JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 67, NO. 4, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER
ISSN 0735-1097/$36.00
http://dx.doi.org/10.1016/j.jacc.2015.09.109
EDITORIAL COMMENT
Genetic Causality in Complex Traits
The Case of Uric Acid*
A.J. Marian, MD
“I
f epidemiologists are compared with fisher-
resultant availability of large databases of human ge-
men, causality is the big fish. It is elusive to
netic variants have illustrated overabundance of the
find, difficult to catch, and claims to have
sequence variants in each genome, including in genes
measured it are often exaggerated.” Burgess et al.
previously implicated in human diseases (5,6). The
(1) were correct: establishing a cause-and-effect rela-
plethora of genetic variants renders unequivocal
tionship is always challenging. In its purest defini-
identification of the true disease-causing variant,
tion, analogous elements of the Koch’s postulates of
even in a single gene disorder, a formidable task.
causality have to be fulfilled (2). In its simplistic defi-
On the other end of the genetic causality spectrum,
nition, the cause has to precede the effect and be
the vast majority of genetic variants that exhibit low
necessary and sufficient for phenotype expression,
penetrance and exert negligible or modest effect sizes
albeit with a variable degree of expressivity.
(2,7). Expectedly, such variants do not exhibit Men-
Yet, these extreme definitions of causality are
delian patterns of inheritance but might show aggre-
seldom germane in genetics. Very few genetic variants
gation in families or cases with the phenotype of
are fully penetrant, independent of the genetic back-
interest. Evidence of their role in susceptibility to
grounds in which they operate (3,4). Fully penetrant
disease typically originates from genetic epidemio-
genetic variants are rare in the population, as well as
logical studies, including genome-wide association
in each genome, and typically cause familial diseases
studies (GWAS), showing an excess burden of such
that exhibit Mendelian patterns of inheritance.
variants in cases as compared to controls. During the
Strength of evidence for their causality depends not
last decade or so, GWAS and candidate gene studies
only on the penetrance but also family size and
have identified a very large number of common var-
structure (number of informative meiosis). Typically,
iants, defined as a population minor allele frequency
a genetic variant exhibits incomplete penetrance and
of >1%, associated with cardiovascular phenotypes.
the family size is not large enough to ascertain co-
As of February 20, 2015, the last update of the GWAS
segregation unambiguously. Therefore, even in single
catalog, 15,396 single nucleotide polymorphisms
gene disorders that exhibit Mendelian patterns of in-
(SNPs) are described in association with various
heritance, definite identification of the causal gene or
complex traits. Pertinent to this editorial is the asso-
variant remains difficult. The advent of massively
ciation of serum uric acid levels with more than 40
parallel nucleic acid sequencing technologies and the
SNPs in at least 30 genes.
Clinically, an association between serum uric acid
levels and gout as well as hypertension, type II dia-
*Editorials published in the Journal of the American College of Cardiology
reflect the views of the authors and do not necessarily represent the
views of JACC or the American College of Cardiology.
From the Center for Cardiovascular Genetics, Brown Foundation Institute
betes mellitus (T2DM), kidney disease, coronary heart
disease (CHD), and heart failure (HF) has been
recognized and substantiated in numerous modern
of Molecular Medicine, The University of Texas Health Science Center
epidemiological studies (8). Consequently, serum uric
and Texas Heart Institute, Houston, Texas. Dr. Marian is supported in
acid is considered a risk factor for cardiovascular and
part by grants from the National Institutes of Health, National Heart,
metabolic diseases and their clinical outcomes (8).
Lung, and Blood Institute (NHLBI, R01 HL088498, and R34 HL105563),
Leducq Foundation (14 CVD 03), Roderick MacDonald Foundation
Conventional epidemiological studies are primarily
(13RDM005), TexGen Fund from Greater Houston Community Founda-
observational and subject to confounding effects of
tion and George and Mary Josephine Hamman Foundation.
multiple factors, as well as potential biases in study
418
Marian
JACC VOL. 67, NO. 4, 2016
FEBRUARY 2, 2016:417–9
Causality in Complex Traits
design and reverse causation. Consequently, the
biological data. GRSs are particularly speculative
findings of epidemiological data, whether conven-
when derived from a diverse group of genes with
tional or GWAS, are vulnerable to confounders and
multifarious functions and in genetically and envi-
seriously limited in inferring causality.
