Effect of FADS gene variants on fatty acid synthesis & brain development in India

描述(申请人提供)：长链多不饱和脂肪酸(LC-PUFA)，如二十二碳六烯酸(DHA)和花生四烯酸(AA)对大脑和眼睛发育至关重要。具体地说，正常的视觉和认知发育依赖于突触和光感受器中充足的DHA和AA供应。此外，缺乏LC-PUFAs或I-3和I-6脂肪酸之间的不平衡与许多行为异常以及儿童和成人的神经和精神障碍有关，特别是注意力缺陷多动(ADHD)和自闭症谱系障碍，以及单相和双相情感障碍。孕妇及其发育中的胎儿以及受营养不良影响的幼儿特别容易受到影响，因为她们摄入的主食中很少或根本没有预制的DHA或AA。在这种情况下，循环中发现的LC-PUFAs的数量取决于中链植物性脂肪酸(MC-FA)的合成能力。奇尔顿博士的实验室与约翰霍普金斯大学医学院的Rasika Mathias博士和Kathen Barnes博士合作进行的研究利用了人类多样性小组中描述的52个种群的DNA，发现在那些包含与MC-FA有效转化为LC-PUFA相关的等位基因的种群中，存在着巨大的差异。具体地说，我们的数据显示，印度位于东部具有促进MC-FA向LC-PUFA转化的等位基因的种群和西部几乎没有转化能力的种群之间。鉴于印度有大量儿童暴露于营养不良，了解影响全印度LC-PUF合成的等位基因分布是至关重要的。目前R-21提案的目标是初步建立一个 维克森林大学健康科学研究所(WFUHS)与印度曼加罗尔的NITTE大学/AB Shetty牙科科学纪念研究所(ABSMIDS)/K.S.Hegde医学院(Kshema)合作开展的一项研究项目，旨在建立基础设施，以分析印度南部卡纳塔克邦沿海城市芒格洛尔人群的脂肪酸营养状况、循环脂肪酸水平和FADS基因簇中的等位基因频率。同时，为了准备在印度人口众多的中心分析DNA和循环脂肪酸的更重要的项目(随后的R01)，我们将为来自印度NITTE大学生物化学系、KSHEMS和印度芒格洛尔ABSMID的研究人员和博士生提供培训机制，培训领域包括人类基因组学的公共卫生方面、营养和大脑发育受损的后果、检测SNPs所需的分子和统计技术、基因/表型关联以及侧重于脂肪酸的食品和血脂分析方法。总而言之，这将创造一个肥沃的当地学术环境和一个经过验证的基础设施，需要更好地了解不同的印度人如何合成对大脑和眼睛发育至关重要的脂肪。 公共卫生相关性：营养不良是东南亚，特别是印度的婴幼儿的一个主要公共卫生问题。我们建议培训印度科学家，使用遗传和生化标记的组合来了解印度多样化人口如何制造脂肪，以及对大脑和眼睛发育至关重要的营养脂肪酸需求，以便在一个拥有全球1.5亿营养不良儿童三分之一的国家对抗脂肪营养不良。

DESCRIPTION (provided by applicant): Long-chain polyunsaturated fatty acid (LC-PUFA), such as docosahexaenoic acid (DHA) and arachidonic acid (AA) are vital for brain and eye development. Specifically, normal visual and cognitive development is dependent on an adequate supply of DHA and AA in synapses and photoreceptors. Additionally, a lack of LC- PUFAs or an imbalance between I-3 and I-6 fatty acids, has been associated with a number of behavioral abnormalities, as well as neurological and psychiatric disorders in both children and adults, particularly attention-deficit hyperactivity (ADHD) and autism spectrm disorders, and unipolar and bipolar disorders. Pregnant mothers and their developing fetuses as well as young children who are impacted by malnutrition are particularly vulnerable because the staple foods they ingest have little or no preformed DHA or AA. Under such circumstances, the amount of LC-PUFAs found in circulation depends on that which can be synthesized from medium chain plant-based fatty acids (MC-FA). Studies from Dr. Chilton's laboratory in collaboration with Drs. Rasika Mathias and Kathleen Barnes at Johns Hopkins University School of Medicine have utilized DNA from the 52 populations described in the Human Diversity Panel and found that there are dramatic differences in populations with regard to those which contain alleles associated with efficient conversion of MC-FA to LC- PUFAs. Specifically, our data reveal that India sits geographically between populations to the east that have the alleles that facilitate the conversion of MC-FAs to LC-PUFAs and populations to the west of that have little capacity for conversion. Given, the high number of children exposed to malnutrition within India, it is vital to understand the distribution of alleles that impact LC-PUF synthesis throughout India. The objective of the current R-21 proposal is to initially establish a collaborative research program between Wake Forest University Health Sciences (WFUHS) and NITTE University/AB Shetty Memorial Institute of Dental Sciences (ABSMIDS)/K.S. Hegde Medical Academy (KSHEMA), Mangalore, India to put in place the infrastructure to analyze fatty acid nutritional status circulating fatty acid levels and allele frequencies in the FADS gene cluster in populations in the coastal city of Mangalore in the State of Karnataka in Southern India. Simultaneously in preparation for a more significant program for analyzing DNA and circulating fatty acids in large population centers of India (a subsequent R01), we will provide training mechanisms for investigators and PhD candidates from the Department of Biochemistry at NITTE University, KSHEMS and ABSMIDS, Mangalore, India in the areas of public health aspects of human genomics, nutrition and the consequences of impaired brain development, in the molecular and statistical techniques necessary to examine SNPs, genotypic/phenotypic associations and in methods involved in the analysis of food and blood lipids focusing on fatty acids. Together this will create a fertile local academic environment and a proven infrastructure needed to better understand how diverse Indian populations synthesize fats that are critical for brain and eye development. PUBLIC HEALTH RELEVANCE: Malnutrition is a major public health problem among infants and young children in Southeast Asia, especially India. We propose to train Indian scientist to use a combination of genetic and biochemical markers to understand how the diverse Indian populations make fats and the nutritional fatty acid requirements that are important in brain and eye development, in order combat fat malnutrition in a country that has 1/3 of the 150 million malnourished children in the world.