STUDY QUESTION Does having a male co-twin, older brothers, or sons lead to an increased probability of persistent male microchimerism in female members of twin pedigrees? SUMMARY ANSWER The presence of a male co-twin did not increase risk of male microchimerism and the prevalence of male microchimerism was not explained by having male offspring or by having an older brother. WHAT IS KNOWN ALREADY Microchimerism describes the presence of cells within an organism that originate from another zygote and is commonly described as resulting from pregnancy in placental mammals. It is associated with diseases with a female predilection including autoimmune diseases and pregnancy-related complications. However, microchimerism also occurs in nulliparous women; signifying gaps in the understanding of risk factors contributing to persistent microchimerism and the origin of the minor cell population. STUDY DESIGN, SIZE, DURATION This cross-sectional study composed of 446 adult female participants of the Netherlands Twin Register (NTR). PARTICIPANTS/MATERIALS, SETTING, METHODS Participants included in the study were female monozygotic (MZ) twins, female dizygotic same-sex twins and females of dizygotic opposite-sex twin pairs, along with the mothers and sisters of these twins. Peripheral blood samples collected from adult female participants underwent DNA extraction and were biobanked prior to the study. To detect the presence of male-origin microchimerism, DNA samples were tested for the relative quantity of male specific Y chromosome gene DYS14 compared to a common β-globin gene using a highly sensitive quantitative PCR assay. MAIN RESULTS AND THE ROLE OF CHANCE We observed a large number of women (26.9%) having detectable male microchimerism in their peripheral blood samples. The presence of a male co-twin did not increase risk of male microchimerism (odds ratio (OR) = 1.23: SE 0.40, P = 0.61) and the prevalence of male microchimerism was not explained by having male offspring (OR 0.90: SE 0.19, P = 0.63) or by having an older brother (OR = 1.46: SE 0.32, P = 0.09). The resemblance (correlation) for the presence of microchimerism was similar (P = 0.66) in MZ pairs (0.27; SE 0.37) and in first-degree relatives (0.091; SE 0.092). However, age had a positive relationship with the presence of male microchimerism (P = 0.02). LIMITATIONS, REASONS FOR CAUTION After stratifying for variables of interest, some participant groups resulted in a low numbers of subjects. We investigated microchimerism in peripheral blood due to the proposed mechanism of cell acquisition via transplacental blood exchange; however, this does not represent global chimerism in the individual and microchimerism may localize to numerous other tissues. WIDER IMPLICATIONS OF THE FINDINGS Immune regulation during pregnancy is known to mitigate allosensitization and support tolerance to non-inherited antigens found on donor cells. While unable to identify a specific source that promotes microchimerism prevalence within pedigrees, this study points to the underlying complexities of natural microchimerism in the general population. These findings support previous studies which have identified the presence of male microchimerism among women with no history of pregnancy, suggesting alternative sources of microchimerism. The association of detectable male microchimerism with age is suggestive of additional factors including time, molecular characteristics and environment playing a critical role in the prevalence of persistent microchimerism. The present study necessitates investigation into the molecular underpinnings of natural chimerism to provide insight into women’s health, transplant medicine and immunology. STUDY FUNDING/COMPETING INTEREST(S) This work is funded by Royal Netherlands Academy of Science Professor Award (PAH/6635 to D.I.B.); The Netherlands Organisation for Health Research and Development (ZonMw)—Genotype/phenotype database for behavior genetic and genetic epidemiological studies (ZonMw 911-09-032); Biobanking and Biomolecular Research Infrastructure (BBMRI–NL, 184.021.007; 184.033.111); The Netherlands Organisation for Scientific Research (NWO)—Netherlands Twin Registry Repository (NWO-Groot 480-15-001/674); the National Institutes of Health—The Rutgers University Cell and DNA Repository cooperative agreement (NIMH U24 MH068457-06), Grand Opportunity grants Integration of genomics and transcriptomics in normal twins and major depression (NIMH 1RC2 MH089951-01), and Developmental trajectories of psychopathology (NIMH 1RC2 MH089995); and European Research Council—Genetics of Mental Illness (ERC 230374). C.B.L. declares a competing interest as editor-in-chief of Human Reproduction and his department receives unrestricted research grants from Ferring, Merck and Guerbet. All remaining authors have no conflict-of-interest to declare in regards to this work. TRIAL REGISTRATION NUMBER N/A.

