Translating Genomic Advances to Physical Therapist Practice: A Closer Look at the Nature and Nurture of Common Diseases

Family History and Disease Heritability Studies: CVD

Parental history of premature CVD (onset age <55 years in father, <65 years in mother) increases risk 2.0-fold in men and 1.7-fold in women.¹⁹ Most CVD is polygenic.¹⁵ Twin and family studies have reported that 40% to 50% of the risk for coronary artery disease (CAD) is heritable.^20,21 In classic twin studies, the variation in a phenotype (an observable trait such as eye color or height) is considered to be due to genetic and environmental influences, including environmental influences shared by a twin pair or unique to each individual.²² Heritability is the proportion of total phenotypic variation of a trait due to the variation in genetic factors among individuals.^22,23 Heritability is calculated in twin studies by comparing the occurrence of a trait in monozygotic versus dizygotic twins, with the variance divided into genetic and environmental components.^22,23 Monozygotic twins are genetically identical, whereas dizygotic twins share about 50% of their genetic material, which is comparable to ordinary siblings.²² Heritability estimates for a trait range from 0% (no genetic influence) to 100% (totally influenced by genetic factors). The longitudinal Swedish Twin Registry revealed that heritability for death due to coronary heart disease was 57% in men and 38% in women.^21,24 Many risk factors also are heritable, as noted in the Framingham Heart Study for body mass index (52% for individuals with a mean age of 60 years), blood pressure (BP; systolic 42%, diastolic 39%), and total cholesterol (57%).¹⁴

Candidate Gene Studies and Genome-wide Association Studies (GWAS): CVD

Candidate gene approaches have been used to identify SNPs and other polymorphisms in genes thought to be implicated in CVD.^16,17,25 Genes in this approach are selected because they are already partially understood and suspected to be associated with a disease or trait of interest.²⁵ These “candidate” genes are then genotyped, and the frequencies of SNPs or other variants are compared in cases (unrelated people with the given disease or trait) versus controls.²⁵ Single-nucleotide polymorphisms and other DNA polymorphisms have been associated with MI and congestive heart failure¹⁶ and with common risk factors.^26,27 For example, the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene was associated with hypertension in older, but not younger, Japanese men.²⁶ Systolic BP in older men (>50 years of age) with ID genotype was, on average, 5.9 mm Hg higher than those with II genotype. Apolipoprotein E (APOE) genotype also affects risk for CVD. Human APOE regulates lipid metabolism and transport and has 3 major protein isoforms (apoE2, apoE3, and apoE4) encoded by 3 APOE (ε2, ε3, and ε4) alleles.²⁷ The ε4 allele has been associated with an increased risk for CAD²⁷ (see Fig. 6 for a description of an allele).

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Figure 6.

Allele. An allele is 1 of 2 or more versions of a gene. An individual inherits 2 alleles for each gene, 1 from each parent. If the 2 alleles are the same, the individual is homozygous for that gene. If the alleles are different, the individual is heterozygous. Though the term “allele” was originally used to describe variation among genes, it now also refers to variation among noncoding DNA sequences. Courtesy of Darryl Leja of the National Human Genome Research Institute, National Institutes of Health, http://www.genome.gov/. Accessed August 30, 2015.

Although candidate genes have been identified and studied for many diseases, including CVD, few associations have been replicated^17,25,28 due to insufficient statistical power, other genetic or environmental influences, and phenotypic heterogeneity (ie, CVD has many causes, and certain genetic factors may play a greater role in some forms than others).²⁸ The candidate gene approach also is limited because the search for associations targets known genes thought to be involved in a disease, precluding discovery of novel loci associated with disease.^12,17

