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 从历史上看 由于传染病而导致的严重疾病以及婴儿死亡率超过两次 在阿拉斯加其他地区。我们已经表明，负责这些健康差异的因素之一是 肉碱棕榈酰转移酶1A（CPT1A）基因（C.1436C> T; P.P479L）中的单核苷酸变体，其中 我们命名了CPT1A的北极变体。北极变体首先在阿拉斯加本地鉴定 在实施扩展的新生儿筛查后，2003年的人口 光谱法，已被证明是Yup'ik和Inupiaq中CPT1A基因的最常见形式 阿拉斯加西部和北部阿拉斯加的土著人（基因频率= 0.7）以及其他土著 加拿大，格陵兰和西伯利亚的北极人口。自从最初发现它以来，已经有多种 在阿拉斯加和加拿大所做的努力，以了解与 北极变体。尽管学到了很多东西，但我们的知识仍然存在很大的差距。高 北极种群中北极变体的患病率是阳性遗传选择的结果，假设 对生活在寒冷环境中的人们和消耗传统的人的有益影响产生 富含N-3多不饱和脂肪酸（N-3 PUFAS）的生存饮食。有益的健康影响 在阿拉斯加西部和格陵兰的成年人中证明，这与我们的观察结果形成鲜明对比 具有两份北极变体副本的婴儿有传染病的风险增加，婴儿 死亡。我们认为，北极变体的有害影响是饮食变化的结果， 包括减少富含N-3 PUFA的传统食物的摄入量。我们假设N-3 PUFA状态 修改了变体的健康影响，以便与纯合性有关的风险 N-3 PUFA水平最高的婴儿将最低。为了检验这一假设，我们组装了 来自阿拉斯加本地医学中心和俄勒冈健康与科学大学的调查人员团队，与PIS 在每个位置，要对阿拉斯加本地儿童进行一项前瞻性队列研究，该研究将开始产前开始 并继续生命的前两年。在AIM 1中，我们将前瞻性地描述 阿拉斯加本地婴儿的CPT1A北极变体。 AIM 2将通过 评估N-3 PUFAS前和产后接触对CPT1A北极健康影响的影响 变体。在AIM 3中，AIM 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CPT1A基因型，N-3 PUFA和其他风险因素对感染性的贡献 与疾病有关的婴儿结局。主要研究目标是将结果转化为基于证据的 通过新生儿筛查确定的婴儿的建议，以具有CPT1A北极变体的两份副本。