Epidemiological and Genetic Studies of Body Mass Index

描述（由申请人提供）：体重指数（BMI）水平升高与心血管疾病、高血压、糖尿病和其他疾病的死亡率和发病率升高相关。最近美国人口中肥胖症的急剧增加已经达到流行病的比例，三分之二的普通人口符合"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变化，但遗传因素也会影响肥胖的易感性。动物和人类研究表明，高热量/高脂肪饮食在不同遗传背景下产生的体重增加差异很大。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，并扭转人口肥胖增加的趋势。 NHLBI家族心脏研究（FHS）发现了染色体7q31-q34上BMI（LOD = 4.9）的令人信服的连锁。 该区域已经涉及至少16个其他肥胖和相关性状的基因组扫描，并且可能是肥胖遗传学中最广泛复制的基因座。我们相信FHS样本是该地区最大的研究，并提供了最好的机会来确定相关基因。这组研究人员与FHS，FRAYSTUDY和Family Blood Pressure Program Project进行了广泛的合作，并在这些大型研究样本中进行了基因组扫描。BMI对染色体7q31-q34的4.9 LOD是这些研究中任何性状报告的最大LOD。然而，如果基因扫描之后没有发现基因，那么它就没有什么价值。我们建议，此应用程序提供了一个独特的机会，以实现这些扫描的目的。 在过去的2年零2个月里，我们在7q31-q34区域对421个SNP进行了基因分型，在我们的重点样本中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，在这个区域的责任基因是不是瘦素。单核苷酸多态性和单倍型关联研究暗示了三个强有力的候选位点，其他位点也值得进一步研究。我们建议在一项对200个家庭的独立研究中证实SNP的关联性，这些家庭显示出与同一位置的连锁（来自R。Arlen Price的团队）。那些已证实相关的基因座将通过测序、基因分型新多态性和基因表达研究进一步表征，以确定相关基因。这项研究为在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.