Genome-wide association studies genotype millions of SNPs, comparing the frequency in cases versus controls.^12,17 The first well-replicated SNP locus for CVD to emerge from GWAS was localized to 9p21 (on the short p-arm of chromosome 9).^17,21 Fine mapping of the risk region on 9p21 identified several tightly linked SNPs significantly associated with CAD.¹⁷ The frequency of the 9p21 risk allele variants (eg, G allele of SNP rs4977574 and C allele of SNP rs1333049) was found to be common in a large cohort of individuals of European and South Asian descent, with approximately 50% having 1 copy and 25% having 2 copies.^12,17,20,21 A 9p21 risk allele variant (SNP rs1333049) also was predictive of CAD severity, as determined by the number of vessels involved based on coronary angiography.^17,29 In addition, the magnitude of the risk for CAD was found to be associated with SNP variants in the 9p21 region, with 1 allele copy increasing risk by approximately 15% to 20% and 2 allele copies increasing risk by approximately 30% to 40%.^29,30 The 9p21 variants associated with CAD risk have been identified in several ethnic populations,^12,17,21 although data from individuals of African or other non-European ancestry ethnic groups are limited.¹² The 9p21 variants are located in a noncoding region^17,21 and, although the mechanism is not fully understood, may play a role in the development of atherosclerosis at the vessel wall.^12,17,25,29

Given the importance of the 9p21 locus to CAD risk, considerable effort is being made to find other key loci. Two GWAS meta-analyses conducted by the CARDIoGRAM and C4D consortia together scanned nearly 40,000 coronary heart disease cases to confirm previous GWAS associations and identify novel variants.²¹ These findings, along with those from other large-scale studies, yielded 35 coronary disease variants, some near protein-coding regions and others not.²¹ Later, the CARDIoGRAMplusC4D Consortium²⁰ found 15 novel loci, for a total of 46 loci at that time and explaining approximately 10.6% of CAD heritability. To identify key biological pathways involved in CAD pathogenesis, this consortium also performed computational analyses to study gene-gene interactions using 233 candidate genes, including the genes associated with the 46 SNP loci. Of the 5 networks generated, the 4 most significant pathways were linked to lipid metabolism and inflammation. Currently, 50 genetic CAD risk variants have been identified.¹⁷

Personalized Medicine and Pharmacogenomic Considerations: CVD

Although CVD variants have been identified through GWAS and meta-analyses of GWAS,^20,21 each variant confers only a small risk effect, with cumulative small effects of many variants predicting susceptibility for common diseases.³¹ Currently, routine genetic testing for common CVD variants at the level of the individual is not recommended,¹² as many variants have at best only a modest impact on risk and uncertain significance in predicting future disease.^12,32–34 Nonetheless, progress is being made to elucidate cellular mechanisms and identify important therapeutic targets.¹² In pharmacogenetics, genotype has been found to influence individual response to CVD drugs.¹⁵ For example, statin-induced myopathy has been strongly associated with certain genetic variants.¹² Also, variants in the CYP2C9 and VKORC1 genes together account for up to 40% of the variation in final adjusted warfarin dose such that the Food and Drug Administration stipulates genotype-specific dose ranges.^15,35 Similarly, other drug-genotype responses have been found for the antiplatelet drug clopidogrel and the use of beta-blockers in heart failure.^15,35

Family History and Disease Heritability Studies: OA

The risk of OA and the risk of progression are familial. Siblings of patients undergoing total hip or knee replacement have increased risk of OA in the same joint.^40,41 In the GARP (Genetics, Arthrosis, and Progression) study, siblings of probands (first identified family member) with OA at multiple sites and a family history of OA had increased risk for OA at the same sites as the proband for the hand (odds ratio [OR]=4.4), hip (OR=3.9), spine (OR=2.2), hip and spine (OR=4.7), and hand and hip (OR=3.4).^37,42 Twin studies also have shown moderate heritability (39%–60%) for the risk of OA of the hand, knee, and hip.³⁷ Similarly, high estimated heritability was found for knee total cartilage volume (73%) in twins.⁴³

