Diet and the CPT1A arctic variant: Impact on the Health of Alaska Native Children

项目总结 来自阿拉斯加西部和北部的阿拉斯加土生土长的婴儿历史上发病率最高 曾经有过因传染病引起的严重疾病的记录，以及两倍以上的婴儿死亡率 在阿拉斯加的其他地方。我们已经证明，造成这些健康差距的因素之一是 肉碱棕榈酰转移酶1A(CPT1A)基因的单核苷酸变异(c.1436C和gt；T；p.P479L)，其 我们已经将CPT1a命名为北极变种。北极变种首先在阿拉斯加原住民中被发现 2003年实施扩大新生儿串联质量筛查后的人口 已被证明是尤普伊克人和伊努皮亚克人中最常见的CPT1A基因形式 阿拉斯加西部和北部的阿拉斯加原住民(基因频率=0.7)，以及其他土著 加拿大、格陵兰岛和西伯利亚的北极种群。自从它第一次被发现以来，已经有了各种各样的 在阿拉斯加和加拿大进行的努力，以了解与 北极变种。尽管已经学到了很多，但我们的知识仍然存在很大差距。高潮 北极变异在北极人群中的流行是积极基因选择的结果，假设为 对生活在寒冷环境中的人们产生了有益的影响，消费了传统的 富含n-3多不饱和脂肪酸(n-3多不饱和脂肪酸)的自给饮食。有益健康的影响一直是 在阿拉斯加西部和格陵兰岛的成年人身上显示，这与我们的观察结果形成鲜明对比 有两个北极变种的婴儿患传染病的风险增加，婴儿 死亡率。我们认为，北极变种的有害影响是饮食变化的结果， 包括减少富含n-3多不饱和脂肪酸的传统食物的摄入量。我们假设n-3PUFA状态 修改变异对健康的影响，以便与变异的纯合性相关联的风险 在n-3多不饱和脂肪酸水平最高的婴儿中将是最低的。为了验证这一假设，我们组装了一个 来自阿拉斯加土著医学中心和俄勒冈健康与科学大学的调查团队，具有PI 在每个地点，对阿拉斯加原住民儿童进行前瞻性队列研究，该研究将从产前开始 并继续度过生命的头两年。在目标1中，我们将前瞻性地描述以下物质对健康的影响 阿拉斯加土著婴儿的CPT1A型北极变异。目标2将通过以下方式明确测试基因饮食假说 评估出生前和出生后接触n-3多不饱和脂肪酸对北极CPT1a健康影响的影响 变种。在目标3中，来自目标1和目标2的数据将用于开发和评估风险预测模型 确定和量化CPT1A型、n-3多不饱和脂肪酸和其他风险因素对传染性疾病的影响 与疾病相关的婴儿结局。研究的主要目标是将结果转化为循证的 建议通过新生儿筛查确认的婴儿携带两份CPT1a北极变种。

PROJECT SUMMARY Alaska Native infants from Western and Northern Alaska historically have had among the highest incidences ever documented of severe illness due to infectious disease, as well as an infant mortality rate more than twice that in other parts of Alaska. We have shown that one of the factors responsible for these health disparities is a single nucleotide variant in the carnitine palmitoyltransferase 1A (CPT1A) gene (c.1436C>T; p.P479L), which we have named the arctic variant of CPT1A. The arctic variant was first identified in the Alaska Native population in 2003 following the implementation of expanded newborn screening by tandem mass spectrometry, and has been shown to be the most common form of the CPT1A gene in the Yup'ik and Inupiaq Alaska Native people of Western and Northern Alaska (gene frequency = 0.7), as well as other indigenous arctic populations in Canada, Greenland, and Siberia. Since it was first identified, there have been a variety of efforts undertaken in both Alaska and Canada to understand the potential health effects associated with the arctic variant. Although much has been learned, there remain significant gaps in our knowledge. The high prevalence of the arctic variant in arctic populations is the result of positive genetic selection, hypothesized to have resulted from beneficial effects to people living in a cold environment and consuming a traditional subsistence diet rich in n-3 polyunsaturated fatty acids (n-3 PUFAs). Beneficial health effects have been demonstrated in adults from Western Alaska and Greenland, which is in stark contrast to our observations that infants with two copies of the arctic variant are at increased risk for infectious diseases, and infant mortality. We believe that the detrimental effects of the arctic variant are a consequence of changes in diet, including reduced intake of traditional foods rich in n-3 PUFA. We hypothesize that n-3 PUFA status modifies the health effects of the variant, such that risks associated with homozygosity for the variant will be lowest in infants with the highest n-3 PUFA levels. To test this hypothesis, we have assembled a team of investigators from the Alaska Native Medical Center and Oregon Health & Science University, with PIs at each location, to undertake a prospective cohort study of Alaska Native children that will begin prenatally and continue through the first 2 years of life. In Aim 1, we will prospectively characterize the health effects of the CPT1A arctic variant in Alaska Native infants. Aim 2 will explicitly test the gene-diet hypothesis by evaluating the impact of pre- and postnatal exposure to n-3 PUFAs on the health effects of the CPT1A arctic variant. In Aim 3, data from Aims 1 & 2 will be used to develop and evaluate a risk prediction model that identifies and quantifies the contribution of CPT1A genotype, n-3 PUFAs, and other risk factors to infectious disease-related infant outcomes. The primary study objective is to translate results into evidence-based recommendations for infants identified by newborn screening to have two copies of the CPT1A arctic variant.