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症的急剧增加已经达到了流行病的程度，三分之二的总人口达到了“超重”的标准，三分之一的人达到了“肥胖”的标准。虽然肥胖率的增加反映了生活方式和饮食习惯的变化，但有证据表明，遗传因素会影响肥胖的易感性。动物和人类的研究表明，高卡路里/高脂肪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，并扭转肥胖增加的人口趋势。 NHLBI家族心脏研究(FHS)发现了染色体7q31-q34上与体重指数(LOD=4.9)的显著连锁。这一区域至少参与了16次其他肥胖及相关特征的基因组扫描，可能是肥胖遗传学中复制最广泛的基因座。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、弗雷明翰研究和家庭血压计划项目进行了广泛的合作，并对这些大型研究样本进行了基因组扫描。染色体7q31-q34上BMI的4.9个LOD是这些研究中报道的所有性状中最大的。然而，如果基因组扫描之后没有发现基因，那么它们就没有什么价值。我们建议该应用程序提供一个独特的机会来实现这些扫描的目的。 在过去的两年零两个月里，我们在7q31-q34区域对421个SNPs进行了基因分型，在我们的焦点样本中，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&lt；0.00005)影响我们样本中男性的体重指数。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有三个候选基因座存在，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与相同的位置相关(来自R.Arlen Price博士的小组)。已确认关联的基因座将通过测序、对新的多态进行基因分型和基因表达研究来进一步表征，以确定相关基因。拟议的研究为在7q31发现重要的BMI相关基因提供了一个独特的机会。

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.