American Gastroenterological Association Future Trends Committee Report: The Application of Genomic and Proteomic Technologies to Digestive Disease Diagnosis and Treatment and Their Likely Impact on Gastroenterology Clinical Practice

(1) An A/C SNP is shown in red within a DNA stretch of chromosome 9. (2) Microsatellite D22S423 consisting of 24 CA repeats is shown in blue within a segment of sequence from chromosome 22. (3) An insertion of 3 bases (ATA) is shown in red. (4) A deletion of 2 bases (GT) is shown in red.

Many thousands of years ago, a SNP (arrowhead) arose on an ancestral chromosome. Five contemporary chromosomes are shown, the products of random meiotic recombination over thousands of generations. Each of the contemporary chromosomes has variable length domains of the common ancestral chromosome (regions shown in white), which hold the original SNP (arrowheads), while new chromosomal segments (shown in gray) are the result of recombination. Modified and reprinted with permission from Ardlie et al. Nat Rev Genet 2002;3:299–309 (http://www.nature.com/).

Patterns of LD are not uniform across the genome. Recombination of chromosomes appears to be localized in short “hot spots” of low LD (red segments), positioned between larger chromosomal domains of high LD (green sections) exhibiting low haplotype diversity called “haplotype blocks.” Specific SNPs (colored triangles) within each haplotype block that are strongly associated with the majority of haplotypes in the population are termed “tag-SNPs” and can be used to detect a haplotype associated with a disease. Non–tag-SNPs (white triangles) are also shown. Reprinted with permission from Trends in Genetics, Vol 18, Stumpf pages 226–228, 2002 from Elsevier.²⁰

In functional cloning, the biochemical defect of a disease (ie, sickle cell anemia) is known before the causative gene is found and mapped on the genome. In contrast, positional cloning seeks first to map the causative gene of the disease (ie, chronic granulomatous disease) in the genome without prior knowledge of its structure or function.

The distribution of genetic disease classification changes by aging. Chromosomal diseases peak before birth. Mendelian diseases are more common before puberty. Complex diseases affect mainly the adult population. Modified and reprinted with permission from Gelehrter T, Collins FS, Ginsburg D, eds. The role of genetics in medicine. Principles of medical genetics. 2nd ed. Media, PA: Williams & Wilkins, 1998:1–8.

In Mendelian disorders, a single gene is usually the cause of the disease. There is a direct correspondence of a genotype to a phenotype. The disease trait is inherited in a predicted pattern (ie, autosomal dominant, autosomal recessive, or X-linked). All affected members in a pedigree carry the same gene mutation. Modified and reprinted with permission from Peltonen et al. Science 2001;291:1224–1229.

In complex disorders, the interplay of multiple genetic variants with the environment determines risk of the disease phenotype. The contribution of each factor to phenotype is small and varies among patients. Thus, complex diseases may be heterogeneous in pathogenesis and progression. Modified and reprinted with permission from Peltonen et al. Science 2001;291:1224–1229.

The genetic susceptibility of 2 nonbiologically related individuals A and B and the unique environmental history will define whether they will remain healthy or develop a complex disease. Modified and reprinted with permission from Sing et al. Genetic architecture of common multi-factorial diseases. In: Chadwick D, Cardew G, eds. Variation in the human genome. Chichester, England: Wiley, 1996:211–232.

On the left, a SNP (red triangle) located within an exon (rectangular box) of a candidate gene will be directly tested for association to a disease phenotype. The proposed causative SNP is selected for testing given prior experimental evidence regarding its effect on the function or expression of the candidate gene. On the right, 3 SNPs (blue triangles) that flank the proposed causative SNP (red triangle) will be genotyped to test indirectly the association of the latter to disease phenotype. The 3 SNPs were selected based on LD patterns in the vicinity of the gene of interest. Modified and reprinted with permission from Hirschhorn et al.³⁸

The proposed impact of genomics in medicine. Knowing the genetic contribution to disease will facilitate prevention, diagnosis, and novel therapies. Modified and reprinted with permission from Collins and McKusick (the AMA does not hold copyright to this article. It was written by an employee of the United States Federal Government and thus is in the public domain.)¹⁰⁷

The putative clinical impact of genomics and proteomics over the next 25 years. Genomics and proteomics are currently in a discovery and research phase, during which time there will be little direct impact on clinical practice. Nevertheless, expected improvements in genomic technology (ie, P450 array, whole genome sequence cost at $100,000 or $1000 per person) and data analysis, coupled with the knowledge gained in the initial period, will result in an exponential increase of clinical impact; use of genetic testing and designer drugs are proposed to be introduced into medical practice in 2015 and 2020, respectively.