41CHAPTER 3
Human Diversity and Variation
Emma L. Kurnat-Thoma
WE ARE NOT ALL GENETICALLY IDENTICAL
CASE EXAMPLE 1
Ellen and Mary are next-door neighbors in Kansas City, Missouri. Both of them have had appointments with the same woman’s health nurse practitioner for preconception counseling. Ellen, who is of Ashkenazi Jewish descent, has been asked to consider genetic testing to determine whether she might be a carrier for Tay–Sachs disease, as well as certain other conditions, but not β-thalassemia. Tay–Sachs disease is an autosomal recessive neurodegenerative disorder. Mary, who is of Greek descent, has been asked to consider genetic testing to determine whether she might be a carrier for β-thalassemia, but not Tay–Sachs disease. β-thalassemia is an autosomal recessive disorder resulting in deficient or absent synthesis of the β hemoglobin chains. After reading this chapter, you should be able to answer why the recommended testing was considered appropriate for each woman.
42CASE EXAMPLE 2
Joan recently experienced a pulmonary embolism and must receive warfarin anticoagulation to prevent life-threatening clot formation. Genetic variation in two genes responsible for the metabolism of the drug accounts for up to 50% of patients’ clinical response to warfarin. The nurse is reviewing a clinical test report for Joan that identifies her as having a VKORC1-1639 G>A single-nucleotide polymorphism (SNP) genotype AA, for which the Food and Drug Administration recommends a reduced warfarin starting dose. After reading this chapter, you will understand what this means and why SNP genotype should be considered before starting warfarin.
GENETIC INDIVIDUALITY
Each individual has a unique genetic constitution that makes him or her genetically and biochemically distinct from all other individuals (except for monozygous twins, triplets, and other identical multiples). No individuals, with the exceptions mentioned, have the exact same genotype or phenotype. Even identical twins can show epigenetic differences. Because a person’s genetic constitution and environmental interactions are unique, each person has his or her own relative state of health and is not at equivalent risk for developing a given disease. A person’s genetic makeup plays a pivotal role in the maintenance of homeostasis and in susceptibility and resistance to disease.
Most genes in humans are shared by all members of the human species. Differences have more to do with variation in frequency of certain alleles than in whether the gene is present or absent. The differing sequences (alleles) that result in genetic variation across individuals are called polymorphisms when they are maintained in a population with a frequency of at least 1%. Historically, genetic variation in humans was assessed by studying variation in proteins. For example, the ABO and Rh blood groups and the human leukocyte antigen (HLA) system are some of the best-known and classical examples of human genetic variation. Understanding genetic variation in these systems resulted in the ability to perform compatible blood product transfusions and tissue transplants between patients. Other classic examples of genetic variation include diseases characterized by microscopically observable alterations in chromosome number or shape (e.g., trisomies, monosomies, aneuploidies, translocations, and microdeletions).
Prior to the Human Genome Project, genetic variation in populations and/or families was evaluated by mapping genes to the chromosomes where they were located; once a gene was located on a chromosome, gene function was identified (e.g., how the cystic fibrosis gene was identified in 1989). Knowledge from recent federal and international scientific initiatives, such as the Human Genome Project (completed in 2003), the HapMap (Phase 3 completed in 2009), and the 1000 Genomes Project (Phase 3 completed in 2014), is fueling new understanding of human health. 43Through advanced genotyping technologies that are also cost-effective, these initiatives have provided millions of newly identified sites of genetic variation, and are driving innovative approaches to detecting, diagnosing, and treating human disease. Knowledge of genetic variation in individuals and populations lays the foundations for understanding diagnostic genetic testing, performing forensic analysis in legal investigations, and determining variable risks/outcomes in disease development and therapeutic treatments Chapter 6, “The Application of Genomics to Pharmacology,” will review how individuals’ genetic differences can impact their responses to drugs.
