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

饮食和 CPT1A 北极变异：对阿拉斯加原住民儿童健康的影响

• 批准号: 9214253
• 负责人: Denise A Dillard
• 金额: $ 43.74万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-13 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9214253
• 关键词: Acute; Adult; Adverse effects; Alaska; Alaska Native; Arctic Regions; British Columbia; Canada; Carbohydrates; Caring; Carnitine O-Palmitoyltransferase; Child; Child health care; Clinical; Communicable Diseases; DNA; Data; Diet; Dietary intake; Environment; Exposure to; Fasting; Food; Gene Frequency; Genes; Genotype; Glucose; Goals; Greenland; Haemophilus influenzae; Health; Health Sciences; High Prevalence; Hypoglycemia; In Vitro; Incidence; Indigenous; Infant; Infant Health; Infant Mortality; Infection; Intake; Inuits; Inupiat; Knowledge; Lead; Life; Liver; Location; Malonyl Coenzyme A; Medical center; N-3 polyunsaturated fatty acid; Names; Native-Born; Neonatal Screening; Nucleotides; Omega-3 Fatty Acids; Oregon; Outcome; PPAR alpha; Physiological; Population; Population Surveillance; Prospective cohort; Prospective cohort study; Research Personnel; Respiratory syncytial virus; Risk; Risk Estimate; Risk Factors; Siberia; Streptococcus pneumoniae; Symptoms; Testing; Transcriptional Activation; Translating; Universities; Variant; Viral; Yup' ik; age group; base; evidence based guidelines; experience; fatty acid oxidation; genetic selection; genetic variant; health disparity; high risk infant; infant outcome; ketogenesis; novel; postnatal; predictive modeling; prenatal; prospective; public health intervention; screening; stem; surveillance data; tandem mass spectrometry

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.

项目摘要 来自阿拉斯加西部和北方的阿拉斯加土著婴儿在历史上的发病率最高 有记录的严重疾病，由于传染病，以及婴儿死亡率超过两倍 在阿拉斯加的其他地方。我们已经表明，造成这些健康差距的因素之一是 肉毒碱棕榈酰转移酶1A（CPT 1A）基因（c.1436C>T; p.P479L）中的单核苷酸变体， 我们将其命名为CPT 1A的北极变体。北极变种首先在阿拉斯加原住民中被发现。 2003年实施扩大新生儿筛查后的人口 CPT 1A基因是Yup'ik和Inupiaq中最常见的基因形式 阿拉斯加西部和北方阿拉斯加的原住民（基因频率= 0.7），以及其他原住民 加拿大、格陵兰和西伯利亚的北极种群。自从它第一次被发现以来，已经有多种 在阿拉斯加和加拿大进行的努力，以了解潜在的健康影响与 北极变种虽然我们学到了很多东西，但我们的知识仍有很大差距。高 北极地区人群中北极变异的流行是积极遗传选择的结果，假设 对生活在寒冷环境中的人们产生了有益的影响， 富含n-3多不饱和脂肪酸（n-3 PUFA）的自给性饮食。有益健康的影响已经 在阿拉斯加西部和格陵兰岛的成年人中证明，这与我们的观察形成鲜明对比， 有两个北极变异体拷贝的婴儿患传染病的风险增加， mortality.我们认为北极变种的有害影响是饮食变化的结果， 包括减少摄入富含n-3 PUFA的传统食物。我们假设n-3 PUFA状态 改变变异体的健康影响，使得与变异体的纯合性相关的风险 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，我们收集了一个 来自阿拉斯加原住民医疗中心和俄勒冈州健康与科学大学的调查小组， 在每个地点，对阿拉斯加土著儿童进行一项前瞻性队列研究，该研究将在产前开始 并持续到生命的头两年。在目标1中，我们将前瞻性地描述 阿拉斯加土著婴儿的CPT 1A北极变体。目标2将明确测试基因饮食假说， 评估出生前和出生后暴露于n-3 PUFA对CPT 1A北极地区健康影响的影响 变量。在目标3中，目标1和2的数据将用于开发和评估风险预测模型， 识别和量化CPT 1A基因型，n-3 PUFA和其他风险因素对感染性疾病的贡献。 疾病相关的婴儿结局。主要研究目标是将结果转化为基于证据的 建议通过新生儿筛查确定的婴儿具有两个CPT 1A北极变体拷贝。