| Description |
Functional vitamin B12 (cobalamin) deficiency is a subtle, progressive clinical disorder affecting 6-23% of elderly adults. Its symptoms, including fatigue, mood disturbances, and decreased strength, are vague and erroneously attributed to aging. Detection of cobalamin deficiency in elderly adults is confounded by clinical heterogeneity and lack of standardization in metabolic tests. Whereas some patients are asymptomatic with slightly altered metabolite profiles, others develop severe clinical outcomes. Better understanding of biologic factors contributing to cobalamin deficiency heterogeneity in older adults is needed. This is a candidate gene association study evaluating the relationship between genetic variation in the cobalamin-transport molecules (transcobalamin II and its receptor) with cobalamin-related outcome parameters in 795 research participants of the Women's Health and Aging 1 and 2 Studies. Research participant DNA was whole genome amplified and genotyped using the iPLEX Sequenom mass spectroscopy platform. Relationships between genotypes and clinical parameters were assessed using two-way analysis of variance and two-way analysis of covariance, on the fixed factors, race and Single Nucleotide Polymorphism genotype. Results of the dissertation research generated several genetic associations that are useful for further hypothesis testing and clinical validation research. In the transcobalamin II gene, two missense variants were associated with homocysteine and methylmalonic acid levels (rs9621049, rs35838082), two intronic variants were associated with serum cobalamin and homocysteine levels (rs4820888, rs4820887), and one missense variant was associated with mean corpuscular volume (rs11801198). A cluster of SNPs in the promoter region of the transcobalamin II gene was associated with the physical performance parameters, hand grip strength, and walking speed. In the transcobalamin II-receptor gene, a missense coding SNP (rs2336573) was associated with mean serum cobalamin concentrations. Scientific advances responsible for the technology used in this dissertation are being incorporated into healthcare. The tailoring of treatment to an individual's genetic make-up is termed Personalized Medicine. To assist nursing professionals in understanding and preparing for use of these technologies, four elements of Personalized Medicine are reviewed, including 1) discovery of novel biology that guides clinical translation mechanisms, 2) genetic risk assessment, 3) molecular diagnostic technology, and 4) pharmacogenetics and pharmacogenomics. Opportunities for nursing profession engagement are addressed. |
