EDITORIAL
European Heart Journal (2016) 37, 1823–1825
doi:10.1093/eurheartj/ehv562
Hypertrophic cardiomyopathy: single gene
disease or complex trait?
Adam S. Helms and Sharlene M. Day*
Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor MI, USA
Online publish-ahead-of-print 27 October 2015
This editorial refers to ‘Hypertrophic remodelling in cardiac
regulatory myosin light chain (MYL2) founder mutation carriers’†, by G.R.F. Claes et al., on page 1815.
Landmark genetic mapping studies beginning in the 1990s defined
hypertrophic cardiomyopathy (HCM) as an autosomal dominant inherited disease caused by specific mutations in cardiac sarcomere
genes.1 Certain mutations in large families were initially described
as being more deleterious than others, giving hope that genetic testing would enable predictions of disease severity. However, a more
complicated story emerged as extreme locus and phenotypic heterogeneity became evident as the rule rather than the exception
in less select populations.2 Indeed, HCM is now recognized as a disease which is primarily caused by a single mutation but then modulated greatly by other factors. In fact, the variability in phenotype
attributable to disease modifiers has confounded studies of genotype–phenotype correlations for the primary mutations themselves.
Founder mutations offer a distinct advantage in studying disease variability in HCM. Not only is the mutation identical in all subjects, but so
also is the surrounding genetic region (haplotype block), which includes the regulatory sequences immediately adjacent to and within
the gene. Therefore, differences in disease expression must arise
from either other genetic variation or environmental factors. Several
previous studies of founder mutations in HCM have shown extreme
disease variability, with a range of clinical expression similar to that
found in studies of HCM with mixed genotypes. The study by Claes
and colleagues adds to this growing evidence in the case of a founder
mutation in MYL2.3 Together, these studies provide robust evidence
for the importance of additional genetic and/or environmental factors
in the development of HCM.
Influence of background genetic
variation on hypertrophic
cardiomyopathy disease
phenotype
Severely affected individuals with HCM across a spectrum of sarcomere genotypes often present early in life, when there has been less
opportunity for environmental influences, such as diet, obesity,
hypertension, or other clinical co-morbidities, to exert a major
role. Therefore, it seems likely that early-onset disease is more
heavily influenced by genetic background, i.e. genetic modifiers
that synergize with the primary mutation to exacerbate the phenotype (Figure 1). The presence of multiple pathogenic sarcomere mutations has clearly correlated with earlier onset and greater disease
severity but only explains a minority of such cases.4 In the study by
Claes and colleagues, the presence of an additional sarcomere variant was found to increase the likelihood of clinical HCM among
MYL2 mutation carriers. The additional sarcomere variants found
in their study were not adjudicated HCM-causing mutations. However, given the low tolerance for variation in sarcomere genes,5
these variants are strong candidates for disease modifiers even if
they are not themselves independently disease-causing. Determination of the precise effect of sarcomere gene variation will require
multicentre collaborative efforts to collate genetic information from
large numbers of individuals with HCM, such as the Sarcomeric Cardiomyopathy Registry (SHaRe, theshareregistry.org). Candidate
gene modifiers outside of the sarcomere have also been explored.
Polymorphisms in the renin, angiotensin, and aldosterone genes may
have a modest influence, but have not consistently proven to have a
significant effect on disease phenotype. A single study showed that a
polymorphism in the promoter region of calmodulin III was more
prevalent in clinically affected gene carriers than in phenotypenegative family members, but this finding has not been pursued in
larger cohorts.6 Since the number of potential pathways that might
modify hypertrophy and/or fibrosis is extensive, the candidate gene
approach has been largely abandoned in favour of non-biased
genomic-based approaches. A genome-wide association study
(GWAS) of 153 individuals with HCM of varying genotypes (27%
with sarcomere gene mutations) compared with 823 controls identified a potential modifying effect of a variant in the formin homology
2 domain containing 3 gene (FHOD3).7 Future GWAS may have potential for finding additional modifying loci, but are only likely to be
successful if modifying loci either have large effects or are studied in
very large populations, given the broad spectrum of primary sarcomere mutations in unrelated individuals. A linkage mapping study
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
†
doi:10.1093/eurheartj/ehv522.
* Corresponding author. Division of Cardiology, University of Michigan Medical School, 1150 W. Medical Center Drive, 7301 MSRB III, Ann Arbor, MI 48109-0644, USA. Tel: +1 734
615 7917, Fax: +1 734 936 8266, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].
1824
Figure 1 Penetrance of a sarcomere mutation increases with
age and males tend to be diagnosed earlier compared with females.
