Genetic Variants and Common Diseases — Better Late Than Never
http://www.100md.com
《新英格兰医药杂志》
Our understanding of the molecular basis for monogenic disorders has made remarkable progress during the past 30 years, leading to new insights into disease mechanisms, a huge increase in the range of prenatal and presymptomatic diagnostic tests, and although still uncommon, some mechanism-based therapies for genetic diseases. However, for most diseases, the nature of an inherited predisposition is more complex. If the genetic variants underlying complex disease could be identified, they too might bring clinical benefits. Such progress might occur, for example, through the identification of new disease pathways that could be exploited by new pharmacotherapy or by more effective targeting of particular treatments to genetically defined subgroups of patients.
As the past millennium closed, there was a growing feeling in the biomedical community that the efforts of geneticists to identify the specific genetic variants underlying polygenic diseases had been less successful than had been promised. Many initial reports of disease associations were not replicated by later studies. Since 2001, however, a number of convincingly replicated reports have identified common genetic polymorphisms that have a major effect on a range of disorders, such as inflammatory bowel disease1 and macular degeneration.2 The power of genome-wide investigations of genetic association in the study of quantitative human traits is illustrated by the recent discovery of a functional single-nucleotide polymorphism responsible for a large proportion of the variation in the pigmentation of human skin.3
The relative homogeneity and the unique genealogy of the Icelandic population are ideal for the use of linkage analysis to pinpoint genomic regions of manageable size and, subsequently, to identify important new genes. The research team at the Icelandic biopharmaceutical company deCODE Genetics has made several important discoveries related to genes that may influence the risk of diseases such as myocardial infarction, stroke,4 and prostate cancer5 and also has recently reported compelling evidence for a new gene that is associated with type 2 diabetes.6 In this issue of the Journal, Florez et al.7 extend these observations by showing that this gene influences the rate of progression from impaired glucose tolerance to diabetes mellitus and that the risk allele seems to be associated with decreased insulin secretion.
In 2003, Reynisdottir et al. reported evidence for linkage of type 2 diabetes in Icelandic pedigrees to chromosome 5q34-q35.2.8 Grant et al. used microsatellite markers localized to this region in association studies in a large Icelandic case–control study.6 Having found a strong association with one marker, they undertook replication studies in two independent populations and found strikingly positive support with a likelihood of less than 10–14 that this association was being found by chance.
The microsatellite marker (called DG10S478) is located within intron 3 of the transcription factor 7–like 2 gene (TCF7L2) on chromosome 10q25.2. Although there are other single-nucleotide polymorphisms in TCF7L2, many of which are in strong linkage disequilibrium with the DG10S478 marker, none of them would be predicted to alter the protein sequence. It is unclear whether the microsatellite itself influences the function of TCF7L2 by, for example, altering gene expression. The risk of diabetes among carriers of a single copy of the risk allele is increased by a factor of 1.45, and among carriers of two risk alleles by an impressive factor of 2.41. This is the largest odds ratio that we are aware of for a gene associated with susceptibility to type 2 diabetes. Florez et al. studied participants in the previously reported Diabetes Prevention Program (DPP) and examined whether the TCF7L2 genotype influences the risk of progression from impaired glucose tolerance to diabetes over a three-year period. They found that participants who were homozygous for the high-risk allele had a 55 percent greater rate of conversion from impaired glucose tolerance to diabetes over a three-year period than those who were homozygous for the low-risk alleles.
How does TCF7L2 affect the risk of diabetes? TCF7L2 is widely expressed and is known to respond to developmental signals from members of the Wnt family of proteins.6 TCF7L2 has a particularly important role in the development of the intestine,9 and Grant et al. suggest that it might impair the function of enteroendocrine cells within the gut that are responsible for producing insulinotropic hormones.6 In their current study, Florez et al. show that persons who are homozygous for the high-risk allele have lower levels of insulin secretion in response to an oral glucose-tolerance test at baseline than do those who are homozygous for the wild-type allele. It is too early to say what the precise mechanisms underlying this reduced insulin secretion might be. In addition to the putative indirect effect on pancreatic endocrine function by means of the endocrine cells of the gut, TCF7L2 could have a direct role in the development or regeneration of pancreatic islets.
The articles by Grant et al. and Florez et al. add TCF7L2 to a short list of genes in which common variants are known to influence the risk of type 2 diabetes.10 Most of these seem to increase the risk of diabetes by impairing insulin secretion. The polygenic determinants of obesity, insulin resistance, and the metabolic syndrome may be distinct and are highly likely to differ from those determining type 2 diabetes, which is the phenotype that occurs when pancreatic beta-cell function fails. The discovery of these genes may require the study of population groups without diabetes and with phenotypes for adiposity and insulin sensitivity.
