Genetic Risk Factors Related to Coronary Artery Disease and Role of Transforming Growth Factor Beta 1 Polymorphisms.

Coronary artery disease (CAD) is one of the leading causes of mortality globally and has long been known to be heritable; however, the specific genetic factors involved have yet to be identified. Recent advances have started to unravel the genetic architecture of this disease and set high expectations about the future use of novel susceptibility variants for its prevention, diagnosis, and treatment. In the past decade, there has been major progress in this area. New tools, like common variant association studies, genome-wide association studies, meta-analyses, and genetic risk scores, allow a better understanding of the genetic risk factors driving CAD. In recent years, researchers have conducted further studies that confirmed the role of numerous genetic factors in the development of CAD. These include genes that affect lipid and carbohydrate metabolism, regulate the function of the endothelium and vascular smooth muscles, influence the coagulation system, or affect the immune system. Many CAD-associated single-nucleotide polymorphisms have been identified, although many of their functions are largely unknown. The inflammatory process that occurs in the coronary vessels is very important in the development of CAD. One important mediator of inflammation is TGFß1. TGFß1 plays an important role in the processes leading to CAD, such as by stimulating macrophage and fibroblast chemotaxis, as well as increasing extracellular matrix synthesis. This review discusses the genetic risk factors related to the development of CAD, with a particular focus on polymorphisms of the transforming growth factor ß (TGFß) gene and its receptor.

A common nonsense mutation of the BLM gene and prostate cancer risk and survival.

BACKGROUND: Germline mutations of BRCA2 and NBS1 genes cause inherited recessive chromosomal instability syndromes and predispose to prostate cancer of poor prognosis. Mutations of the BLM gene cause another chromosomal instability clinical syndrome, called Bloom syndrome. Recently, a recurrent truncating mutation of BLM (Q548X) has been associated with a 6-fold increased risk of breast cancer in Russia, Belarus and Ukraine, but its role in prostate cancer etiology and survival has not been investigated yet. METHODS: To establish whether the Q548X allele of the BLM gene is present in Poland, and whether this allele predisposes to poor prognosis prostate cancer, we genotyped 3337 men with prostate cancer and 2604 controls. RESULTS: Q548X was detected in 13 of 3337 (0.4%) men with prostate cancer compared to 15 of 2604 (0.6%) controls (OR=0.7; 95% CI 0.3-1.4). A positive family history of any cancer in a first- or second-degree relative was seen only in 4 of the 13 (30%) mutation positive families, compared to 49% (1485/3001) of the non-carrier families (p=0.3). The mean follow-up was 49months. Survival was similar among carriers of Q548X and non-carriers (HR=1.1; p=0.9). The 5-year survival for men with a BLM mutation was 83%, compared to 72% for mutation-negative cases. CONCLUSIONS: BLM Q548X is a common founder mutation in Poland. We found no evidence that this mutation predisposes one to prostate cancer or affect prostate cancer survival. However, based on the observed 0.6% population frequency of the Q548X allele, we estimate that one in 100,000 children should be affected by Bloom syndrome in Poland.