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女性男性微嵌合体：双胞胎谱系的定量研究以研究机制

研究问题 拥有男性同卵双胞胎、哥哥或儿子是否会导致双胞胎谱系的女性成员中持续存在男性微嵌合体的可能性增加？总结答案 男性同卵双胞胎的存在并没有增加男性微嵌合体的风险，并且男性微嵌合体的流行不能用有男性后代或有一个哥哥来解释。什么是已知的 微嵌合体描述了生物体内存在源自另一个受精卵的细胞，通常被描述为由胎盘哺乳动物怀孕引起的。它与女性偏爱的疾病有关，包括自身免疫性疾病和妊娠相关并发症。然而，微嵌合体也发生在未产妇女身上。表明对导致持续微嵌合体和小细胞群起源的风险因素的理解存在差距。研究设计、规模、持续时间 这项横断面研究由荷兰双胞胎登记 (NTR) 的 446 名成年女性参与者组成。参与者/材料、设置、方法 参与研究的参与者是女性同卵双胞胎 (MZ)、女性异卵同性双胞胎和异卵异性双胞胎的女性，以及这些双胞胎的母亲和姐妹。从成年女性参与者收集的外周血样本进行了 DNA 提取，并在研究前进行了生物样本库。为了检测男性来源的微嵌合体的存在，使用高度灵敏的定量 PCR 测定法测试 DNA 样本中男性特异性 Y 染色体基因 DYS14 与常见 β-珠蛋白基因的相对数量。主要结果和机会的作用 我们观察到大量女性 (26.9%) 在其外周血样本中检测到男性微嵌合体。男性同卵双胞胎的存在不会增加男性微嵌合的风险（优势比 (OR) = 1.23: SE 0.40, P = 0.61），并且男性微嵌合的流行并不能用雄性后代来解释（OR 0.90: SE 0.19 , P = 0.63) 或有一个哥哥 (OR = 1.46: SE 0.32, P = 0.09)。在 MZ 对 (0.27; SE 0.37) 和一级亲属 (0.091; SE 0.092) 中微嵌合体存在的相似性 (相关性) 相似 (P = 0.66)。然而，年龄与男性微嵌合体的存在呈正相关（P = 0.02）。限制，谨慎的原因 在对感兴趣的变量进行分层后，一些参与者组导致受试者数量较少。由于提出的通过胎盘血液交换获得细胞的机制，我们研究了外周血中的微嵌合现象；然而，这并不代表个体的全局嵌合现象，微嵌合现象可能定位于许多其他组织。研究结果的更广泛意义 众所周知，怀孕期间的免疫调节可减轻同种异体致敏并支持对供体细胞上发现的非遗传抗原的耐受性。虽然无法确定促进谱系中微嵌合现象流行的特定来源，这项研究指出了普通人群中天然微嵌合体的潜在复杂性。这些发现支持以前的研究，这些研究已经确定没有怀孕史的女性中存在男性微嵌合体，这表明微嵌合体的替代来源。可检测到的男性微嵌合体与年龄的关联暗示了其他因素，包括时间、分子特征和环境，这些因素在持续性微嵌合体的流行中起关键作用。本研究需要对自然嵌合体的分子基础进行调查，以深入了解女性健康、移植医学和免疫学。研究资助/竞争兴趣这项工作由荷兰皇家科学院教授奖 (PAH/6635 to DIB) 资助；荷兰卫生研究与发展组织 (ZonMw) - 用于行为遗传和遗传流行病学研究的基因型/表型数据库 (ZonMw 911-09-032)；生物银行和生物分子研究基础设施（BBMRI-NL，184.021.007；184.033.111）；荷兰科学研究组织 (NWO) — 荷兰双登记库 (NWO-Groot 480-15-001/674)；美国国立卫生研究院 - 罗格斯大学细胞和 DNA 存储库合作协议 (NIMH U24 MH068457-06)，大机会拨款在正常双胞胎和重度抑郁症中整合基因组学和转录组学 (NIMH 1RC2 MH089951-01)，以及精神病理学的发展轨迹（NIMH 1RC2 MH089995）；和欧洲研究委员会——精神疾病遗传学 (ERC 230374)。CBL 宣布作为 Human Reproduction 的主编存在竞争利益，他的部门从 Ferring、Merck 和 Guerbet 获得了不受限制的研究资助。所有剩余的作者都没有关于这项工作的利益冲突声明。试用注册号 不适用。