Review For reprint orders, please contact: [email protected]
Pediatric perspective on pharmacogenomics The advances in high-throughput genomic technologies have improved the understanding of disease pathophysiology and have allowed a better characterization of drug response and toxicity based on individual genetic make up. Pharmacogenomics is being recognized as a valid approach used to identify patients who are more likely to respond to medication, or those in whom there is a high probability of developing severe adverse drug reactions. An increasing number of pharmacogenomic studies are being published, most include only adults. A few studies have shown the impact of pharmacogenomics in pediatrics, highlighting a key difference between children and adults, which is the contribution of developmental changes to therapeutic responses across different age groups. This review focuses on pharmacogenomic research in pediatrics, providing examples from common pediatric conditions and emphasizing their developmental context. KEYWORDS: adverse drug reactions n pediatrics n personalized medicine n pharmacogenomics
The use of genetic information has played a major role in the development of personalized medicine, selecting the best medicine at the right dose with the lowest risk of side effects [1]. Pharmacogenomics is defined as “the study of the variability of the expression of individual genes relevant to the disease susceptibility as well as drug response at cellular, individual or population level” [2]. Pharmacogenomic research provides a method for potentially identifying patients who are likely to respond to medication and/or those in whom there is a high probability of developing severe adverse drug reactions (ADRs) [3]. The drug regulatory agencies, US FDA and EMA, recommend the use of pharmacogenomics in drug development and have begun to build up a common approach. Furthermore, both FDA officials and EMA committee members recently expressed the view that pharmacogenomics, unlike other forms of genetic testing, does not present any special ethical or social concerns [4]. The aim of the regulatory agencies is the development of international policies and standards to assist in guiding and promoting the adoption of pharmacogenomics. An increasing number of studies are being published that describe differences in drug response as a result of individual genetic background, but most of these reports include only adult individuals. Only a few studies have shown the impact of pharmacogenomics in pediatrics and have highlighted important differences
between children and adults. A major issue is the relative contribution of ontogeny and genetic variation to therapeutic response across different age groups and developmental stages, which range through newborns, infants, children and adolescents [5–7]. The normal background of child development over which pediatric conditions arise adds a complexity to pharmacogenomic study that is superimposed upon genetic variation [7]. In addition, several diseases are more prevalent in children or have no adult correlate, and some ADRs are unique or occur at a higher frequency in children [1,8]. The aim of this review is to focus on pediatric pharmacogenomics, highlighting the impact of child development and the importance of this approach in clinical practice.
10.2217/PGS.13.193 © 2013 Future Medicine Ltd
Pharmacogenomics (2013) 14(15), 1889–1905
Genetic ontogeny of childhood development & its relationship to pediatric pharmacogenomics Pediatric medicine is set against the background of the developing child [5,6]. Recently it has been shown that gene expression changes in a set of evolutionarily conserved growth pathways (e.g. WNT, TGFB, VEGF and NOTCH) vary in a tissue-independent manner that is correlated with stage of human development (Figure 1) [7]. These pathways have been found to correlate with age and different phases of human growth, ranging from infancy to childhood and adulthood. A similar phenomenon has been shown in rodents [9], and
Adam Stevens‡1, Chiara De Leonibus‡1, Daniel Hanson1, Andrew Whatmore1, Philip Murray1, Rachelle Donn2, Stefan Meyer3, Pierre Chatelain4 & Peter Clayton*1 Institute of Human Development, Medical & Human Sciences, University of Manchester & Royal Manchester Children’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, 5th Floor Research, Oxford Road, Manchester, M13 9WL, UK 2 Musculoskeletal Research Group, NIHR Biomedical Research Unit, Medical & Human Sciences, University of Manchester, UK 3 Stem Cell & Leukaemia Proteomics Laboratory, School of Cancer & Imaging Sciences, Medical & Human Sciences, University of Manchester, UK 4 Department Pediatrie, Hôpital MèreEnfant – Université Claude Bernard, 69677 Lyon, France *Author for correspondence: Tel.: +44 161 701 6949 [email protected] ‡ Authors contributed equally 1
part of
ISSN 1462-2416
1889
Review
Stevens, De Leonibus, Hanson et al.
