Identification of Single Nucleotide Polymorphisms in Can

个体的遗传背景在他们对癌症的易感性、疾病进展和对治疗的反应中起着重要作用。单核苷酸多态性（SNPs）和其他遗传变异可以作为理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，该基因的几个多态性产生的单倍型与乳腺癌风险降低有关。TRIM5基因代表了一种新描述的蛋白质，参与保护细胞免受病毒感染。我们已经对大量正常个体和HIV-1感染风险患者的TRIM5基因进行了测序。我们在该基因中发现了大量的非同义变体，这表明这些变体已被选择并赋予了对疾病的某种保护。炎症被认为是癌症发展的一个重要因素。人体对抗细菌和真菌的重要防御机制之一是补体蛋白。通过研究一种补体基因的变异，补体因子H (CFH)，我们已经确定该基因对年龄相关性黄斑变性（AMD）的发展至关重要。老年性黄斑变性是导致老年人失明的主要原因，据估计有多达1000万美国人受其影响。AMD是一种复杂的疾病，通常在65岁以后发病，已知的危险因素包括吸烟、饮食和年龄。女性更常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这种疾病与遗传有关。我们之前确定了ABCA4基因在AMD中的作用，但该基因的贡献很小。通过对一种由CFH基因突变引起的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8种遗传变异，我们发现这些变异与该疾病之间存在显著关联。在50%的AMD患者中发现了最常见的风险基因型，而在对照组中只有29%。我们还发现CFH蛋白在眼囊肿中积累，这是AMD早期的特征性沉积。该研究是对AMD认识的重大突破。这表明一种传染因子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。补体途径在机体对与癌症相关的其他病原体和刺激物的反应中也可能很重要。对先天免疫这一重要组成部分的进一步研究可能会导致对人类疾病的深入了解。

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.