genetic factors associated with FM (primarily through polymorphism association studies) have yielded inconsistent results,
FMは強い家族集積性を示すが、FMに関与する遺伝的要因を同定する試み (主に多型関連研究による) は一致しない結果を生じてきた。

with some investigators showing associations between FM and specific genes

(including, but not limited to, genes for catechol-O-methyltransferase [11–13], serotonin-2A receptor [14, 15], serotonin transporter gene regulatory region [16, 17], dopamine D4 receptor [18], β-2 adrenergic receptor [19], gamma-aminobutyric acid receptor subunit beta-3, trace amine-associated receptor 1, interferon-induced guanylate-binding protein 1, regulator of G protein signaling 4, cannabinoid receptor type 1, and glutamate receptor 4 [20]),
(遺伝子には以下が含まれるがそれに限定されない。カテコール-O-メチルトランスフェラーゼ (COMT)、セロトニン-2A受容体、ドーパミンD4受容体、β-2アドレナリン受容体、ガンマアミノ酪酸 (GABA) 受容体サブユニットβ-3、微量アミン関連受容体1 (TAAR1)、インターフェロン誘導グアニル酸結合タンパク質1 (GBP1)、Gタンパク質シグナル伝達調節因子4 (RGS4)、カンナビノイド受容体1 (CB1)、グルタミン酸受容体4)、

while others failed to identify a relationship [21–25].

Since a consistent, straightforward association with a gene(s) has not yet been forthcoming, scientists have suggested that the familial influence on FM may more likely reflect a genetic susceptibility to environmental events [21, 26, 27].

For example, Klengel and Binder [28] identified differential methylation for a glucocorticoid response element (the FKBP5 gene) that resulted from the presence of both an “at-risk” allele (polymorphism) and the occurrence of childhood trauma in subjects they studied who had posttraumatic stress disorder.
例えば、PTSDの患者を研究していたKlengelとBinderは、糖質コルチコイド応答因子 (FKBP5遺伝子) のメチル化の状態に違いがあることを確認したが、それはリスクが高いアレル (多型)と、子ども時代のトラウマの出来事、その両方による結果だった。

Epigenetics, which refers to the process that affects gene expression independent of actual DNA sequence (such as methylation changes, histone alterations, and micro-RNA expression), has enabled scientists to conceptualize the impact of the environment upon one's genes and one's health [29].
エピジェネティクスは、実際のDNA配列とは独立して遺伝子発現に影響する過程 (例えばメチル化の変化、ヒストンの修飾、マイクロRNAの発現のような) を表し、それにより科学者は個々人の遺伝子と健康へ環境が与える影響を概念化することが可能になっている。

Genes can be turned on or off and display variations in their level of expression, in part, due to epigenetic modifications [30].

Thus, epigenetics provides a biological means for understanding the molecular processes of complex biological networks that connect the brain, behavior, and health outcomes [31].

Given the overlap in symptoms and the medical/adverse social histories present in people who have FM, when compared to other conditions that have been shown to be impacted by somatic epigenetic and genetic alterations (such as depression and stress), it is plausible that similar epigenetic mechanisms may underlie the individual variability in the outcome of genetic and emotional inputs for FM.
FMの人々に症状と社会歴 (医学的/社会的な) の重複が存在すると仮定すると、肉体的な変化、エピジェネティックな変化、または遺伝的な変化によって影響を受けることが示されている他の病的状態 (うつ状態やストレスのような) と比較される時に、同様のエピジェネティックなメカニズムが「FMへの遺伝的で感情的な入力」の結果において個人が差異を示すことの根底にあるかもしれないとするのは、もっともらしく思われる。

social history: 社会歴。患者が経験してきた様々な環境。出生地、発育、職業、収入、家族構成、習慣や趣味、性的嗜好、旅行歴など

Knowing that histone and other epigenetic modifications play a key role in establishing and maintaining chromatin structure, it follows that changes in epigenetic profiles, as a consequence of initiating events (such as stress/environmental exposure), could also lead to an increased frequency of somatic chromosomal changes.
染色体の構造を確立して維持する際にヒストンと他のエピジェネティックな修飾が重要な役割を演じると知れば、始まりの出来事 (ストレス/環境への曝露) の結果として起きるエピジェネティックな状態における変化は、当然、体細胞の染色体の変化の頻度の増加にもつながり得るということになる。