VARIATIONS AND POLYMORPHISMS IN PROTEINS
Blood Group Systems
Immunogenetics is the study of the genetics of the immune system, and encompasses all the cells and mechanisms the body uses to determine “self” from “non-self” (e.g., to fight invading pathogens, foreign substances, etc.). The field came into being in 1900 when Dr. Karl Landsteiner first discovered that fatal hemolytic reactions after blood transfusions were caused by incompatible cell-surface antigens on red blood cells, known as the ABO blood group system. Presently, the ABO blood group system is one of 35 blood group systems, with hundreds of antigens recognized to be clinically significant in transfusion medicine (International Society of Blood Transfusions, 2014). However, the best characterized and most important are the ABO and Rhesus (Rh) systems. Compatibilities between the ABO and Rh blood group systems are crucial for successful blood transfusions and tissue graft transplantations. Incompatibilities in these systems between mothers and their developing fetuses can also have severe, even life-threatening consequences.
ABO System
The ABO system is the most clinically important blood group system. There are two major antigens found on the surface of red blood cells: A and B. These two antigens correspond to four blood group types: A (individual has the A antigen), B (individual has the B antigen), AB (individual has both the A and B antigens), and O (individual carries neither the A nor B antigen). In plasma, individuals with A antigen have anti-B antibodies, and individuals with B antigen have anti-A antibodies. The ABO locus is on chromosome 9; while A and B alleles are codominant, O is recessive. The A and B alleles code for glycosyltransferases, which are enzymes that add carbohydrate sugar precursors to form the A and B glycoprotein antigens. The O allele does not produce an enzyme. The A and B antigens are not confined to the red blood cell but are widely distributed throughout the body. There are various subtypes and polymorphisms of the A, B, and O alleles, and are beyond the scope of this chapter. The relationships between blood group phenotypes and genotypes are shown in Table 3.1, and examples of the inheritance of the ABO and Rh blood groups are illustrated in Figure 3.1. Persons with blood group O are universal blood transfusion donors, and are sometimes said to have a “null” phenotype. Persons with blood group AB are universal blood transfusion recipients because they have no antibodies in their plasma. Frequency of the ABO blood group varies across ethnic and geographic groups and has been used in population genetics to study human diversity, migration, and selection. The ABO blood group has also been associated with various diseases. For example, the A antigen is linked to slightly increased risk of gastric cancer.
44
Rhesus (Rh) System
The Rh system is the second most clinically important blood group system because of its role in blood transfusion incompatibilities. It was not until 1940 that Dr. Landsteiner and Dr. Alexander Wiener discovered this system in experiments involving Rhesus monkeys. Since the initial discovery, this system has become complex with identification of over 40 known antigens encoded by two highly polymorphic genes. The most common is the D/d antigen. If D is present, this confirms a patient’s “Rh-positive” status; conversely, if no D antigen is present the individual is “Rh-negative.” Two other allele pairs, C/c and E/e, are also found on the Rh protein but are much less antigenic than D. The Rh antigen genes D/d, E/e, and C/c are very closely linked on chromosome 1 and are inherited as a haplotype (e.g., cDe, CDe, etc.). Figure 3.1 outlines this inheritance pattern. An Rh-negative (dd) woman and an Rh-positive man are more likely to have an Rh-positive child if the father is homozygous (DD) than if he is heterozygous (Dd). In the latter case, the chance that the child would be Rh-positive at each pregnancy is 50% as opposed to 100%. The frequency of Rh-positive, Rh-negative status varies widely based on ethnicity. Approximately 85% of Caucasians are Rh-positive, compared to 92% for African Americans and 99% for Asians.
FIGURE 3.1. Selected examples of blood group gene transmission.
