The UMOD Locus: Insights Into The Pathogenesis and Prognosis of Kidney Disease
The UMOD Locus: Insights Into The Pathogenesis and Prognosis of Kidney Disease
The UMOD Locus: Insights Into The Pathogenesis and Prognosis of Kidney Disease
org
ABSTRACT
The identification of genetic factors associated with kidney disease has the potential and hypothesis-free, unbiased approach.11
to provide critical insights into disease mechanisms. Genome-wide association stud- Typically, genetic variants uncovered
ies have uncovered genomic regions associated with renal function metrics and risk through GWAS are associated with a rela-
of CKD. UMOD is among the most outstanding loci associated with CKD in the tively small increase in disease risk, and
general population, because it has a large effect on eGFR and CKD risk that is their identification requires large study
consistent across different ethnic groups. The relevance of UMOD for CKD is clear, populations.12 The GWASs performed in
because the encoded protein, uromodulin (Tamm–Horsfall protein), is exclusively nephrology were first addressing CKD-
produced by the kidney tubule and has specific biochemical properties that mediate defining traits, such as the eGFR on the
important functions in the kidney and urine. Rare mutations in UMOD are the major basis of serum creatinine (eGFRcrea) and
cause of autosomal dominant tubulointerstitial kidney disease, a condition that the urinary albumin-to-creatinine ratio
leads to CKD and ESRD. In this brief review, we use the UMOD paradigm to describe (UACR), whereas a second group of studies
how population genetic studies can yield insight into the pathogenesis and prognosis focused on specific CKD etiologies, such
of kidney diseases. as IgA nephropathy or membranous ne-
phropathy. Of note, the latter GWASs
J Am Soc Nephrol 29: 713–726, 2018. doi: https://doi.org/10.1681/ASN.2017070716
have been successful in small- to modest-
sized cohorts in identifying common alleles
that confer large effects.12
To date, without including studies on
CKD is a global public health burden, our knowledge of the genetic architecture diabetic nephropathy, there are .20
affecting as many as 10%–15% of the of kidney diseases, including the role of GWASs of CKD-defining traits,10,13–32
population worldwide and exceeding APOL1 in progression of various ne- including one in pediatric subjects 25
20% in individuals about 60 years old.1 phropathies in individuals of African and two on renal decline.24,30 Of these
Even in the early stages, CKD is associ- ancestry,3 the strong signals (HLA-DQA1 studies, only a few considered the study
ated with increased prevalence and se- and PLA2R1) associated with the risk of of CKD in addition to eGFRcrea or
verity of multiple disorders and adverse membranous nephropathy,4 and the path- UACR. Most of them limited their
outcomes, and it is a major risk factor for ogenesis of IgA nephropathy.5 In parallel, analyses to eGFRcrea,60 ml/min per
accelerated cardiovascular disease and the development and implementation of 1.73 m2,10,13,15,16,18,20,22,26 some of them
aging.2 Very few pharmacologic inter- genetic testing, in particular next genera- extended their analyses to eGFRcrea,45
ventions have been developed specifi- tion sequencing, allowed to identify the ge- ml/min per 1.73 m2,20 and only a few fo-
cally for treating CKD, primarily due to netic basis of a large number of rare kidney cused their analyses on ESRD.19,23 Studies
the lack of mechanistic understanding diseases.6 Emerging analyses of the com-
and the lack of biomarkers reflecting bined effect of rare mutations and modifier
the severity of organ damage. gene variants help to explain some phenotype
Published online ahead of print. Publication date
The familial clustering of kidney dis- heterogeneity observed in these disorders.7–9 available at www.jasn.org.
orders has long been recognized, and the Since 2007, genome-wide association
Correspondence: Prof. Olivier Devuyst, Institute of
genetic predisposition to such diseases is studies (GWASs) have become a very
Physiology, University of Zurich, Winterthurerstrasse
emerging as a major source of insights popular tool to uncover genomic regions 190, CH-8057 Zurich, Switzerland. Email: olivier.