Genetic modifiers could either exacerbate or dampen the effects
of the primary sarcomere mutation leading to earlier or delayed
onset of clinical disease, respectively. Comorbid conditions, such
as hypertension, obesity, diabetes, obstructive sleep apnoea, and
sedentary lifestyle, are likely to have cumulative effects and be
most influential in increasing disease penetrance and severity in
older individuals. Conversely, healthy lifestyle choices and stringent adherence to treatment of comorbid disease could positively
impact the natural history of HCM in sarcomere mutation carriers.
explored the potential for disease-modifying variants in a large family (n ¼ 100) with a single MYBPC3 mutation.8 In this study, three loci
were identified as containing potential disease-modifying variants,
with a resolution ranging from 41 to 180 cM. Candidate genes
were identified for one of these loci based on biological plausibility
that warrant further investigation, though the resolution of linkage
mapping for potentially multiple modifying variants in this type of
study is limited. Whole-exome or genome sequencing are promising approaches for identifying genetic modifiers in HCM but will
probably require large numbers of patients given the genetic and
clinical heterogeneity of the disease.
Influence of age, gender, and
clinical co-morbidities on
hypertrophic cardiomyopathy
disease phenotype
While HCM was initially thought to manifest primarily during adolescence, reaching a stable level of hypertrophy in adulthood, we
now recognize that overt hypertrophy develops over a continuum
with age, into late adulthood.9 Male gender has also been associated
with an earlier clinical diagnosis of HCM, both in unselected HCM
populations10 and in founder mutation populations.11 Claes and colleagues again have noted a clear pattern of earlier HCM diagnosis in
males with the MYL2 founder mutation. The effect of gender may be
due to hormonal influences on cardiac pathology, or may be due to
differences in regulation of X-chromosome genes in HCM, as has
Editorial
recently been demonstrated for the gene Fhl1 in a mouse model of
HCM.12 The influence of additional clinical variables on the development of HCM has also recently been investigated. Obesity and sleep
apnoea are highly prevalent in the HCM population; obesity is associated with greater hypertrophy while both obesity and sleep apnoea
are associated with greater symptom burden in HCM patients.13,14
HCM patients on average are also less active than the general population, which may contribute to obesity.15 A sedentary lifestyle itself may
also have a detrimental impact. In a mouse model of HCM, implementation of voluntary wheel running reduced fibrosis, myofibre disarray,
and hypertrophic remodelling.16 It remains to be seen through ongoing (clinicaltrials.gov, NCT01127061, RESET-HCM) and future clinical studies whether the same observations will hold true in patients.
Hypertension has been suggested as a likely and intuitive trigger for
HCM, though it has not been thoroughly evaluated since individuals
with hypertension have been excluded from many studies of HCM.
Claes and colleagues have identified hypertension as a major cause
for the development of HCM among individuals with the MYL2 founder mutation. This finding is consistent with a previous report of a
founder mutation in MYBPC3. In that report, among 45 relatives carrying the founder mutation, all with hypertension had clinical HCM with
asymmetric septal hypertrophy and no mutation carrier without
hypertension was affected clinically.11 While Claes and colleagues investigated other potential risk factors (hyperlipidaemia and diabetes)
that improved their statistical model, the number of individuals with
these co-morbidities was too few to draw clear conclusions about
any individual risk factor other than hypertension. Interestingly, the
study by Claes et al. did not show a difference in age between
genotype-positive individuals with and without HCM. This result
may be related to the method of analysis, in which age was captured
for individuals with HCM at the time of diagnosis, but for individuals
without HCM at time of last follow-up. However, the fact that age
was not different between those with and without HCM using these
definitions allows a stronger conclusion to be drawn for the contributory role of hypertension in hypertrophy development.
The findings of Claes and colleagues are encouraging, because they
offer a potential therapeutic window in HCM that has not previously
been recognized. While most early-onset severe HCM cases may be
driven by genetic background, later onset disease evolution could
perhaps be attenuated with early and strict blood pressure control.
This strategy would result in a shift from the ‘watchful waiting’ typically applied to genotype-positive individuals to a proactive approach
of early initiation of antihypertensive therapy where appropriate.
Since no disease-specific medications are currently proven to alter
the disease course, a strict blood pressure target could represent
an important new treatment avenue for HCM. Likewise, other lifestyle interventions such as weight loss, exercise, and screening and
treatment of sleep apnoea could also have a measurable impact on
disease penetrance and severity. One key question to be addressed
is to what extent these results can be extrapolated to a broader range
of sarcomere genotypes, as this particular mutation in MYL2 seems to
display reduced expressivity relative to other thick and thin filament
mutations, with older age of disease onset, fewer symptoms, and less
hypertrophy.17 Ultimately, prospective studies that focus on lifestyle
interventions in HCM will be an important adjunct to novel pharmacologicals, not only for alleviating symptoms, but for potentially modifying underlying disease pathology.
Editorial
Conflict of interest: none declared.
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