45The D Rh-antigen is highly immunogenic. Individuals without the D antigen produce anti-D antibodies if exposed, resulting in a hemolytic reaction. The significance of the Rh-system lies in its application to maternal–fetal Rh incompatibility. When the father is Rh-positive and the mother is Rh-negative, the Rh-positive fetus can receive maternal anti-Rh antibodies across the placenta in utero or during delivery and trigger hemolytic disease of the newborn (erythroblastosis fetalis). Hemolytic disease of the newborn is most often seen during the second or later pregnancies, after maternal sensitization to the D antigen develops. First pregnancies are often unaffected unless the mother experienced previous lost pregnancies that sensitized her immune system; later pregnancies can become progressively more severe as sensitization increases.
Rh incompatibility between a mother and fetus has a range of symptoms ranging from mild to fatal. In its mildest form, Rh incompatibility results in destruction of red blood cells, leading to jaundice in the newborn. At its most severe, infants may die in utero as a result of massive antibody-induced hemolytic anemia. Factors such as concurrent ABO incompatibility, volume of transplacental exposure, and extent of maternal immune response determine reaction severity. Consequently, determination of maternal Rh blood type is a standard requirement of prenatal care (The American College of Obstetricians and Gynecologists, 2013). For Rh-negative women, Rh immunoglobulin (i.e., RhoGAM) is administered at 28 weeks gestation and 72 hours after delivery to reduce the incidence of antenatal alloimmunization to about 0.1%. If the Rh of the father of the child is unknown and other conditions indicate the possibility of incompatibility (e.g., mother Rh [−], second pregnancy), Rh immunoglobulin should be administered.
Since the availability of Rh (D) immunoglobulin in 1968, the incidence of hemolytic disease of the newborn has markedly decreased. However, not all women who should be receiving Rh immunoglobulin are. Therefore, nurses need to be aware of events that can cause sensitization requiring Rh immunoglobulin administration, such as fetomaternal hemorrhage, spontaneous or induced abortion even in early pregnancy, any previous blood transfusion that was (or might have been) Rh incompatible, amniocentesis, chorionic villus sampling, fetal blood sampling, fetoscopy, abdominal trauma, and cesarean section.
The HLA System
A particular group of molecules located on the surfaces of most cells in the human body is known as the major histocompatibility complex (MHC; class I). MHC 46molecules (class II) also present protein fragments to immune cells when detecting foreign substance(s), and triggers the body to mount an immune response. In humans, these MHC molecules are called human leukocyte antigens (HLAs). Major functions of the HLA system include acting as a marker of “self” and the presentation of antigens to T-helper cells. There is a large group of over 220 MHC genes located close together (within 4-Mb) on the short arm of chromosome 6, at 6p21.3. The MHC genes are categorized into three classes (I, II, and III) based on structure and function (World Health Organization Committee for HLA Nomenclature, 2014). The most clinically important antigen groups are the class I loci—HLA-A, HLA-B, HLA-C—and the class II loci—HLA-DR, HLA-DP, and HLA-DQ (Genetics Home Reference, 2009). Roles of others continue to emerge. The HLA system is the most polymorphic system known and expresses hundreds of different alleles. It provides tremendous human variability and ensures resistance to a wide variety of pathogens.
The major class I genes—HLA-A, HLA-B, and HLA-C—encode for antigens that are present on cell membranes of nucleated cells throughout the body. Class I antigens present antigenic peptide to cytotoxic-T (CD8+) cells and determine the response of natural killer cells. Class II locus antigens—HLA-DQ, HLA-DP, and HLA-DR—are primarily expressed on the surfaces of immunocompetent cells (e.g., B-lymphocytes, monocytes, endothelial cells, dendritic cells, activated T-lymphocytes, and macrophages) and present antigenic peptide to T-helper (CD4+) cells. The class III locus encodes numerous serum proteins and membrane receptors that are important for proper immune function, including complement components C2, Bf, C4A, C4B, as well as products unrelated to the immune system such as steroid 21-hydroxylase, the major heat shock protein, and tumor necrosis factors (TNFs).