Candidate Gene Studies and GWAS: OA

Osteoarthritis candidate genes and genetic variants have been linked to joint structure (eg, articular cartilage integrity), risk factors (eg, obesity), and clinical outcomes (eg, pain).^{13,37,39,44,45} Collagen, type IX, alpha-2 (COL9A2) gene, which encodes 1 of 3 alpha chains of type IX collagen, was associated with both lumbar disk degeneration and hip OA in twins.⁴⁶ One candidate gene study⁴⁷ and several large-scale GWAS (see review by Panoutsopoulou and Zeggini¹³ for additional details) identified common variants at 15 loci associated with hip or knee OA attaining genome-wide significance, but together explained <10% of the genetic component.¹³ The largest of these GWAS by the arcOGEN Consortium compared 7,410 cases with severe hip or knee OA (80% had undergone a total joint replacement) and 11,009 population-based controls from the United Kingdom and replicated the most significant loci in 7,473 cases and 42,938 controls of European descent.⁴⁸ The biological contribution of many of these 15 variants (in both coding and noncoding regions) to OA is unknown, as the associated genes and pathways have not been fully characterized.¹³ Some of these loci given the nearest identified gene, however, may play a role in the immune response, pain, obesity, or development and homeostasis of cartilage or bone.¹³ Of these 15 variants, the locus associated with growth differentiation factor 5 (GDF5) is one of the most robustly replicated and best understood.^13,39,44,45

The GDF5 protein is a growth factor that induces cartilage and bone growth when implanted subcutaneously.^13,39 The GDF5 protein is important for the development, maintenance, and repair of synovial joint elements,¹³ and GDF5 mutations result in skeletal dysplasias.³⁹ Miyamoto and colleagues⁴⁷ found that the GDF5 rs143383 (T/C) SNP was associated with hip and knee OA in Japanese and Chinese cohorts (OR=1.30–1.79) with the T allele conferring increased risk. Subsequent large-scale meta-analyses confirmed the rs143383 association with hip and knee OA in European and Asian cohorts,^13,39,49 with the T allele increasing knee OA risk by 17% (OR=1.17).⁴⁹ The GDF5 rs143383 SNP also is associated with risk for lumbar disk degeneration.⁵⁰

Personalized Medicine and Pharmacogenomic Considerations: OA

Osteoarthritis has a long asymptomatic molecular phase, a preradiographic phase, and a final radiographic phase with hallmark structural joint changes.⁵¹ Efforts are being made to identify cellular, biochemical, molecular, and genomic (RNA and DNA) biomarkers to define subtypes, identify those at risk, monitor progression, and develop disease-modifying agents.^51,52 Biomarkers, along with new therapies, have the potential to alter the course of OA, as in rheumatoid arthritis.^51,52 Currently, no OA disease-modifying drugs are universally recommended,^45,53,54 but drugs in development exhibit disease-modifying effects, such as those targeting cartilage or inflammatory pathways.⁵³ Three available supplements (glucosamine sulphate, chondroitin sulphate, and diacerein) that are recommended for symptomatic relief of knee or hip OA also may have disease-modifying effects.^53,54 Current surgical or analgesic treatment options⁵⁴ primarily offer symptomatic relief and are largely palliative.⁵¹ Genetic factors, however, still play a role in aseptic loosening following arthroplasty⁵⁵ or response to opioids⁵⁶ used to manage OA-related pain.