The risk of diabetes is driven by major environmental determinants, both prenatally and postnatally. How might these interact with the known genetic factors? In the DPP, the risk of progression to diabetes in the high-risk alleles of TCF7L2 was lower in persons who were randomly assigned to intensive diet, exercise, or metformin than to placebo, but there was no significant interaction according to intervention group. Such an interaction seems plausible, since the interventions in the DPP trial primarily affected insulin sensitivity, but the single-nucleotide polymorphism in TCF7L2 is more likely to influence the capacity of the pancreatic beta cell to cope in the face of insulin resistance.
Does this new genetic information have any practical health implications? At first glance, TCF7L2 is not the most attractive of drug targets, since it is closely involved in fundamental developmental processes.9 The main effect of the high-risk single-nucleotide polymorphisms in relation to diabetes may be developmental and may not be amenable to therapeutic manipulation in the adult patient. Nevertheless, the pharmaceutical industry will be looking carefully at agents that modulate the signaling pathways of TCF7L2. Perhaps a more immediate use of this information, in combination with other genetic and nongenetic information, will be in refining a risk profile for diabetes in order to determine the need for and the intensity of follow-up or to influence decisions about staged implementation of preventive interventions with behavioral or drug therapy.
With hindsight we can see that the race to find genetic variants underlying common diseases had a somewhat faltering start, weighed down by excessive expectations and an inadequate understanding of the methodologic pitfalls. Recent developments show that the race has, at last, entered a fast-moving, exciting, and highly productive phase.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Department of Clinical Biochemistry and Medicine, University of Cambridge, Addenbrooke's Hospital (S.O.); and the Medical Research Council Epidemiology Unit (N.J.W.) — both in Cambridge, United Kingdom.
References
Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 2001;411:603-606.
Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005;308:385-389.
Lamason RL, Mohideen MA, Mest JR, et al. SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Science 2005;310:1782-1786.
Helgadottir A, Manolescu A, Thorleifsson G, et al. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet 2004;36:233-239.
Amundadottir LT, Sulem P, Gudmundsson J, et al. A common variant associated with prostate cancer in European and African populations. Nat Genet 2006;38:652-658.
Grant SF, Thorleifsson G, Reynisdottir I, et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 2006;38:320-323.
Florez JC, Jablonski KA, Bayley N, et al. TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med 2006;355:241-250.
Reynisdottir I, Thorleifsson G, Benediktsson R, et al. Localization of a susceptibility gene for type 2 diabetes to chromosome 5q34-q35.2. Am J Hum Genet 2003;73:323-335.
Korinek V, Barker N, Moerer P, et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet 1998;19:379-383.
O'Rahilly S, Barroso I, Wareham NJ. Genetic factors in type 2 diabetes: the end of the beginning? Science 2005;307:370-373.(Stephen O'Rahilly, M.D., )
As the past millennium closed, there was a growing feeling in the biomedical community that the efforts of geneticists to identify the specific genetic variants underlying polygenic diseases had been less successful than had been promised. Many initial reports of disease associations were not replicated by later studies. Since 2001, however, a number of convincingly replicated reports have identified common genetic polymorphisms that have a major effect on a range of disorders, such as inflammatory bowel disease1 and macular degeneration.2 The power of genome-wide investigations of genetic association in the study of quantitative human traits is illustrated by the recent discovery of a functional single-nucleotide polymorphism responsible for a large proportion of the variation in the pigmentation of human skin.3
The relative homogeneity and the unique genealogy of the Icelandic population are ideal for the use of linkage analysis to pinpoint genomic regions of manageable size and, subsequently, to identify important new genes. The research team at the Icelandic biopharmaceutical company deCODE Genetics has made several important discoveries related to genes that may influence the risk of diseases such as myocardial infarction, stroke,4 and prostate cancer5 and also has recently reported compelling evidence for a new gene that is associated with type 2 diabetes.6 In this issue of the Journal, Florez et al.7 extend these observations by showing that this gene influences the rate of progression from impaired glucose tolerance to diabetes mellitus and that the risk allele seems to be associated with decreased insulin secretion.
In 2003, Reynisdottir et al. reported evidence for linkage of type 2 diabetes in Icelandic pedigrees to chromosome 5q34-q35.2.8 Grant et al. used microsatellite markers localized to this region in association studies in a large Icelandic case–control study.6 Having found a strong association with one marker, they undertook replication studies in two independent populations and found strikingly positive support with a likelihood of less than 10–14 that this association was being found by chance.