Since letters are assigned to the HLA loci in the order of their discovery, they do not reflect their order on the chromosome. The HLA genes are tightly linked and are usually inherited together codominantly, with infrequent recombination (less than 1%) occurring. Linkage disequilibrium occurs when two or more of the alleles in the HLA system are inherited together in a haplotype more frequently than would be expected by chance. In European populations, HLA-A1 and HLA-B8 occur together with an observed frequency that far exceeds the expected frequency from random assortment of alleles during meiotic recombination. The frequency of individual HLA antigens varies according to different ethnic populations; for example, HLA-A9 is present in 65% of Asian populations but only 17% of European Caucasian populations. HLA-B8 is common in White populations and rare in Asians. There is also significant variation in the ethnic distribution of HLA haplotypes.
The largest single use for HLA typing is in tissue and organ transplantation, including blood products. In some institutions, typing of the HLA-A, HLA-B, and HLA-C loci is used to screen donors for platelet and leukocyte transfusions because of the problem of sensitivity for those persons already having such multiple transfusions.
HLA and Disease Associations
Intense interest in the HLA system was originally generated because of the realization of its role in successful tissue graft and organ transplantation. This interest expanded to include the relationship among HLA antigens, haplotypes, and the development 47of certain diseases. It was recognized that individuals with specific HLA alleles and haplotypes were much more likely to develop certain diseases. Some of the strongest associations involve autoimmune diseases or disorders featuring an immunologic defect.
In genetics, scientists can study the expected frequency of disease prevalence in groups of patients with and without certain genotypes and/or haplotypes, and calculate an estimate for the strength of the association and a patient’s risk for developing an illness. Relative risk refers to how much more frequently a specific disease develops in individuals carrying a specific HLA antigen, compared to the frequency of disease in individuals who do not carry it. It is important to remember that relative risk calculations produced from genetic association studies are estimates and not an absolute prediction of risk. Not all individuals with a particular HLA genotype may develop a certain illness despite the strong association. In addition to disease susceptibilities, genetic association studies can also identify protective genetic effects. For example HLA-B*53 is protective against severe malaria in West Africa.
Two of the most striking HLA-disease associations are between HLA-B27 and ankylosing spondylitis, an inflammatory joint disease often resulting in vertebral fusion, and of HLA-DQB1*0602 and narcolepsy, a primary sleep disorder characterized by excessive daytime sleepiness and disturbances of rapid eye movement (REM) sleep due to deficiency of the neuropeptide hypocretin. HLA-B27 is found in 90% to 95% of patients with idiopathic ankylosing spondylitis regardless of ethnic group. In populations without the disorder, HLA-B27 is found in 6% to 8% of European and North American Whites, 2% of Chinese and Black Americans, and 0.2% of Japanese populations. It is estimated that a male with the B27 antigen has a relative risk of developing the disorder that is 90 to 100 times greater than a male not possessing this antigen. The chance for a person who has HLA-B27 to develop ankylosing spondylitis is estimated at 5% to 20%. Thus, not all those with HLA-B27 develop ankylosing spondylitis, although some may have subtle symptoms that never develop into disease and are not detected. HLA-B27 is found in 75% of persons with Reiter disease, and up to 90% of persons who develop arthritis after enteric infection due to Shigella, Salmonella, and certain Yersinia species.
In narcolepsy, HLA DQB1*0602 is present in 90% to 100% of persons with narcolepsy and cataplexy (brief sudden episode of weakness in voluntary muscles triggered by emotions such as laughing or anger). In contrast, HLA DQB1*0602 is present in 12% to 38% of the general population. Hypocretin genes are located in the HLA vicinity, although how they interact is not known. There has also been an association between HIV-1 disease and various HLA genotypes. For example, both HLA-B27 and HLA-B57 have been associated with slow progression, while certain HLA-B35 alleles (HLA-B*3502, *3503, and *3504) have been associated with rapid progression.