18
Height: boys Height: girls Height velocity: boys Height velocity: girls
170
16 14
150
Height (cm)
10 110
8 6
90
Height velocity (cm/year)
12 130
4 70
2
50 0 2
2
4
6
8
4
10 12 Age (years)
6
8
14 10
16 12
14
18 16
20 17
0
30
2
Evolutionarily conserved growth pathways
3 1
NOTCH signaling FDR: Infancy = 1.45 × 10-5 Puberty = 4.76 × 10-5 VEGF signaling FDR: Infancy = 7.69 × 10-6 Puberty = 8.47 × 10-6 WNT signaling FDR: Infancy = 3.45 × 10-5 Puberty = 5.92 × 10-5 Adult = 1.25 × 10-4 TGFB signaling FDR: Infancy = 3.70 × 10-5 Puberty = 7.52 × 10-6
-2.5
0.00
+2.5
Figure 1. Gene expression associated with age and phase of growth. (A) Heat map of age-associated changes in gene expression correlated with phases of human growth: 927 probes were significantly associated with age and phase of human growth (ANOVA; FDR-corrected p-value; q
Pediatric perspective on pharmacogenomics The advances in high-throughput genomic technologies have improved the understanding of disease pathophysiology and have allowed a better characterization of drug response and toxicity based on individual genetic make up. Pharmacogenomics is being recognized as a valid approach used to identify patients who are more likely to respond to medication, or those in whom there is a high probability of developing severe adverse drug reactions. An increasing number of pharmacogenomic studies are being published, most include only adults. A few studies have shown the impact of pharmacogenomics in pediatrics, highlighting a key difference between children and adults, which is the contribution of developmental changes to therapeutic responses across different age groups. This review focuses on pharmacogenomic research in pediatrics, providing examples from common pediatric conditions and emphasizing their developmental context. KEYWORDS: adverse drug reactions n pediatrics n personalized medicine n pharmacogenomics
The use of genetic information has played a major role in the development of personalized medicine, selecting the best medicine at the right dose with the lowest risk of side effects [1]. Pharmacogenomics is defined as “the study of the variability of the expression of individual genes relevant to the disease susceptibility as well as drug response at cellular, individual or population level” [2]. Pharmacogenomic research provides a method for potentially identifying patients who are likely to respond to medication and/or those in whom there is a high probability of developing severe adverse drug reactions (ADRs) [3]. The drug regulatory agencies, US FDA and EMA, recommend the use of pharmacogenomics in drug development and have begun to build up a common approach. Furthermore, both FDA officials and EMA committee members recently expressed the view that pharmacogenomics, unlike other forms of genetic testing, does not present any special ethical or social concerns [4]. The aim of the regulatory agencies is the development of international policies and standards to assist in guiding and promoting the adoption of pharmacogenomics. An increasing number of studies are being published that describe differences in drug response as a result of individual genetic background, but most of these reports include only adult individuals. Only a few studies have shown the impact of pharmacogenomics in pediatrics and have highlighted important differences
between children and adults. A major issue is the relative contribution of ontogeny and genetic variation to therapeutic response across different age groups and developmental stages, which range through newborns, infants, children and adolescents [5–7]. The normal background of child development over which pediatric conditions arise adds a complexity to pharmacogenomic study that is superimposed upon genetic variation [7]. In addition, several diseases are more prevalent in children or have no adult correlate, and some ADRs are unique or occur at a higher frequency in children [1,8]. The aim of this review is to focus on pediatric pharmacogenomics, highlighting the impact of child development and the importance of this approach in clinical practice.
10.2217/PGS.13.193 © 2013 Future Medicine Ltd
Pharmacogenomics (2013) 14(15), 1889–1905
Genetic ontogeny of childhood development & its relationship to pediatric pharmacogenomics Pediatric medicine is set against the background of the developing child [5,6]. Recently it has been shown that gene expression changes in a set of evolutionarily conserved growth pathways (e.g. WNT, TGFB, VEGF and NOTCH) vary in a tissue-independent manner that is correlated with stage of human development (Figure 1) [7]. These pathways have been found to correlate with age and different phases of human growth, ranging from infancy to childhood and adulthood. A similar phenomenon has been shown in rodents [9], and
Adam Stevens‡1, Chiara De Leonibus‡1, Daniel Hanson1, Andrew Whatmore1, Philip Murray1, Rachelle Donn2, Stefan Meyer3, Pierre Chatelain4 & Peter Clayton*1 Institute of Human Development, Medical & Human Sciences, University of Manchester & Royal Manchester Children’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, 5th Floor Research, Oxford Road, Manchester, M13 9WL, UK 2 Musculoskeletal Research Group, NIHR Biomedical Research Unit, Medical & Human Sciences, University of Manchester, UK 3 Stem Cell & Leukaemia Proteomics Laboratory, School of Cancer & Imaging Sciences, Medical & Human Sciences, University of Manchester, UK 4 Department Pediatrie, Hôpital MèreEnfant – Université Claude Bernard, 69677 Lyon, France *Author for correspondence: Tel.: +44 161 701 6949 [email protected] ‡ Authors contributed equally 1
part of
ISSN 1462-2416
1889
Review
Stevens, De Leonibus, Hanson et al.
18
Height: boys Height: girls Height velocity: boys Height velocity: girls
170
16 14
150
Height (cm)
10 110
8 6
90
Height velocity (cm/year)
12 130
4 70
2
50 0 2
2
4
6
8
4
10 12 Age (years)
6
8
14 10
16 12
14
18 16
20 17
0
30
2
Evolutionarily conserved growth pathways
3 1
NOTCH signaling FDR: Infancy = 1.45 × 10-5 Puberty = 4.76 × 10-5 VEGF signaling FDR: Infancy = 7.69 × 10-6 Puberty = 8.47 × 10-6 WNT signaling FDR: Infancy = 3.45 × 10-5 Puberty = 5.92 × 10-5 Adult = 1.25 × 10-4 TGFB signaling FDR: Infancy = 3.70 × 10-5 Puberty = 7.52 × 10-6
-2.5
0.00
+2.5
Figure 1. Gene expression associated with age and phase of growth. (A) Heat map of age-associated changes in gene expression correlated with phases of human growth: 927 probes were significantly associated with age and phase of human growth (ANOVA; FDR-corrected p-value; q
