Identification of Single Nucleotide Polymorphisms in Can

一个人的遗传背景在他们对癌症的易感性、疾病的进展和对治疗的反应方面起着重要作用。单核苷酸多态(SNPs)和其他遗传变异可用作了解复杂疾病的遗传标记。我们已经确定了雌激素受体基因(ESR1)的变异，并在一组乳腺癌患者中对这些变异进行了基因分型。结果表明，该基因的几种多态产生的单倍型与乳腺癌风险的降低有关。TRIM5基因是一种新发现的保护细胞免受病毒感染的蛋白质。我们已经对一大批正常人以及有感染HIV-1风险的患者的TRIM5基因进行了测序。我们在基因中发现了大量的非同义变异，这表明这些变异是为疾病而选择的，并提供了一些保护作用。炎症被认为是癌症发展的一个重要因素。人体对细菌和真菌的重要防御机制之一是补体蛋白。通过研究补体基因之一的补体因子H(CFH)的变异，我们已经确定该基因对老年性黄斑变性(AMD)的发展至关重要。AMD是导致老年人失明的主要原因，据估计，多达1000万美国人患有AMD。AMD是一种复杂的疾病，通常在65岁之后发病，已知的危险因素包括吸烟、饮食和年龄。女性更容易受到这种疾病的影响，它是老年人视力丧失的主要原因。也有强有力的证据表明，基因对这种疾病有贡献。我们之前发现了ABCA4基因在AMD中的作用，但该基因的贡献很小。通过对CFH基因突变引起的一种罕见肾脏疾病的分析，证明这些人也有早发性AMD。通过检查HF1基因中的八个遗传变异，我们发现这些变异与疾病之间存在显著的关联。最常见的高危基因型在50%的AMD患者中发现，而在对照组中只有29%。我们还发现CFH蛋白在眼部玻璃体积聚，这是与AMD早期阶段相关的特征性沉积。该研究是对AMD认识的重大突破。这表明，感染源可能是一个关键的触发因素，通过识别病原体，可以预防疾病或限制其进展。补体途径在机体对其他与癌症相关的病原体和刺激物的反应中也可能是重要的。对先天免疫这一重要组成部分的进一步研究可能有助于深入了解人类疾病。

An individual's genetic background plays a major role in their susceptibility to cancer, disease progression, and response to therapy. Single nucleotide polymorphisms (SNPs) and other genetic variations can be used as genetic markers to understand complex diseases. We have characterized variants in the estrogen receptor gene (ESR1) and genotyped these variants in a cohort of breast cancer patients. The results show a haplotype generated by several polymorphisms in this gene is associated with a reduced risk of breast cancer. The TRIM5 gene represents a newly described protein involved in the protection of cells from viral infection. We have sequenced the TRIM5 gene in a large collection of normal individuals as well as patients at risk for HIV-1 infection. We find a large number of non-synonymous variants in the gene suggesting that these variants have been selected for and confer some protection to disease. Inflammation is thought to be an important factor in the development of cancer. One of the bodies' important defense mechanisms against bacteria and fungi are the complement proteins. By studying variants in one of the complement genes, complement factor H (CFH) we have identified this gene as critical to the development of age-related macular degeneration (AMD). AMD is the leading cause of blindness in the elderly and is estimated to effect as many as of 10 million Americans. AMD is a complex disease, with onset typically after the age of 65, and the known risk factors include smoking, diet, and age. Women are more often affected by this disease, and it is the leading cause of vision loss in the elderly. There is also strong evidence for a genetic contribution to the disease. We previously identified a role of the ABCA4 gene in AMD, but the contribution of this gene is small. Through the analysis of a rare kidney disease caused by mutations in the CFH gene, it was demonstrated that these people also have an early onset form of AMD. By examining the eight genetic variants in the HF1 gene, we found a significant association between these variants and the disease. The most common at-risk genotype was found in 50% of AMD patients and only 29% of controls. We also found an accumulation of the CFH protein in ocular drusen, characteristic deposits associated with the early stages of AMD. The research is a major breakthrough in the understanding of AMD. It suggests an infectious agent might be a critical trigger, and that by identifying the pathogen the disease may be prevented or its progression limited. The complement pathway may also be important in the bodies response to other pathogens and irritants associated with cancer. Further study of this important component of innate immunity could lead to insight into human disease.