1、饮食和遗传因素对动脉粥样硬化的影响,qiming_,Ming Qi 祁鸣, PhD, FACMGHUGO LecturerCAP InspectorCenter for Genetic & Genomic MedicineJames Watson Institute of Genomic Sciences& Medical School of Zhejiang UniversityBGI-ShenzhenDepartment of Pathology and Lab. Med.University of Rochester Medical Center,Office：ZJU Med Schoo
2、l A-713NanoSystem Building 101,现代医学导论2014/2015级食品安全与营养专业求是科学班营养基因组学模块 2017-04-5,References,Textbook: 营养基因组学：发现通往个性化营养的途径第13章， Jim Kaput，Raymond L.Rodriguez. 祁鸣，朱心强等（译）：浙江大学出版社2011Kiran Musunuru Atherogenic Dyslipidemia: Cardiovascular Risk and Dietary Intervention. Lipids (2010) 45:907914Jinying Zha
3、o, Jack Goldberg, and Viola Vaccarino，Leukotriene A4 Hydrolase Haplotype, Diet and Atherosclerosis: A Twin Study，Atherosclerosis. 2013 Jan; 226(1): 238244.,Genetics, epigenetics and genomics for personalized nutrition,动脉粥样硬化 （Atherosclerosis）,由于脂肪、血栓、结缔组织和碳酸钙在血管（主要是动脉，但也包括静脉）沉积所造成的一种对人体有害的状态。,导致动脉粥样
4、硬化的血脂异常,多种疾病，包括超重或者肥胖、胰岛素抵抗和代谢综合症以及2型糖尿病增加冠状动脉病风险，导致动脉粥样硬化的血脂异常是它们的一个主要特征。高甘油三酯浓度、高密度脂蛋白（HDL)胆固醇水平降低以及小分子低密度脂蛋白（LDL)颗粒的增加是导致动脉粥样硬化的血脂异常的标志性特征。遗传和环境方面的决定因素都能影响这种表型。重要的一点是，环境因子促发血脂异常特点的能力可能取决于个人的遗传易感性。,Atherosclerosis,An inflammatory process resulting from the interaction between genetic and environme
5、ntal factors. Leukotrienes (白三烯) are inflammatory mediators generated from arachidonic acid (花生四烯酸), and genetic polymorphisms involved in leukotriene metabolism are implicated in atherosclerosis.,Leukotriene biosynthesis,The role of leukotrienes in atherosclerosis,Measurement for carotid intima-med
6、ia thickness (IMT),Subclinical atherosclerosis was assessed by carotid intima-media thickness (颈动脉内膜中层厚度, IMT) , an established surrogate marker for early atherosclerosisusing high resolution B-mode ultrasonography arachidonate 5-lipoxygenase activating protein (ALOX5AP ) and leukotriene A4 hydrolas
7、e (LTA4H) genes were analyzed with 32 single nucleotidepolymorphisms (SNPs) in 169 Caucasian twin pairs,Study population,The Twins Heart Study (THS) is an investigation of psychological, behavioral and biological risk factors for subclinical CVD in twins. composed of 7,369 middle-aged male-male twin
8、 pairs both of whom served in the United States military during the time of the Vietnam War without a history of symptomatic CVD and major depression 180 twin pairs (102 monozygotic and 78 dizygotic),Dietary assessment,Willett self-administered semiquantitative food frequency questionnaire, collecte
9、d dietary data for the 12 months prior to testing,Risk factor measurements,All measurements were performed in the morning after an overnight fast, and both twins in a pair were tested at the same time. A medical history and a physical exam were obtained from all twins. Weight and height were used to
10、 calculate body mass index (BMI) as weight in kilograms divided by height in meters squared. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured by mercury sphygmomanometer on the right arm with the subject in sitting position after 10 minutes of rest.,SNPs genotyping,A to
11、tal of thirty-two tagging SNPs, including nineteen in the ALOX5AP gene and thirteen in the LTA4H gene, were genotyped in all twins. 16 out of the 19 SNPs in ALOX5AP and 9 out of the 13 SNPs in LTA4H were tag SNPs chosen by the computer program Haploview 4.2 with minor allele frequency (MAF) 5% based
12、 on pair-wise linkage disequilibrium (r2 0.80) and Illumina design scores (quantifying how likely a SNP can be genotyped).,LTA4H Gene Structure,Haplotype & HapMap,Alleles of SNPs that are close together tend to be inherited together”block”. A chromosome region may contain many SNPs, but researchers
13、can use only a few tag SNPs to obtain most of the information on the pattern of genetic variation in the region.,Haplotype & HapMap,Association between a novel leukotriene haplotype and atherosclerosis,All SNPs were in Hardy-Weinberg equilibrium. None of the SNPs was individually associated with car
14、otid IMT after accounting for multiple comparisons. a 6-SNP haplotype (“HapE”) in the LTA4H gene was significantly associated with carotid IMT. This haplotype spans the markers rs61937881 (C), rs1978331 (G), rs17677715 (T), rs2660899 (G), rs2540482 (T) and rs2660845 (A). The prevalence of this leuko
15、triene haplotype was 21% in the sample. Compared to twins without HapE, those carrying HapE had significantly lower carotid IMT (742 m vs. 701 m, p = 0.007), suggesting a potential protective effect of HapE on atherosclerosis.,Increased intake of n-3 and n-6 fatty acidsassociated with a decrease in
16、IMT among HapE carriers, but not noncarriers,n-3 fatty acids,n-6 fatty acids,HapE diet interaction,an increased intake of n-3 and n-6 polyunsaturated fatty fatty acids was associated with a decrease in IMT among HapE carriers, but not noncarriers,suggesting a nutrigenetic interaction effect on atherosclerosis. a dose-response relationship between dietary intake of fatty acids and IMT among twins carrying HapE but not those not carrying this haplotype.,
