rs75215331

Dopamine beta‐hydroxylase (DβH) is an essential neurotransmitter‐synthesizing enzyme that catalyzes the formation of norepinephrine (NE) from dopamine and has been extensively studied since its discovery in the 1950s. NE serves as a neurotransmitter in both the central and peripheral nervous systems and is the precursor to epinephrine synthesis in the brain and adrenal medulla. Alterations in noradrenergic signaling have been linked to both central nervous system and peripheral pathologies. DβH protein, which is found in circulation, can, therefore, be evaluated as a marker of norepinephrine function in a plethora of different disorders and diseases. In many of these diseases, DβH protein availability and activity are believed to contribute to disease presentation or select symptomology and are believed to be under strong genetic control. Alteration in the DβH protein by genetic polymorphisms may result in DβH becoming rate‐limiting and directly contributing to lower NE and epinephrine levels and disease. With the completion of the human genome project and the advent of next‐generation sequencing, new insights have been gained into the existence of naturally occurring DβH sequencing variants (genetic polymorphisms) in disease. Also, biophysical tools coupled with genetic sequences are illuminating structure‐function relationships within the enzyme. In this review, we discuss the role of genetic variants in DβH and its role in health and disease.

2020 · Eugene Gonzalez‐Lopez, Kent E. Vrana

Smoking poses significant threats to public health. Despite 50 years of prevention efforts, smoking remains the greatest cause of preventable diseases and deaths. Even though today’s users smoke fewer cigarettes than those 50 years ago, they are at higher risk of developing lung cancer because of changes in cigarettes. Our group and others have shown strong evidence for the involvement of genetics in nicotine dependence (ND), with an average heritability of 0.56. This dissertation contributes to our understanding of the genetic structure of smoking from four perspectives. In the first study, leveraging computational efficiency of the GPU-based Generalized Multifactor Dimensionality Reduction (GMDR-GPU) program, we detected variants in genes encoding the 5-HT3AB receptors (HTR3A and HTR3B) and the serotonin transporter (SLC6A4) interactively affecting etiology of alcohol, cocaine, and nicotine dependence, although their individual effect was weak. In the second study, targeted next-generation sequencing was used to discover rare variants from ND candidate genes. Although none of the genotyped common variants showed significant association with different smoking measures, the weighted sum statistic (WSS) and combined sum test results indicated that rare variants alone or combined with common variants in a subset of candidate genes contribute significantly to the risk of ND. In the third study, we developed an ND genetic susceptibility map based on the results obtained by the approaches commonly used in recent years, which include genomewide linkage, candidate gene association, GWAS, and targeted sequencing studies. Converging and diverging results from these empirical approaches have elucidated a preliminary genetic...

2016 · JJ Yang