VARIATIONS AND POLYMORPHISMS IN DNA
With the exception of identical multiples, humans resemble each other in 99.9% of their DNA. This means that out of the total 3 billion base pairs in the human genome, there are ~10 million polymorphisms that make us uniquely different from one 48another. Thus, the remaining 0.1% difference creates a unique “fingerprint” among individuals and populations, and occurs within the coding (exonic) regions or noncoding (intronic) regions. Polymorphisms occur with a frequency of approximately 1:300 base pairs and are more frequent outside of gene coding areas. Polymorphisms may be single or multiple, and the more alternate alleles that exist in populations, the more useful they are for genetic and medical applications (see genetic testing in Chapter 5). Table 3.2 summarizes the most common types of human genetic variation. Genetic variation provides the basis of various DNA tests used for:
Genetic testing for diagnosis of certain disease conditions
Prenatal diagnosis of genetic disease
Tissue typing for organ transplantation
Distinguishing between similar-appearing diseases at the molecular level
Determining carrier status for certain genetic disorders
Determining the microbial etiology of a person’s infectious disease, and tracing variations in microbes to determine origins and patterns of spread
Determining genetic parentage and other family relationships in clinical testing, criminal investigations, and legal disputes
Individual identification in legal and forensic cases, including disasters and military personnel, and matching DNA in material at crime scenes or on victims with that of suspects on file in data banks
Defining population structure and performing research studies elucidating the clinical impact of genetic sequence (functional studies)
TABLE 3.2. Selected DNA Variations | |
Variation | Description |
RFLPs | Single base pair changes in DNA sequence resulting in “cutting” at a recognition site for a restriction enzyme. This produces increased or decreased strand lengths for cut restriction fragments, and can be measured in laboratory analysis. Used in classic genetic mapping experiments. |
SNPs | Single-nucleotide changes in DNA. Patterns of SNPs are being used to look at particular variation patterns across populations and ethnic groups. SNPs may or may not be associated with disease, and are used in laboratory research studies to elucidate a gene’s function (functional studies). SNP applications are fueling genomic health care, or personalized medicine. |
STRs | Short nucleotide repeats of two to five base pairs that are repeated a few to several hundred times. Commonly used in forensic analyses. |
VNTRs | Short DNA sequences from 10 to 100 base pairs that are repeated in tandem order a varying number of times. Used in forensic analyses. |
49Restriction Fragment Length Polymorphisms (RFLPs)
An early method of detecting DNA polymorphisms used bacterial restriction enzymes (restriction endonucleases) to recognize short, specific nucleotide sequences and make a “cut” in the DNA strand (Nussbaum, McInnes, & Willard, 2004). During RFLP laboratory analysis, the presence or absence of polymorphisms (can also be deletions or insertions) determines if “cuts” are made. When a particular polymorphism sequence is present and a “cut” occurs, one long strand of DNA is cut into shorter fragments (i.e., a 1.3 kb segment becomes 1.1 kb and 200 bp). The variable lengths of these restriction fragments can be separated and sorted by gel electrophoresis, transferred to a radioactive-isotope-labeled probe, and visualized by x-ray. RFLP analysis was the method used to identify polymorphisms instrumental in mapping the genes for cystic fibrosis and Huntington disease. While RFLP analysis was essential to early genetics medical care and research, it is not used frequently today. The enzyme can only detect two possible alleles (presence or absence of polymorphism) at the restriction site sequence, so the amount of genetic diversity that can be detected is limited. Since high-throughput genotyping has become so cost-effective in the past decade, SNPs are more plentiful, informative, relevant, and appropriate for use with genomic technologies.
Minisatellite and Microsatellite Polymorphisms—Variable Number of Tandem Repeats (VNTRs) and Short Tandem Repeats (STRs)
Another class of polymorphism similar to RFLPs allowing for detection of greater human diversity is minisatellites and microsatellites (Nussbaum, McInnes, & Willard, 2004). Minisatellites and microsatellites are distinct areas of the genome where the same DNA sequence repeats over and over. The terms are often used interchangeably to denote VNTRs and STRs. Minisatellites (VNTRs) are characterized by longer repeating DNA segments (i.e., 10 to 100 bp) while microsatellites (STRs) are characterized by shorter repeating DNA segments (i.e., 2, 3, 4, 5 bp). The number of repeats occurring within minisatellite and microsatellite regions of the genome can vary between individuals and is a significant type of human variation.
