Eat More : seen in menopausal women, and as they are associated t Plant-based foods, especially fresh fruits and with an increased risk for cardiovascular disease, it may be vegetables such as cabbage family vegetables – appropriate to ensure optimal intake of these nutrients either broccoli, cabbage, brussel sprouts, cauliflower, bok choy, Chinese broccoli, broccolini, Garlic and oni
C:\jag4\invited editorial.vpInvited Editorial
Molecular biomedicine and the unraveling
of complex phenotypes
Section of Biology and Genetics, Department of Mother and Child, Biology and Genetics, University of Verona, Italy Introduction
Analysis of complex phenotypes
The completion of the human genome project has The interplay of genetic and environmental factors laid a firm basis on which to build molecular that are involved in complex phenotype determi- biomedicine, as recently indicated (Collins et al.
nation is related to several different genes for 2003). In particular, the progress in the identifica- a given phenotype, as well as to several different tion of human genes has allowed a paradigm shift environmental causes, at odds with the classic in the study of human genetics, so that now com- plex phenotypes are amenable to genetic analysis.
where it is usually easier to causally relate a gene Complex phenotypes include some of the most with a disease (Peltonen and Mc Kusick 2001).
common diseases in the economically developed Therefore, the search for genetic determinants in countries, such as cardiovascular, allergic, asth- the new millennium has to adopt differentschemes, including association and linkage stud- matic and Alzheimer diseases, as well as diabetes, ies, but extending to family studies and animal ex- obesity, tumors, and some others. Pharmaco- perimentation (Risch 2000), and to functional genetics and pharmacogenomics may be included, genomics (Evans and Relling 1999), proteomics, as also in this case a mix of genetic and environ- bioinformatics, or human phenomics (Freimer and mental factors contribute to the trait. Hence it now Sabatti 2003). In an association study - a kind of seems that there is a case to be made for prospec- experimental design presently most utilized - it tive studies of genes and the environment in hu- might be easier to detect common genetic variants man health and disease in order to reach rigorous related to a trait (the “common disease/ common and unbiased conclusions about the causes of dis- variant” hypothesis), rather than rare genetic vari- eases and their population-wide impact (Collins ants (the “common disease/ rare variant” hypothe- 2004). On the one hand, genetics will identify sis). These traits may therefore be named as genes related to complex phenotypes (Merikangas “oligogenic” with respect to truly “polygenic” and Risch 2003), and on the other hand, genetic epidemiology research will increasingly focus oncomplex multifactorial diseases (Dekker and vanDuijn 2003). Therefore, even if “we are not there Examples in complex diseases
yet”, genomic information may become a funda-mental part of medical care in the future (Jasny Cardiovascular diseases may be related to several out of a list of possibly hundreds of genes involved Received: October 4, 2004.
Correspondence: PF Pignatti, Section of Biology and Genetics, Department of Mother and Child, Biology and Genetics, Uni-versity of Verona, I-37134 Verona, Italy, e-mail: email@example.com in vascular physiology and pathology, among as with other causes, related to the disease, indi- which are genes involved in homocysteine or lipid vidual, drug, or lifestyle (Evans and McLeod metabolism, vascular wall oxidation, blood pres- 2003). There are traits more directly related to sin- sure regulation, thrombosis, leukocyte adhesion, gle gene variation - a case similar to the direct re- lation between mutation and single gene disorder On the other hand, several environmental factors as mentioned above, e.g. the “acetylator” pheno- are known or supposed to play a role in cardiovas-cular disease, and the relative contribution of each type due to mutations in the N-acetyltransferase of the genetic and environmental factors may be gene (Weinshilbaum 2003). There are traits that calculated (Peyser 1997). Multiple genetic tests statistically modify drug response - a case similar for detecting several mutations at a time in a given to the indirect relation between DNA polymor- individual may be devised, so that a more general phism and complex disease as discussed above, approach to association determination may be e.g. beta 2 adrenergic receptor gene mutation used (Cheng et al. 1999), including the microarray Arg 16 Gly and response to albuterol in asthmatic technology (Petricoin et al. 2002). A specific cor- children (Martinez et al. 1997, Pignatti 2004), or relation between an environmental factor and a ge- the correlation between blood platelet glyco- notype may be found, which then may be used in protein genotypes and response to antiaggregant predictive testing. An example may be the correla- therapy with clopidogrel in patients undergoing tion between low serum folate and MTHFR genemutation C677T in determining hyperhomo- coronary stent (Angiolillo et al. 2004a, b). The in- cysteinemia (Girelli et al. 1998). Results of terplay of an individual’s genotype at two differ- ent genes, e.g. one drug metabolism gene and one cysteinemia is a cause of ischemic heart disease, receptor gene, may produce a continuous variation deep vein thrombosis, and stroke (Wald et al of drug response in a given population (Evans and 2002). A dietary increase in folate, easily obtained Relling 1999). Pharmacogenetic predictive testing by folic acid fortification of food (Jacques et al.