into mechanisms potentially relevant for associated with renal function metrics devuyst@uzh.ch
CKD. In less than a decade, genome-wide and CKD risk.10 The success of GWASs Copyright © 2018 by the American Society of
studies yielded major breakthroughs in was built on their conceptual simplicity Nephrology
focusing on CKD on the basis of eGFRcrea for the same outcome on one single-nucle- as diabetes or hypertension, GWASs of clin-
did not identify any further genome-wide otide polymorphism (SNP) at a time. SNPs ically defined CKD require large sample
significant locus other than those already represent common genetic variations be- sizes that are realistically difficult to ob-
identified by the analysis of eGFRcrea. Tak- tween human subjects and are measured tain.12 To overcome the sample size issue,
ing all studies together, .60 loci are now using commercial genotyping arrays. After cross-sectional studies carried out in the
reported in association with CKD-defining obtaining a first set of directly genotyped general adult population were used.15,22,28
traits, most of them with eGFRcrea in Eu- SNPs, the numberof SNPs can be expanded In these studies, CKD 3+ was defined as
ropean ancestry individuals.26,29,31 via genetic imputation, obtaining a cover- eGFRcrea,60 ml/min per 1.73 m2 on the
Among all of the loci associated with age of the genome that is at least ten times basis of a single serum creatinine assess-
CKD in the general population, the larger than the initial set of genotyped ment. No genome-wide significant loci
UMOD one is of particular interest due SNPs. Imputation is performed using have been identified out of those already
to its large effect on both eGFR and CKD probabilistic methods (usually Markov reported as significantly associated with
risk, the consistency of the effect across dif- Chain Monte Carlo) on the basis of large eGFRcrea.13,15,20,22,26 Attempts to decrease
ferent ethnic groups, and its relationship sets of reference fully sequenced genomes, the eGFRcrea threshold to 45 ml/min per
with age.33 The relevance of UMOD for such as those of the 1000 Genomes Consor- 1.73 m2 did not successfully identified new
CKD is immediate, because the encoded tium or the Haplotype Reference Con- loci due to lack of power.20 Cross-sectional
protein, uromodulin (Tamm–Horsfall sortium (HRC).35,36 As an example, a studies may perform GWASs on CKD stage
protein), is exclusively produced by the recent GWAS of kidney function traits 3+, but they would miss patients with the
kidney tubule and has specific biochemi- has been run on nearly 11 million SNPs most severe cases of CKD stages 4 and 5.
cal properties that sustain its role in the and insertion/deletion markers.31 Ex- Conversely, enrichment for patients with
kidney and urine. Furthermore, rare mu- haustive overviews of the GWAS method ESRD would then miss the earlier, asymp-
tations in UMOD are the major cause of with applications in nephrology have been tomatic stages of disease. A recent trans-
autosomal dominant tubulointerstitial given previously.11,37 ethnic analysis showed that most of the
kidney disease (ADTKD), a condition Among the renal function metrics, eGFRcrea-associated loci are associated
that leads to CKD and ESRD.34 Because eGFRcrea has been probably the most with increased risk of CKD defined as
UMOD is involved in a continuum be- studied outcome. 12 After uncovering eGFRcrea,60 ml/min per 1.73 m2 or in-
tween rare mutations and common regu- the UMOD locus as associated with cident ESRD.28 Böger et al.43 showed that
latory variants, physiologically relevant, eGFRcrea, 13 over 60 loci were found most of the eGFRcrea-associated loci
biochemical investigations of uromodulin in association with this trait in Euro- were also associated with incident CKD
are essential to understand its complex pean,13,15,16,17,20,26,31 Asian,22 and mixed or ESRD after 7 years median follow-up.
role—in the kidney and beyond. This brief ethnic groups.28 Additional results were Taken together, these findings support the
review will describe how population ge- provided by rare mutation and exome- evidence that, although it is challenging to
netic studies evidenced risk loci for CKD chip analyses.29,38 The strong transethnic perform gene discovery analyses on clini-
and related traits and will use the UMOD differences in renal function regulation cally defined CKD, the analysis of CKD-
paradigm to show how this genetic signal are especially highlighted in the study of defining traits is providing insight into
may yield pathogenesis and prognostic in- albuminuria.32 For the UACR trait, a few the biologic pathways underlying CKD.