VNTRs are a type of polymorphism detected between two restriction sites. Individuals can have as few as 2 to 3 copies of repeating 10 to 100 bp DNA sequence in a minisatellite region, while others could have more than 20 copies. VNTRs are detected by a process similar to that described in the RFLP section above. A restriction enzyme digest is performed, and cut fragments are separated by gel electrophoresis, transferred to a radioactive-isotope-labeled probe, and visualized by x-ray. VNTRs are characterized by many alleles, as the number of repeats across individuals at specific sites in the genome varies greatly.
Occurring in even greater frequency than VNTRs, STRs are also a type of polymorphism, but cannot be detected between two restriction sites. The polymerase chain reaction (PCR) laboratory technique is used to amplify large quantities of a specific segment of DNA that contain STRs. Individuals can have as many as several 50hundred repeats of 2, 3, 4, or 5bp sequence copies (i.e., TAC, TAC, TAC, etc.). STRs occur widely throughout the genome and are extremely useful for gene mapping.
Both VNTRs and STRs are used for forensic applications including criminal investigations, genetic parenthood testing, and identification of deceased individuals following disasters and military conflicts. Since DNA is present in all tissues, it can be isolated and accurately amplified with PCR from most samples (e.g., tissue, blood, saliva, hair, semen, etc.), even if the sample is very small or has been stored for several years. Because VNTRs and STRs have so many alleles, a combination of several loci can be used to generate a highly specific DNA profile for an individual. Since two persons could have the same DNA profile at one locus, multiple sets of specific and highly variable regions are used to decrease the probability that a randomly selected person in the population has the exact same genotype; for example, estimated random match probability that two individuals have the exact same number of allelic repeats for all loci in a Federal Bureau of Investigation (FBI) standardized panel (Combined DNA Index System—CODIS) of 13 STRs approaches 1 in 100 trillion (Federal Bureau of Investigation, 2014; Hill, 2012). The greater the number of VNTRs or STR loci that are used in conducting forensic analyses, the greater the odds are that the match is not coincidental, but more time and expense is involved. Typically the 13 CODIS markers suffice for most general forensic matching applications, but more can be used. The uniqueness of the DNA profile is often referred to as a form of “fingerprinting” and serves as a powerful tool in criminal investigations. Given sound sample collection techniques and carefully calibrated laboratory conditions, DNA evidence using VNTRs and STRs provides solid proof of innocence, guilt, or personal identity.
Single-Nucleotide Polymorphisms (SNPs)
Completion of the Human Genome and HapMap projects provided a detailed map of the human genome and the extent of human genetic variation from single-nucleotide polymorphisms (pronounced “snips”). SNPs are genetic polymorphisms involving the variation of a single base pair at a given loci among individuals in a population. The difference between SNPs and RFLPs is that more than two options for SNPs are possible—SNPs can have any range of C, T, A, G, or deletion, at a given loci—versus the specific presence/absence of a singular difference for RFLP. In the following example, the third patient has a C-to-T base pair polymorphism in the second position. In medical, research, and clinical literature, this C-to-T SNP substitution could be indicated in several ways: C/T, C → T, or C > T.
