Sjöqvist Hugo, Brynge Martin, Tammimies Kristiina, Kuja-Halkola Ralf, Bölte Sven, Dalman Christina, Gardner Renee M, Karlsson Håkan
Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Neuroscience, Division of Psychiatry, Karolinska Institutet, Stockholm, Sweden.
Brain Behav Immun Health. 2025 Sep 12;49:101097. doi: 10.1016/j.bbih.2025.101097. eCollection 2025 Nov.
Levels of neonatal Acute Phase Proteins (APPs) have been associated with autism and schizophrenia. The relative contributions of genetic and environmental factors to variation in APP levels in the neonatal period are not known. Therefore, we used one of the largest twin samples to date to map the proportions of heritable and non-heritable factors to variations in APPs measured shortly after birth. Moreover, we investigated if any association existed between neonatal APP levels and autism, among monozygotic and dizygotic twins discordant for autism. Twins were identified and enrolled from registers and a clinical twin study of autism in Sweden. The distributions of APPs measured in dried blood spots taken a few days after birth as part of a national screening program were standardized to reduce any analytical artifacts. The additive genetic (A), common (C) and unique (E) environment components were estimated, using the ACE model, on a sample of 92 twin pairs. We included 61 autism discordant twin pairs for estimating the association between the APPs and autism, using both non-fixed (between) and fixed (within) effects regression models. For the ACE models, variations in α-2 macroglobulin, C-reactive protein, ferritin, fibrinogen, haptoglobin, serum amyloid A and serum amyloid P were all largely explained by additive genetic factors (70-90 %). Variation in tissue plasminogen activator and procalcitonin were predominantly explained by common environmental factors (60-70 %) with a negligible contribution by genetic factors. Variations in levels of tissue plasminogen activator and procalcitonin in the neonatal period appear to be mainly explained by pregnancy and birth related factors. Variations in levels of other investigated acute phase proteins were largely explained by additive genetic factors. None of the APPs exhibited any significant association with autism in discordant mono- or dizygotic twin pairs. Our findings highlight the importance of considering potential familial confounding in future studies of association between any APP and autism.
新生儿急性期蛋白（APPs）水平与自闭症和精神分裂症有关。目前尚不清楚遗传和环境因素对新生儿期APPs水平变异的相对贡献。因此，我们使用了迄今为止最大的双胞胎样本之一，来确定出生后不久测量的APPs变异中遗传和非遗传因素的比例。此外，我们还研究了在患自闭症的单卵双胞胎和双卵双胞胎中，新生儿APPs水平与自闭症之间是否存在关联。双胞胎是从瑞典的登记册和一项自闭症临床双胞胎研究中识别并招募的。作为国家筛查计划的一部分，在出生几天后采集的干血斑中测量的APPs分布进行了标准化，以减少任何分析误差。使用ACE模型，在92对双胞胎样本中估计了加性遗传（A）、共同（C）和独特（E）环境成分。我们纳入了61对自闭症不一致的双胞胎对，使用非固定（组间）和固定（组内）效应回归模型来估计APPs与自闭症之间的关联。对于ACE模型，α-2巨球蛋白、C反应蛋白、铁蛋白、纤维蛋白原、触珠蛋白、血清淀粉样蛋白A和血清淀粉样蛋白P的变异在很大程度上由加性遗传因素解释（70%-90%）。组织纤溶酶原激活剂和降钙素原的变异主要由共同环境因素解释（60%-70%），遗传因素的贡献可忽略不计。新生儿期组织纤溶酶原激活剂和降钙素原水平的变异似乎主要由妊娠和分娩相关因素解释。其他研究的急性期蛋白水平的变异在很大程度上由加性遗传因素解释。在不一致的单卵或双卵双胞胎对中，没有任何一种APPs与自闭症表现出显著关联。我们的研究结果强调了在未来任何APP与自闭症关联研究中考虑潜在家族混杂因素的重要性。
