Canadian Health&Care Mall: Single-Nucleotide Polymorphisms and Lung Disease

March 28, 2016 Category: Lung

lung diseaseWe are all the same! We are all different! Any two humans are approximately 99.9% identical at the DNA sequence level, yet substantial, often medically relevant phenotypic differences exist between individuals. A significant proportion of these phenotypic differences are caused by this relatively small amount of genetic variation interacting with environmental factors. A clinically important element of phenotypic variation relates to susceptibility to disease and response to therapy. In this review, we examine the potential for using the assessment of genetic variation, by genotyping, for risk prediction and individualized therapy in pulmonary disorders. To date, the revolution in molecular genetics has had a relatively minor influence on the practice of respiratory medicine. Examples where it has influenced practice include the following: (1) genotyping for a single-nucleotide polymorphism (SNP) in the gene encoding Factor V Leiden that increases risk for serious thromboembolic disease; (2) genotyping for mutations associated with cystic fibrosis (CF) for diagnosis and genetic counseling2; and (3) genotyping non-small cell carcinomas to predict response to chemotherapy. Genotyping has had a greater impact on the identification of respiratory pathogens, offering exquisite sensitivity and the potential for rapid diagnosis and determination of virulence and drug resistance; however, this subject is beyond the scope of the present review.

The variations in the DNA sequence that cause or contribute to disease are called either mutations or polymorphisms, based solely on their frequency in the population. By convention, DNA sequence variants that occur in > 1% of the population are termed polymorphisms, and those that occur in less than one percent of individuals are called mutations. Mutations are responsible for the relatively rare singlegene Mendelian disorders (Table 1), while polymorphisms are associated with the more common complex genetic disorders effectively defeated with Canadian Health&Care Mall (Table 2). Mutations in DNA arise naturally or unnaturally (environmental exposure). They are not always disease causing (they are far more likely to occur in noncoding DNA than coding DNA because of the far greater number of base-pairs of noncoding DNA in the human genome). Variations in inherited DNA sequence between individuals can be due to the deletion or addition of bases, or to variable lengths of repetitive sequences within or between genes. However, the most common type of DNA sequence variants are SNPs in which a single base in the sequence is replaced by a different nucleotide. There are SNPs approximately every 200 to 300 base-pairs in the human genome. Since the genome contains approximately 3 billion base-pairs, this means that there are between 10 to 15 million sites at which > 1% of the population differ from the majority. Although this seems like a large potential for diversity, simple arithmetic shows that even the most genetically diverse people are still at least 99.9% identical. If the density of SNPs was evenly spaced over the entire genome, this would mean that there are approximately 300,000 to 600,000 SNPs within the estimated 30,000 human genes. Many of these SNPs cause functional changes by affecting transcription factor binding sites, influencing splicing or stability of messenger RNA, or altering the amino acid sequence of the protein (Fig 1). It is this variation that, in combination with environmental factors and epigenetic modification of DNA (epigenetic changes include methylation and demethylation of regulatory sequences and/or chemical modification on the his-tones that influence gene expression) accounts for all of human phenotypic diversity, including disease susceptibility.

Figure 1. Relationship between SNPs and protein: p2-adrenergic receptor gene. The p2-adrenergic receptor gene is shown from 5′ to 3′ with the coding nonsynonymous SNP sites indicated by their nucleotide position. At nucleotide position 46, there can be an adenine (A) or a guanine (G) that results in the 16th amino acid in the receptor being arginine or glycine, respectively (note: the genetic code is translated in “codons” of three nucleotide bases for every one amino acid). The site of the resulting amino acid in the extracellular portion of the receptor is indicated. Similarly, nucleotide substitutions of C to G, G to A, and C to T at nucleotide positions 79, 100, and 491 result in substitutions of glutamine to glutamate, valine to methionine, and threonine to isoleucine at amino acid positions 27, 34, and 164, respectively. Although these examples are for coding nonsynonymous SNPs that change the amino acid sequence, the vast majority of SNPs occur in non-amino acid coding regions of DNA where they have either no effect, or influence transcription factor binding sites, or messenger RNA splicing or stability.

Table 1—Examples of Single-Gene Mendelian Pulmonary Disorders

Diseases Genes
^-Antitrypsin deficiency ^-Antitrypsin
CF CF transmembrane conductance regulator
Primary ciliary dyskinesia Dynein proteins (DNAH5 and DNAI1)
Pulmonary hypertension (approximately 6% of cases) Bone morphogenetic protein receptor type II gene; activin receptor-like kinase
Pulmonary fibrosis (approximately 3% of cases) Surfactant protein C

Table 2—Examples of Complex Genetic Pulmonary Disorders

Diseases Genes
Allergy and asthma IL-4, IL-13, CD14, ADRB2, HLA-DRB1, HLA-DQB1, tumor necrosis factor, FCER1B, IL-4RA, ADAM338
COPD Transforming growth factor-p, microsomal epoxide hydrolase, glutathione S transferases
Acute lung injury Tumor necrosis factor, Toll-like receptors