Patient 1 sequence: TCCAGT
Patient 2 sequence: TCCAGT
Patient 3 sequence: TTCAGT
Patient 4 sequence: TCCAGT
There are different types of SNPs, and they can be located in exons and introns. SNPs in exons are categorized as being synonymous or nonsynonymous. Synonymous 51SNPs are single-nucleotide alleles that do not result in an amino acid change. Nonsynonymous SNPs are single-nucleotide alleles that do result in a different amino acid being incorporated into a protein. Thus, the most clinically relevant SNPs are those occurring in exons of genes that produce amino acid changes—the nonsynonymous category. SNPs in critical locations of an exon can exert functional effects on protein translation just like mutations do. Nonsynonymous SNPs mirror the categories of genetic mutations discussed in Chapter 2 and include the following types: missense (a SNP results in an amino acid substitution); nonsense (a SNP results in an amino acid being switched for a stop codon, causing a shortened protein); and frameshift (a SNP is a single base indel that throws the reading frame off for all downstream amino acids). While it seems counterintuitive for intronic sequence variants to have an impact on protein coding, this can be the case for intronic SNPs near splice sites or in gene flanking regions that regulate transcription (the 5′ or 3′ untranslated regions). SNPs that are near a gene, or within several thousand base pairs, can still have an impact on protein assembly. SNPs in introns at a great distance from any gene are called genomic or extragenic. Effects of extragenic SNPs may impact the regulation of gene expression or other DNA functions such as replication.
SNPs have multiple ways of being identified, and significant inconsistency exists in SNP documentation for clinical applications and scientific research (Human Genome Variation Society, 2014). Thus, patient genetic test reports containing SNP results can include any combination of the content discussed in this paragraph. The Human Genome Variation Society (HGVS) provides some general SNP nomenclature guidelines, the most important of which include either (a) the use of a reference sequence number to denote a SNP’s genomic position (i.e., rs9621049) or (b) a gene coding position (c.1043C>T). There is significant debate in the field for which approach to use. Typically, SNPs are given an established reference sequence number (rs#) in dbSNP, a federal database (www.ncbi.nlm/nih.gov/SNP) that catalogs millions of formally registered SNPs. Knowing the SNP rs# or coding position is very useful because a clinician can go to dbSNP, enter this information, and obtain the gene name, position in the gene where the SNP is located, and what category of SNP it is. Different letters before a gene coding position are used to describe the type of reference sequence being used: “c” for a coding DNA sequence (e.g., c.1043C > T); “g” for a genomic sequence (e.g., g.15259C > T); “p” for a protein sequence (e.g., p.Ser348Phe); “r” for an RNA sequence (e.g., r.76a > u); or “m” for a mitochondrial sequence (e.g., m.8993T > C). SNP insertions or deletions are indicated by the shortened abbreviations “del” (e.g., c.205delC) or “ins” (e.g., c.103insT). Readers are referred to the HGVS (www.hgvs.org/content/guidelines) for additional details beyond the content summarized here. Box 3.1 provides an example of SNP naming and its clinical application.
As high-throughput technologies have drastically reduced DNA sequencing costs in the past 10 years, use of SNPs in health care applications exploded. Currently, SNPs are driving personalized medicine—an emerging health care specialty that uses an individual’s genetic profile to make decisions about disease prevention, diagnosis, and treatment. Similar to how knowledge of the ABO and Rh proteins transformed transfusion medicine safety and treatments, knowledge of SNPs and gene sequences are being harnessed to understand patients’ individual disease presentations, drug responses (see Chapter 6), and other phenotypes of interest. Although each person’s SNP pattern is unique (except for monozygotic multiples), most SNPs are not responsible for causing disease. But SNPs can be located near a gene associated with a disease of interest, similar to the previous HLA disease association examples in this chapter. SNPs can also contribute to disease development if the person carries a higher risk SNP allele and is exposed to a particular environment or toxin (e.g., higher risk genotype plus smoking). Recent research in this field uses genomic sequence generated by the Human Genome Project to correlate SNPs in linkage disequilibrium with diseases, drug responses, environmental exposures, and clinical phenotypes. Greater understanding of genetic contributions to multifactorial diseases (e.g., diabetes mellitus, cancer, addictions, depression) is leading to the development of novel therapies, identification of target genes responsible for diseases, and quantification of disease risks, given specific lifestyle choices (e.g., nutrition, smoking, alcohol use, etc.).