※it follows from/that… : 当然…ということになる

Indeed, we have shown that stress levels can impact the frequency of acquired chromosomal abnormalities by demonstrating a significantly increased frequency of somatic cell chromosomal instability in adult women who experienced childhood sexual abuse when compared to their identical cotwins who did not experience childhood sexual abuse (quantified using a micronucleus assay) [32].
それは幼児期の性的虐待を経験した成人女性では、一卵性双生児の性的虐待を経験していないもう片方と比較して、体細胞の染色体の不安定さの頻度が明らかに増加することを証明することによる (小核分析法により定量化)。

Further support that chromosomal instability could arise as a downstream effect following perturbations in methylation comes from studies of individuals who have immunodeficiency, centromeric region instability, and facial anomalies (ICF) syndrome, which is an autosomal recessive condition resulting from a mutation in the methyltransferase gene 3B.
メチル化の異常に続いて起きる下流の影響として染色体の不安定性が上昇し得るという考えは、「免疫不全・セントロメア領域不安定性・顔貌異常 (ICF) 症候群」の患者の研究からさらに支持される。
ICF症候群は、メチル基転移酵素3B (DNMT3B) 遺伝子の変異による結果として起きる常染色体の劣性遺伝性の異常である。

※immunodeficiency, centromeric region instability, and facial anomalies (ICF) syndrome: ICF症候群。B細胞は存在するが、免疫グロブリンが低下または欠損する

People with this condition have an increased frequency of acquired chromosomal abnormalities [33].

An efficient means for quantifying the frequency of acquired (somatic) chromosomal abnormalities is the cytokinesis block micronucleus (CBMN) assay, which provides information regarding the presence of chromosomal errors in somatic cells with minimal influences attributable to in vitro selective growth pressures [34].
後天的な体細胞の染色体異常の頻度を定量化するための効果的な方法は「細胞質分裂阻害小核 (CBMN) 分析法」である。
これは体細胞の染色体異常の存在を評価するための情報を提供しながら、影響は最小で済む (この影響はin vitroで選択的に細胞を成長させるための圧力が原因)。

This technique is less labor intensive than conventional cytogenetic studies but provides results that are in close agreement to those obtained using the “gold standard” of metaphase chromosomal analyses [35].

※metaphase: 細胞分裂の中期。染色体が最も凝縮して、紡錘体内の中央部に並ぶ

Micronuclei, which are the primary cytological structures scored in the CBMN assay, are thought to contain chromatin (from one or more chromosomes) that was not incorporated (“lagging” or “lost”) into the daughter binucleates following nuclear division [34].
これは一つまたはそれ以上の染色体 (「遅れた」か「失われた」) を含むと考えられ、細胞分裂後の娘細胞の二つの核へ組み込まれなかったものである。

Micronuclei frequencies have been shown to increase with age and have been associated with a variety of health conditions [36, 37].

However, to date, no investigators have reported the frequency of MN in women with FM.
しかし、今までFMの女性における小核 (MN) の頻度を報告した調査は存在しない。

Based on the symptomatology and comorbidities related to this condition, we hypothesized that women with FM will have an increased frequency of acquired epigenetic and chromosomal alterations.

※comorbidity: 共存症。同時に存在するが、互いに無関係な病気

To test this hypothesis, we initiated a pilot study to quantify chromosomal instability levels and genome-wide methylation patterns in women having FM and to compare these genetic/epigenetic values to those present in comparably aged, healthy control women.

by travelair4000ext | 2014-02-05 17:00 | 翻訳  

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