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.
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