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

描述（由申请人提供）：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。具体来说，正常的视觉和认知发育依赖于突触和光感受器中DHA和AA的充足供应。此外，LC- PUFAs的缺乏或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疾病有关，特别是注意缺陷多动症（ADHD）和自闭症谱系障碍，以及单极和双相情感障碍。受到营养不良影响的孕妇及其发育中的胎儿以及年幼的儿童尤其容易受到影响，因为他们摄入的主食中很少或根本没有预先形成的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）可以合成的数量。奇尔顿博士的实验室与布朗博士合作进行的研究。约翰霍普金斯大学医学院的Rasika Mathias和Kathleen Barnes利用了人类多样性小组中描述的52个人群的DNA，发现人群中含有与MC-FA有效转化为LC- PUFAs相关的等位基因的差异很大。具体来说，我们的数据显示，印度在地理上处于东部人口之间，东部人口具有促进MC-FAs向LC-PUFAs转化的等位基因，而西部人口几乎没有转化能力。鉴于印度有大量儿童营养不良，了解影响印度LC-PUF合成的等位基因分布至关重要。当前R-21提案的目标是初步建立一个

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.