ronmentally heterogeneous populations. Unfortunately, data on serum uric acid levels and the clinical
SEE PAGE 407
phenotypes were not consistently available in the
Considering the shortcomings of the conventional
present study populations to assess whether serum
epidemiological studies, in this issue of the Journal,
uric levels, independent of the genetic variants, were
Keenan et al. (9) sought to determine the causal role
associated with the clinical phenotypes.
of serum uric acid in CHD, T2DM, HF, and ischemic
The present study’s null results regarding serum
stroke. To reduce effects of potential confounders,
uric acid and CHD echo the findings of a recently
the authors used genetic variants associated with
published large-scale MR study in a homogeneous
serum uric acid levels as instrumental variables. The
Danish population (12). Yet another MR study, per-
rationale for using genotypes as instrumental vari-
formed in a population of European origin, with a
ables, referred to as Mendelian randomization (MR)
study design similar to the present one, concluded
(10), is that genetic variants are assorted randomly
that each 1 mg/dl increase in genetically predicted
during meiosis, except for variants that are in close
uric acid concentration was causally associated with
genetic proximity (linkage disequilibrium). There-
cardiovascular death and sudden cardiac death (13).
fore, confounders are to be distributed randomly
To quote Johann Wolfgang von Goethe, “It’s in
the anomalies that nature reveals its secrets”(14).
among 3 genotypes of each SNP.
Accordingly, Keenan et al. (9) analyzed the causal
A notable example of nature’s anomalies on uric
role of 28 SNPs individually and 14 SNPs exclusively
acid
associated
X-linked disease due to mutations in HPRT (hypo-
with
serum
uric
acid
levels
(non-
metabolism
is
Lesch-Nyhan
syndrome,
pleiotropic), collectively, as a genetic risk score (GRS)
xanthine
in cardiometabolic syndromes. To support validity of
manifests with severe hyperuricemia since birth,
the approach, they showed that genetically deter-
gout, renal stones, and neurological impairment but
mined increased serum uric level was associated with
not CHD, T2DM, HF, or ischemic stroke. Perhaps,
increased risk of gout, a well-established phenotypic
despite lifelong exposure, the relatively short life-
consequence of hyperuricemia. However, SNPs were
span of patients with Lesch-Nyhan syndrome masks
neither individually nor collectively as a GRS associ-
expression of CHD. A few other rare forms of single
ated with T2DM, CHD, ischemic stroke, or HF. Hence,
gene disorders also cause severe hyperuricemia but
the authors speculate that lowering serum uric acid
do not express as these cardiovascular diseases.
levels is not expected to improve risk of car-
Collectively, these rare anomalies of nature do not
diometabolic syndromes.
support a causal role for uric acid in CHD or
This well-designed and meticulously performed
study benefits from a large study population sample
phosphoribosyltransferase
1)
gene.
an
It
ischemic heart disease but there are scant data to
make a firm conclusion.
size, albeit comprised of ethnically mixed populations
Various randomized clinical trials are ongoing to
with considerable cultural and environmental differ-
test beneficial effects of lowering serum uric acid
ences. The findings show that a modest shift in serum
levels on various cardiovascular phenotypes, with
uric acid levels is sufficient to increase risk of gout but
negative results thus far (15). A beneficial effect, if
not risk of CHD, T2DM, ischemic stroke, or HF. The
observed, would not necessarily indicate a causal
rs12498742 SNP at the SLC2A9 locus had the largest
role, as the benefits might result from interventions
effect size on serum uric acid levels, which was only
modulating various biological effects of uric acid and
0.37 mg/dl, and associated with risk of gout but, once
the xanthine oxidase metabolic pathway (16), analo-
again, not cardiovascular nor metabolic syndromes.
gous to the beneficial effects of inhibiting the renin-
The small effect size of the genetic variants, typical in
angiotensin-aldosterone system in HF.
genetic studies of complex traits (11), renders geno-
Causality in genetics is seldom deterministic, as it
types as weak instrumental variables. The 14-SNP GRS,
is in rare large families with single gene disorders. It
however, shifted serum uric acid levels by 1.4 mg/dl.
is commonly probabilistic, as in complex traits.