The microsatellite marker (called DG10S478) is located within intron 3 of the transcription factor 7–like 2 gene (TCF7L2) on chromosome 10q25.2. Although there are other single-nucleotide polymorphisms in TCF7L2, many of which are in strong linkage disequilibrium with the DG10S478 marker, none of them would be predicted to alter the protein sequence. It is unclear whether the microsatellite itself influences the function of TCF7L2 by, for example, altering gene expression. The risk of diabetes among carriers of a single copy of the risk allele is increased by a factor of 1.45, and among carriers of two risk alleles by an impressive factor of 2.41. This is the largest odds ratio that we are aware of for a gene associated with susceptibility to type 2 diabetes. Florez et al. studied participants in the previously reported Diabetes Prevention Program (DPP) and examined whether the TCF7L2 genotype influences the risk of progression from impaired glucose tolerance to diabetes over a three-year period. They found that participants who were homozygous for the high-risk allele had a 55 percent greater rate of conversion from impaired glucose tolerance to diabetes over a three-year period than those who were homozygous for the low-risk alleles.
How does TCF7L2 affect the risk of diabetes? TCF7L2 is widely expressed and is known to respond to developmental signals from members of the Wnt family of proteins.6 TCF7L2 has a particularly important role in the development of the intestine,9 and Grant et al. suggest that it might impair the function of enteroendocrine cells within the gut that are responsible for producing insulinotropic hormones.6 In their current study, Florez et al. show that persons who are homozygous for the high-risk allele have lower levels of insulin secretion in response to an oral glucose-tolerance test at baseline than do those who are homozygous for the wild-type allele. It is too early to say what the precise mechanisms underlying this reduced insulin secretion might be. In addition to the putative indirect effect on pancreatic endocrine function by means of the endocrine cells of the gut, TCF7L2 could have a direct role in the development or regeneration of pancreatic islets.
The articles by Grant et al. and Florez et al. add TCF7L2 to a short list of genes in which common variants are known to influence the risk of type 2 diabetes.10 Most of these seem to increase the risk of diabetes by impairing insulin secretion. The polygenic determinants of obesity, insulin resistance, and the metabolic syndrome may be distinct and are highly likely to differ from those determining type 2 diabetes, which is the phenotype that occurs when pancreatic beta-cell function fails. The discovery of these genes may require the study of population groups without diabetes and with phenotypes for adiposity and insulin sensitivity.
The risk of diabetes is driven by major environmental determinants, both prenatally and postnatally. How might these interact with the known genetic factors? In the DPP, the risk of progression to diabetes in the high-risk alleles of TCF7L2 was lower in persons who were randomly assigned to intensive diet, exercise, or metformin than to placebo, but there was no significant interaction according to intervention group. Such an interaction seems plausible, since the interventions in the DPP trial primarily affected insulin sensitivity, but the single-nucleotide polymorphism in TCF7L2 is more likely to influence the capacity of the pancreatic beta cell to cope in the face of insulin resistance.
Does this new genetic information have any practical health implications? At first glance, TCF7L2 is not the most attractive of drug targets, since it is closely involved in fundamental developmental processes.9 The main effect of the high-risk single-nucleotide polymorphisms in relation to diabetes may be developmental and may not be amenable to therapeutic manipulation in the adult patient. Nevertheless, the pharmaceutical industry will be looking carefully at agents that modulate the signaling pathways of TCF7L2. Perhaps a more immediate use of this information, in combination with other genetic and nongenetic information, will be in refining a risk profile for diabetes in order to determine the need for and the intensity of follow-up or to influence decisions about staged implementation of preventive interventions with behavioral or drug therapy.
With hindsight we can see that the race to find genetic variants underlying common diseases had a somewhat faltering start, weighed down by excessive expectations and an inadequate understanding of the methodologic pitfalls. Recent developments show that the race has, at last, entered a fast-moving, exciting, and highly productive phase.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Department of Clinical Biochemistry and Medicine, University of Cambridge, Addenbrooke's Hospital (S.O.); and the Medical Research Council Epidemiology Unit (N.J.W.) — both in Cambridge, United Kingdom.
References
Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 2001;411:603-606.
Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005;308:385-389.
Lamason RL, Mohideen MA, Mest JR, et al. SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Science 2005;310:1782-1786.
Helgadottir A, Manolescu A, Thorleifsson G, et al. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet 2004;36:233-239.
Amundadottir LT, Sulem P, Gudmundsson J, et al. A common variant associated with prostate cancer in European and African populations. Nat Genet 2006;38:652-658.
Grant SF, Thorleifsson G, Reynisdottir I, et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 2006;38:320-323.
Florez JC, Jablonski KA, Bayley N, et al. TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med 2006;355:241-250.
Reynisdottir I, Thorleifsson G, Benediktsson R, et al. Localization of a susceptibility gene for type 2 diabetes to chromosome 5q34-q35.2. Am J Hum Genet 2003;73:323-335.
Korinek V, Barker N, Moerer P, et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet 1998;19:379-383.
O'Rahilly S, Barroso I, Wareham NJ. Genetic factors in type 2 diabetes: the end of the beginning? Science 2005;307:370-373.(Stephen O'Rahilly, M.D., )