Osteoarthritis pain is highly variable and can be discordant with radiographic features.^13,44,57 Depression, anxiety, and stress also play a role in the experience of pain.^56,58 Pain heritability was found to be 28% to 44%, depending on the site (neck, back, elbow, knee, thigh, hand, foot).⁵⁷ Considering the genetic contribution to individual differences in pain perception and analgesia response, familial effects in twins accounted for 24% to 32% of the observed variance in experimental heat and cold pressor pain thresholds and elevation in cold pressor pain tolerance following opioid administration.⁵⁶ One experimental study showed that pain sensitivity was influenced by a complex interplay of SNPs, sex, ethnicity, and psychological state.⁵⁸ Efforts such as these to elucidate the genetic contributions to pain are on the forefront of pharmacogenetics, with the end goal being more personalized approaches to improve the efficacy and safety of pain management.⁵⁹

Heritability of Physical Activity and Fitness Attributes

Physical activity participation was found to have an estimated heritability of 57% based on accelerometry data in twins.⁶² In adult twins (mean age=50.4 years), low diastolic but not low systolic BP was associated with aerobic exercise performed in adolescence and intensity over the lifetime.⁶³ Although environmental effects, including exercise participation, explained the majority of BP variance, 35% of the variance in diastolic BP and 39% of the variance in systolic BP were attributable to genetic factors. Genetic factors also can influence the variation in musculoskeletal and performance phenotypes.⁷ For example, the heritability for total lumbar range of motion was estimated to be 47%.²³ Katzmarzyk and colleagues⁶⁴ reported moderate heritability for grip strength (48%), number of push-ups (37%), number of sit-ups in 60 seconds (59%), and sit-and-reach distance (64%).

Candidate Gene Studies and GWAS: Physical Activity and Exercise Response

Genetic variants in candidate genes have been linked to physical activity participation and exercise response. The Québec Family Study showed that a C/T polymorphism of the melanocortin-4 receptor (MC4R) gene, which plays a role in feeding behavior and energy homeostasis, was associated with physical activity.^7,65 Individuals with the T/T genotype reported lower moderate-to-strenuous physical activity and higher inactivity than those with the C allele. In white male military recruits, left ventricular mass increased for those with ACE DD but not II genotype after 10 weeks of physical training.⁶⁶ Obisesan and colleagues⁶⁷ found that ethnicity, defined as black or white Americans, interacts with the APOE ε2/ε3 genotype, influencing response to 24 weeks of endurance training on the advantageous high-density lipoprotein cholesterol (HDL-C) subfractions. Black American APOE ε2/ε3 carriers, compared with white Americans, had greater exercise training–induced improvements in HDL-C particle size and concentration, whereas no black or white American differences were found for ε4 carriers. Obisesan and colleagues⁶⁷ suggested that APOE genotype may help target high-risk populations who may benefit more readily from aerobic training to reduce CVD risk. Genotype also was found to influence response to a walking and weight lifting intervention in sedentary adults with knee OA who were older and obese or overweight.⁶⁸ Individuals with an A allele at position −308 in the promoter (regulatory) region of the tumor necrosis factor alpha (TNFα) gene had greater improvements after the intervention than those homozygous for the G allele in stair climbing time at 6 months and physical disability at 18 months.⁶⁸ Also, the alpha-actinin-3 (ACTN3) genotype influenced knee extensor peak power with strength training in older adults.^7,69

Although few exercise performance GWAS have been conducted, due, in part, to issues identifying large populations to participate in exercise training,^7,70 findings in this area are highly relevant to physical therapist practice. Rankinen and colleagues⁷¹ in a GWAS involving a HERITAGE Family Study group of 472 healthy but sedentary individuals from 99 families, identified 40 SNPs associated with submaximal HR training-induced changes following 20 weeks of cycle ergometry. Of the 40 SNPs identified, 9 of the most significant SNPs fully accounted for the maximal estimated heritability of 34% for changes in steady-state HR in response to endurance training and are implicated in cardiomyocyte and neuronal functions. They also calculated a SNP summary score based on the number of alleles of the 10 most favorable training SNPs. They found that participants with ≤9 of these favorable alleles showed no training improvements in their submaximal steady-state HR, whereas those with ≥16 of these alleles decreased their HR by more than 20 bpm. Rankinen and colleagues⁷¹ suggested that the identification of these novel variants provides an alternative explanation for the variability in HR training response beyond an insufficient exercise prescription or lack of training adherence.