Despite the relatively larger effect size compared to
Because hyperuricemia does not meet either the strict
individual SNPs, GRS was associated with gout but not
Koch’s postulates or simple definition of causality, it
the selected cardiometabolic phenotypes.
is not a deterministic cause of the aforementioned
GRS, while benefiting from a larger effect size, is
cardiovascular phenotypes. However, uric acid and
based on numerous assumptions not supported by
the metabolic pathway that generates it are involved
Marian
JACC VOL. 67, NO. 4, 2016
FEBRUARY 2, 2016:417–9
Causality in Complex Traits
in a diverse array of biological functions (15), possibly
contributing to pathogenesis of cardiovascular and
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
metabolic phenotypes, rendering it pathogenic but
Ali J. Marian, Center for Cardiovascular Genetics, The
not causal. The results of ongoing randomized clinical
Brown Foundation Institute of Molecular Medicine,
trials might shed some light on serum uric acid’s
The University of Texas Health Sciences Center, 6770
pathogenic role in cardiovascular and metabolic
Bertner Street, Suite C900A, Houston, Texas 77030.
syndromes.
E-mail: [email protected].
REFERENCES
1. Burgess S, Butterworth A, Malarstig A,
Thompson SG. Use of Mendelian randomisation to
assess potential benefit of clinical intervention. Br
7. Marian AJ. Nature’s genetic gradients and the
clinical phenotype. Circ Cardiovasc Genet 2009;2:
537–9.
13. Kleber ME, Delgado G, Grammer TB, et al. Uric
acid and cardiovascular events: a Mendelian randomization study. J Am Soc Nephrol 2015;26:2831–8.
Med J 2012;345:e7325.
8. Feig DI, Kang DH, Johnson RJ. Uric acid and
cardiovascular risk. N Engl J Med 2008;359:
14. Goethe JW. Johan Wolfgang von Goethe quotes.
Available at: http://www.bestquotes4ever.com/
genetic effects and back to Koch’s postulates of
causality. Circ Res 2014;114:e18–21.
1811–21.
quote/it-s-in-the-65771. Accessed December 4, 2015.
9. Keenan T, Zhao W, Rasheed A, et al. Causal
15. Givertz MM, Anstrom KJ, Redfield MM, et al.
3. MacArthur DG, Manolio TA, Dimmock DP, et al.
Guidelines for investigating causality of sequence
variants in human disease. Nature 2014;508:
469–76.
assessment of serum urate levels in cardiometabolic diseases: through a Mendelian Randomization study. J Am Coll Cardiol 2016;67:407–16.
Effects of xanthine oxidase inhibition in hyperuricemic heart failure patients: the Xanthine Oxidase
Inhibition for Hyperuricemic Heart Failure Patients
(EXACT-HF) study. Circulation 2015;131:1763–71.
2. Marian AJ. Causality in genetics: the gradient of
4. Marian AJ, Belmont J. Strategic approaches to
unraveling genetic causes of cardiovascular diseases. Circ Res 2011;108:1252–69.
10. Wehby GL, Ohsfeldt RL, Murray JC. ’Mendelian
randomization’ equals instrumental variable analysis with genetic instruments. Stat Med 2008;27:
2745–9.
5. Wheeler DA, Srinivasan M, Egholm M, et al. The
complete genome of an individual by massively
11. Marian AJ. Molecular genetic studies of complex phenotypes. Transl Res 2012;159:64–79.
parallel DNA sequencing. Nature 2008;452:
872–6.
12. Palmer TM, Nordestgaard BG, Benn M, et al.
Association of plasma uric acid with ischaemic
6. Levy S, Sutton G, Ng PC, et al. The diploid
genome sequence of an individual human. PLoS
Biol 2007;5:e254.
heart disease and blood pressure: mendelian randomisation analysis of two large cohorts. Br Med J
2013;347:f4262.
16. Zhang Y, Yamamoto T, Hisatome I, et al. Uric
acid induces oxidative stress and growth inhibition
by activating adenosine monophosphate-activated
protein kinase and extracellular signal-regulated
kinase signal pathways in pancreatic beta cells.
Mol Cell Endocrinol 2013;375:89–96.
KEY WORDS association studies, causality,
genetics, Mendelian randomization, single
nucleotide variants, uric acid
419