Epidemiological and Genetic Studies of Body Mass Index

体重指数的流行病学和遗传学研究

基本信息

批准号：
7176190
负责人：
RICHARD H MYERS
金额：
$ 67.06万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-12-05 至 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7176190
关键词：
7q22 7q31 7q31.3 7q32.3 7q36 Accounting Actins Adipocytes Adipose tissue American Animals Binding Proteins Biopsy Blood Pressure Body mass index Brain Candidate Disease Gene Cardiovascular Diseases Cell Line Cerebellum Collaborations Data Development Diabetes Mellitus Diet Diet Habits Disease Epidemic Family Family Study Fatty acid glycerol esters Follow-Up Studies Framingham Heart Study Gene Expression General Population Genes Genetic Genetic Polymorphism Genome Scan Genotype Haplotypes Heart Histocompatibility Testing Human Genome Hypertension Hypothalamic structure Individual Investigation Label Leptin Letters Life Style Link Maps Methods Morbidity - disease rate Muscle Myosin ATPase Names Obesity Operative Surgical Procedures Overweight Participant Personal Satisfaction Persons Phase Population Positioning Attribute Pre-study Predisposition Prevalence Price Protein Isoforms Proteins Province Purpose Reporting Research Ethics Committees Research Personnel Residual state Role SNP genotyping Sampling Sampling Studies Scanning Sequence Analysis Serum Signal Transduction Single Nucleotide Polymorphism Map Specimen Statistical Methods Testis Time Tissue Sample Tissues Universities Washington Weight Gain Woman Work analytical method caldesmon density gene discovery genetic analysis high throughput analysis human study lymphoblast men mortality prevent programs success trait trend

项目摘要

DESCRIPTION (provided by applicant): Increased levels of Body Mass Index (BMI) are associated with increased mortality and morbidity from cardiovascular disease, hypertension, diabetes and other disorders. The recent dramatic increase in obesity in the American population has reached epidemic proportions, with two-thirds of the general population meeting criteria for "over-weight" and one-third meeting criteria for "obese". While the increase in the prevalence of obesity reflects changing lifestyle and dietary habits, genetic factors are shown to influence the susceptibility for obesity. Animal and human studies reveal that a high-calorie/high fat-diet produces substantial differences in weight gain on different genetic backgrounds. Understanding the genes that influence susceptibility to obesity will permit investigation into treatment to prevent or reduce weight gain and reverse the population trend for increasing obesity. The NHLBI Family Heart Study (FHS) found compelling linkage for BMI (LOD = 4.9) on chromosome 7q31-q34. This region has been implicated in at least sixteen other genome scans for obesity and related traits, and may be the most widely replicated locus in obesity genetics. We believe the FHS sample to be the largest study of the region and to provide the best opportunity to identify the implicated genes. This group of investigators has worked extensively with the FHS, the Framingham Study, and the Family Blood Pressure Program Project, and has performed genome scans in these large study samples. The 4.9 LOD for BMI to chromosome 7q31-q34 is the largest reported for any trait in these studies. Yet genome scans have little value if they are not followed by gene discovery. We suggest that this application offers a unique opportunity to fulfill the purpose of those scans. Over the past 2 years and 2 months we have genotyped 421 SNPs in the 7q31-q34 region, and SNP linkage in our focus sample generates a LOD = 16 for BMI. We will show compelling evidence for a haplotype in the 5' region of the Leptin gene (p<0.00005) influencing BMI among men in our sample. We will further demonstrate that the responsible gene in this region is not Leptin. SNP and haplotype association studies implicate three strong candidate loci and other loci also warrant additional study. We propose to confirm SNP association in an independent study of 200 families showing linkage to the same position (from Dr. R. Arlen Price's group). Those loci with confirmed association will be further characterized by sequencing, genotyping new polymorphisms, and gene expression studies to identify the responsible genes. The proposed studies offer a unique opportunity to discover important BMI related genes at 7q31.

描述（由申请人提供）：体重指数（BMI）水平的增加与心血管疾病、高血压、糖尿病和其他疾病的死亡率和发病率增加相关。最近美国人口肥胖率急剧上升，已达到流行病的程度，三分之二的总人口符合“超重”标准，三分之一的人符合“肥胖”标准。虽然肥胖患病率的增加反映了生活方式和饮食习惯的变化，但遗传因素已被证明会影响肥胖的易感性。动物和人类研究表明，高热量/高脂肪饮食会导致不同遗传背景的体重增加存在显着差异。了解影响肥胖易感性的基因将有助于研究预防或减少体重增加并扭转人口肥胖趋势的治疗方法。 NHLBI 家庭心脏研究 (FHS) 发现染色体 7q31-q34 上的 BMI (LOD = 4.9) 存在令人信服的关联。该区域与至少 16 个其他肥胖及相关性状基因组扫描有关，并且可能是肥胖遗传学中复制最广泛的位点。我们相信 FHS 样本是该地区最大的研究，并提供了识别相关基因的最佳机会。这组研究人员与 FHS、弗雷明汉研究和家庭血压计划项目进行了广泛合作，并对这些大型研究样本进行了基因组扫描。 BMI 与染色体 7q31-q34 的 4.9 LOD 是这些研究中报告的所有性状中最大的。然而，如果不进行基因发现，基因组扫描就没有什么价值。我们建议该应用程序提供了一个独特的机会来实现这些扫描的目的。在过去的 2 年零 2 个月中，我们对 7q31-q34 区域的 421 个 SNP 进行了基因分型，我们的焦点样本中的 SNP 连锁产生了 BMI 的 LOD = 16。我们将展示令人信服的证据，证明瘦素基因 5' 区域的单倍型 (p<0.00005) 影响我们样本中男性的 BMI。我们将进一步证明该区域的负责基因不是瘦素。 SNP 和单倍型关联研究表明三个强大的候选基因座，其他基因座也值得进一步研究。我们建议在一项对 200 个家庭进行的独立研究中确认 SNP 关联，该研究显示出与相同位置的联系（来自 R. Arlen Price 博士的小组）。那些已确认关联的基因座将通过测序、新多态性基因分型和基因表达研究来进一步表征，以确定相关基因。拟议的研究为发现 7q31 的重要 BMI 相关基因提供了独特的机会。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

(D)-Amino acid analogues of DT-2 as highly selective and superior inhibitors of cGMP-dependent protein kinase Ialpha.

DOI：
10.1016/j.bbapap.2009.12.004
发表时间：
2010-03
期刊：
Biochimica et biophysica acta
影响因子：
0
作者：
Nickl CK;Raidas SK;Zhao H;Sausbier M;Ruth P;Tegge W;Brayden JE;Dostmann WR
通讯作者：
Dostmann WR

Polymorphisms near EXOC4 and LRGUK on chromosome 7q32 are associated with Type 2 Diabetes and fasting glucose; the NHLBI Family Heart Study.

DOI：
10.1186/1471-2350-9-46
发表时间：
2008-05-22
期刊：
BMC medical genetics
影响因子：
0
作者：
Laramie JM;Wilk JB;Williamson SL;Nagle MW;Latourelle JC;Tobin JE;Province MA;Borecki IB;Myers RH
通讯作者：
Myers RH

Mode of action of cGMP-dependent protein kinase-specific inhibitors probed by photoaffinity cross-linking mass spectrometry.

通过光亲和交联质谱法探测 cGMP 依赖性蛋白激酶特异性抑制剂的作用模式。