Pharmacogenetics and Pharmacogenomics
It has been noted for decades that patient response to the administration of a drug was highly variable within a diverse patient population. Efficacy as determined in clinical trials is based upon a standard dose range derived from the large population studies. Better understanding of the molecular interactions occurring within the pharmacokinetics phase of a drug’s action, coupled with new genetics knowledge and then genomics knowledge of the human have advanced us closer to a rational means to optimize drug therapy. Optimization with respect to the patients’ genotype, to ensure maximum efficacy with minimal adverse effects is the goal. Environment, diet, age, lifestyle, and state of health all can influence a person’s response to medicines, but understanding an individual’s genetic makeup is thought to be the key to creating personalized drugs with greater efficacy and safety. Approaches such as the related pharmacogenetics and pharmacogenomics promise the advent of “personalized medicine”, in which drugs and drug combinations are optimized for each individual’s unique genetic makeup (Silber, 2001; Huang and Lesko, 2005).
While comparing the base sequences in the DNA of two individuals reveals them to be approximately 99.9 per cent identical, base differences, or poly-morphisms, are scattered throughout the genome. The best-characterized human polymorphisms are SNPs occurring approximately once every 1000 bases in the 3.5 billion base pair human genome (Cargill et al., 1999; Silber, 2001; Kassam et al., 2005). The DNA sequence variation is a single nucleotide — A, T, C, or G — in the genome difference between members of a species (or between paired chromosomes in an individual). For example, two sequenced DNA frag-ments from different individuals, AAGTTCCTA to AAGTTCTTA, contain a difference in a single nucleotide. Commonly referred to as “snips,” these subtle sequence variations account for most of the genetic differences observed among humans. Thus, they can be utilized to determine inheritance of genes in successive generations. Technologies available from several companies allow for genotyping hundreds of thousands of SNPs for typically under $1,000 in a couple of days.
Research suggests that, in general, humans tolerate SNPs as a probable survival mechanism. This tolerance may result because most SNPs occur in non-coding regions of the genome. Identifying SNPs occurring in gene coding regions (cSNPs) and/or regulatory sequences may hold the key for elucidating complex, polygenic diseases such as cancer, heart disease, and diabetes, and understanding the differ-ences in response to drug therapy observed in individual patients (Grant and Phillips, 2001; also see SNP Consortium website, http://snp.cshl.org/). Some cSNPs do not result in amino acid substitutionsin their gene’s protein product(s) due to the degen-eracy of the genetic code. These cSNPs are referred to as synonymous cSNPs. Other cSNPs, known as non-synonymous, can produce conservative amino acid changes, such as similarity in sidechain charge or size, or more significant amino acid substitutions.
SNPs, when associated with epidemiological and pathological data, can be used to track suscept-ibilities to common diseases such as cancer, heart disease, and diabetes (Davidson and McInerney, 2004). Biomedical researchers have recognized that discovering SNPs linked to diseases will lead poten-tially to the identification of new drug targets and diagnostic tests. The identification and mapping of hundreds of thousands of SNPs for use in large-scale association studies may turn the SNPs into biomar-kers of disease and/or drug response (McCarthy, 2005). The projected impact of SNPs on our under-standing of human disease led to the formation of the SNP Consortium in 1999, an international research collaboration involving pharmaceutical companies, academic laboratories, and private support.
In simplest terms, pharmacogenomics is the whole genome application of pharmacogenetics, which ex-amines the single gene interactions with drugs. Tremendous advances in biotechnology are causing a dramatic shift in the way new pharmaceuticals are discovered, developed, and monitored during patient use. Pharmacists will utilize the knowledge gained from genomics and proteomics to tailor drug therapy to meet the needs of their individual patients employing the fields of pharmacogenetics and phar-macogenomics (Evans and Relling, 1999; Lau and Sakul, 2000; Kalow, 2004; Weinshilboum and Wang, 2004; Lindpaintner, 2007).