Epidemiological and Genetic Studies of Body Mass Index

描述（由申请人提供）：身体质量指数（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有关。最近美国人口中肥胖的急剧增加已达到流行病的程度，总人口中有三分之二符合“超重”标准，三分之一符合“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改变，但遗传因素也显示出对肥胖易感性的影响。动物和人类的研究表明，高热量/高脂肪的饮食在不同的遗传背景下会产生显著的体重增加差异。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的治疗方法，并扭转肥胖人口增长的趋势。

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.