may be, according to one study, useful in 10-20% 1999) or by the choice of proper food, or by direct of treatments to avoid adverse reactions and to folate administration, may therefore be beneficial better health, of uncertain utility in 15-40% of in the prevention of cardiovascular disease in indi- cases due to a reduced penetrance of the polymor- viduals with hyperhomocysteinemia and lowfolatemia. The determination of MTHFR C677T phism in a trait with polygenic influences, and of genotype may then help in determining the thresh- no use in 50% of cases for the presence of other old value to be obtained, depending on each indi- vidual’s genotype (Girelli et al. 2003).
(Ingelman-Sundberg 2001). The progress in Another example of interaction between a ge- pharmacogenetics and human genomics has led to netic and an environmental factor contributing to the development of pharmacogenomics and to in- risk variation for cardiovascular disease involves creased optimism on the possible transfer of this a paraoxonase gene and cigarette smoke: in carri- discipline into clinical practice. The present chal- ers of the 311 Cys variant of the PON2 gene, lenges are: research, translation into the health the risk may increase up to 5 times over non carri- system, education of the sanitary personnel, and ers, but only in smokers, not in non-smokers patient acceptance (Weinshilboum and Wang 2004) - challenges that are equally to be applied to Other mutations in other complex diseases may increase the risk for factors from RR = 2, as in neu-ral tube defects colon cancer, or insulin-dependentdiabetes, to RR = 10 or so for some cases of Alz- Conclusions
heimer’s disease or venous thrombosis (Botsteinand Risch 2003).
Molecular biomedicine is unraveling complexphenotypes (Collins et al. 2003). The transfer ofgenomics to biology seems already well advanced, Examples in pharmacogenomics
the transfer to health in its beginning, and to soci-ety will come next. The predictive genetic tests Variation in drug efficacy and adverse drug reac- that will be developed (Quinzii et al.2001), will tions may be associated with hereditary differ- need to be evaluated by clinicians, policy makers, ences in drug metabolism or drug targets, as well Molecular biomedicine and the unraveling of complex phenotypes Girelli D, Martinelli N, Pizzolo F, Friso S, Olivieri O, Stranieri C, et al. 2003. The interaction between Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso MTHFR 677 C->T genotype and folate status is a F, Sabate M, Fernandez C, et al. 2004a. PlA poly- determinant of coronary atherosclerosis risk. J Nutr clopidogrel loading dose in patients undergoing Ingelman-Sundberg M, 2001. Pharmacogenetics: an opportunity for a safer and more efficient pharmacotherapy. J Intern Med 250: 186–200.
Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Jacques PF, Selhub J, Bostom AG, Wilson PW, Ramirez C, Escaned J, Moreno R, et al. 2004b. 807 Rosenberg IH, 1999. The effect of folic acid fortifi- C/T polymorphism of the glycoprotein Ia gene and cation on plasma folate and total homocysteine con- pharmacogenetic modulation of platelet response to centrations. N Engl J Med 340: 1449–1454.
