van Exel Eric, Koopman Jacob J E, Bodegom David van, Meij Johannes J, Knijff Peter de, Ziem Juventus B, Finch Caleb E, Westendorp Rudi G J
Department of Psychiatry, VU University Medical Center/GGZinGeest, Amsterdam, the Netherlands.
EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, the Netherlands.
PLoS One. 2017 Jul 6;12(7):e0179497. doi: 10.1371/journal.pone.0179497. eCollection 2017.
The apolipoprotein-ε4 allele (APOE-ε4) is strongly associated with detrimental outcomes in affluent populations including atherosclerotic disease, Alzheimer's disease, and reduced lifespan. Despite these detrimental outcomes, population frequencies of APOE-ε4 are high. We hypothesize that the high frequency of APOE-ε4 was maintained because of beneficial effects during evolution when infectious pathogens were more prevalent and a major cause of mortality. We examined a rural Ghanaian population with a high pathogen exposure for selective advantages of APOE-ε4, to survival and or fertility.
This rural Ghanaian population (n = 4311) has high levels of mortality from widespread infectious diseases which are the main cause of death. We examined whether APOE-ε4 was associated with survival (total follow-up time was 30,262 years) and fertility after stratifying by exposure to high or low pathogen levels. Households drawing water from open wells and rivers were classified as exposed to high pathogen levels while low pathogen exposure was classified as those drawing water from borehole wells. We found a non-significant, but positive survival benefit, i.e. the hazard ratio per APOE-ε4 allele was 0.80 (95% confidence interval: 0.69 to 1.05), adjusted for sex, tribe, and socioeconomic status. Among women aged 40 years and older (n = 842), APOE-ε4 was not associated with the lifetime number of children. However, APOE-ε4 was associated with higher fertility in women exposed to high pathogen levels. Compared with women not carrying an APOE-ε4 allele, those carrying one APOE-ε4 allele had on average one more child and those carrying two APOE-ε4 alleles had 3.5 more children (p = 0.018).
Contrary to affluent modern-day populations, APOE-ε4 did not carry a survival disadvantage in this rural Ghanaian population. Moreover, APOE-ε4 promotes fertility in highly infectious environments. Our findings suggest that APOE-ε4 may be considered as evolutionarily adaptive. Its adverse associations in affluent modern populations with later onset diseases of aging further characterize APOE-ε4 as an example of antagonistic pleiotropy.
载脂蛋白ε4等位基因（APOE-ε4）与富裕人群的不良后果密切相关，包括动脉粥样硬化疾病、阿尔茨海默病和寿命缩短。尽管存在这些不良后果，但APOE-ε4的人群频率却很高。我们推测，APOE-ε4的高频率得以维持是因为在进化过程中，当感染性病原体更为普遍且是主要死亡原因时，它具有有益作用。我们研究了加纳一个病原体暴露水平高的农村人群中APOE-ε4在生存和/或生育方面的选择优势。
这个加纳农村人群（n = 4311）因广泛的传染病导致高死亡率，而传染病是主要死因。我们在按高或低病原体暴露水平分层后，研究了APOE-ε4与生存（总随访时间为30262人年）和生育的关系。从露天水井和河流取水的家庭被归类为高病原体暴露，而从钻孔井取水的家庭被归类为低病原体暴露。我们发现了一个虽不显著但呈正相关的生存益处，即每个APOE-ε4等位基因的风险比为0.80（95%置信区间：0.69至1.05），对性别、部落和社会经济地位进行了调整。在40岁及以上的女性（n = 842）中，APOE-ε4与终身生育子女数无关。然而，APOE-ε4与高病原体暴露水平的女性的较高生育力相关。与未携带APOE-ε4等位基因的女性相比，携带一个APOE-ε4等位基因的女性平均多生育一个孩子，携带两个APOE-ε4等位基因的女性多生育3.5个孩子（p = 0.018）。
与富裕的现代人群相反，APOE-ε4在这个加纳农村人群中没有生存劣势。此外，APOE-ε4在高传染性环境中促进生育。我们的研究结果表明，APOE-ε4可能被认为具有进化适应性。它在富裕现代人群中与迟发性衰老疾病的不良关联进一步表明APOE-ε4是拮抗性多效性的一个例子。