Jasny BR, Roberts L, 2003. Are we there yet? Science Botstein D, Risch N, 2003. Discovering genotypes un- Martinelli N, Girelli D, Olivieri O, Stranieri C, Trabetti derlying human phenotypes: past successes for E, Pizzolo F et al. 2004. Interaction between smok- mendelian disease, future approaches for complex ing and PON2 Ser311Cys polymorphism as a deter- disease. Nat Genet suppl 33: 228–237.
minant of the risk of myocardial infarction. Eur J Burke W, Atkins D, Gwinn M, Guttmacher A, Haddow J, Lau J, et al. 2002. Genetic test evaluation: infor- Martinez FD, Graves PE, Baldini M, Solomon S, mation needs of clinicians, policy makers, and the Erickson R, 1997. Association between genetic public. Am J Epidemiol 156: 311–318.
polymorphisms of the beta2-adrenoreceptor and re- Cheng S, Pallaud C, Grow MA, Klitz W, Erlich HA, sponse to Albuterol in children with and without a Visvikis S, et al. 1998. A multilocus genotyping as- history of wheezing. J Clin Invest 100: 3184–3198.
say for cardiovascular disease. Clin Chem Lab Med Merikangas KR, Risch N, 2003. Genomic priorities and public health. Science 302: 599–601.
Cheng S, Grow MA, Pallaud C, Klitz W, Erlich HA, Peltonen L, McKusick VA, 2001. Genomics and medi- Visvikis S, et al. 1999. A multilocus genotyping as- cine. Dissecting human disease in the postgenomic say for candidate markers of cardiovascular disease Peyser PA, 1997. Genetic epidemiology of coronary ar- Collins FS, Green ED, Guttmacher AE, Guyer MS, tery disease. Epidemiological Reviews 19: 80–90.
2003. A vision for the future of genomics research.
Petricoin EF, Hackett JL, Lesko LJ, Puri RK, Gutman SI, Chumakov K, et al. 2002. Medical applications Collins FS 2004. The case for a US prospective cohort of microarray technologies: a regulatory science study of genes and environment. Nature 429: perspective. Nat Genet Suppl. 32: 479–479.
Pignatti PF, 2004. Trends in pharmacogenomics of Dekker MC, Duijn CM, 2003. Prospects of genetic epi- drugs used in the treatment of asthma. Pharmacol demiology in the 21st century. Eur J Epidemiol 18: Quinzii C, Belpinati F, Pignatti PF, 2001. Predictive ge- Evans WE, McLeod HL, 2003. Pharmacogenomics – netic testing – new possibilities in determination of drug disposition, drug targets, and side effects. New risk of complex diseases. Croat Med J 42: 458–462.
Risch NJ, 2000. Searching for genetic determinants in Evans PDA, Relling MV, 1999. Pharmacogenomics: the new millennium. Nature 405: 847– 856.
translating functional genomics into rational thera- Wald DS, Law M, Morris JK, 2002. Homocysteine and cardiovascular disease: evidence on causality from Freimer N, Sabatti C, 2003. The human phenome pro- a meta-analysis. Br Med J 325: 1202–1208.
Weinshilbaum R, 2003. Inheritance and drug response.
Girelli D, Friso S, Trabetti E, Olivieri O, Russo C, Pessotto R, et al. 1998. Methylenetetrahydrofolate Weinshilbaum R, Wang 2004. Pharmacogenomics: reductase C677T mutation, plasma homocysteine, bench to bedside. Nat Rev Drug Discov 3: 739–748.
and folate in subjects from Northern Italy with or Wright A, Charlesworth B, Rudan I, Carothers A, without angiographically documented severe coro- Campbell H, 2003. Polygenic basis for late-onset nary atherosclerotic disease: evidence for an impor- tant genetic-environmental interaction. Blood 91:4158–4163.
COMMISSION DE LA TRANSPARENCE L’avis de la Commission de la transparence du 6 juin 2012 a fait l’objet d’une audition le 19 septembre 2012 PROCORALAN 5 mg, comprimé pelliculé B/56 (CIP : 371 676-2) B/100 (CIP : 567 208-1) PROCORALAN 7,5 mg, comprimé pelliculé B/56 (CIP : 371 679-1) B/100 (CIP : 567 209-8) Laboratoires SERVIER ivabradine Code ATC : C01EB17 (