sights into kidney diseases. but well characterized loci have been iden- An overview of the effect of different
tified, including the CUBN gene identified genetic loci on CKD for different ethnicities
in European, black, and Southern Ameri- (Europeans, Asians, and multiethnic) is
DISCOVERING GENETIC RISK can populations 39,40 ; the RAB38 and given in Figure 1. In general, odds ratios
FACTORS FOR CKD HS6ST1 genes identified in diabetic Euro- (ORs) are small, indicating that each ad-
pean ancestry subjects27; the BCL2L11 gene ditional copy of the risk allele at each locus
In recent years, GWASs established them- identified via genome-wide admixture confers only a modest increase in the risk
selves as the most powerful tool to detect analysis in Amerindians41; and the HBB of CKD. Just a handful of SNPs would
new genetic variants associated with com- gene identified via candidate gene approach have shown genome-wide significance
mon diseases. Using this technique, thou- but showing genome-wide significance in in a GWAS of CKD, including UMOD,
sands of loci have been associated with Africans and Southern Americans.42 PRKAG2, CPS1, ALMS1-NAT8, and
several biomarkers and complex disorders. In contrast with the successful GWASs of GATM in Europeans (Figure 1A) and
The GWAS technique is rather simple: it CKD-defining traits, it has been difficult to WDR72 in Asians (Figure 1B). Among
consists of running an association test mil- perform GWASs of clinically defined CKD these, loci, such as GATM for instance, re-
lions of times over the entire genome using (i.e., kidney damage or GFR,60 ml/min flect the creatinine production pathway11
linear, logistic, or survival regression mod- per 1.73 m2 for at least 3 months).2 Taking and probably have little to do with the risk
els, depending on whether a quantita- into account the heterogeneity of disease of CKD. Notably, several loci are associ-
tive, dichotomous, or survival outcome is etiologies and the small genetic effects that ated with CKD across ethnicities, includ-
considered respectively. Models are fitted are anticipated for complex diseases, such ing UMOD, SHROOM3, MPPED2, BCAS3,
714 Journal of the American Society of Nephrology J Am Soc Nephrol 29: 713–726, 2018
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and UNCX. The analysis also indicates that the observed difference by diabetes sta- in uromodulin knockout mice suggested
the P value criterion, which drives GWAS tus in the CKDGen Consortium is con- that uromodulin interacts with trans-
discovery, does not reflect effect size but pre- founded by age. In fact, age was shown to porters operating in the TAL to regulate
cision. Loci with small but consistent effect interact with UMOD in its association salt transport,53 protects against urinary
across studies will get lower P values than with serum creatinine and CKD.17 tract infections (UTIs) via high-affinity
loci with larger but variable effect between In addition to eGFRcrea and CKD, binding to the type 1 fimbriae of uropa-
populations, maybe because of population- UMOD has been associated with the risk thogenic Escherichia coli, 54,55 reduces
specific features increasing heterogeneity of of hypertension and incident cardiovascu- the propensity to form calcium crystals
genetic effects. lar disease events in an extreme patient- and kidney stones,56 and plays a role in
control study from the Global BPGen innate immunity by binding IGs and cy-
Consortium.45 UMOD has also been sig- tokines and/or activating monocytes
DISCOVERY AND ASSOCIATIONS nificantly associated with uric acid levels and dendritic cells. 57,58 In the urine,
OF THE UMOD LOCUS in an Icelandic cohort17 and a Chinese uromodulin forms a three-dimensional
community–based cohort,46 and it has matrix consisting of high molecu-
The UMOD locus stands out among the been associated with reduced risk of kid- lar weight polymers. The extracellular
loci associated with CKD. In European ney stones (OR, 0.88; 95% CI, 0.83 to polymerization is mediated by the pro-
ancestry individuals, UMOD was the first 0.94) in a combined sample of Icelandic teolytic cleavage of the protein in the api-
locus uncovered in association with and Dutch subjects.17 Furthermore, the cal membrane of TAL cells by the serine
eGFRcrea, and it was already associated UMOD promoter variants were highly protease hepsin.59
with CKD at a genome-wide significance associated with urinary levels of uro- In 2002, Hart et al. 60 showed that
level.13 CKD association at the UMOD modulin (both 24-hour urinary excretion dominant mutations in UMOD are a
locus is related to the three SNPs in link- and uromodulin-to-creatinine ratio) major cause of ADTKD, a rare disorder
age disequilibrium located in the pro- in a meta-analysis of 10,884 individuals often associated with hyperuricemia
moter. For these SNPs, the “risk” allele is of European descent.47 (due to decreased fractional excretion
the common allele, which has a frequency of urate), gout, and tubulointerstitial
of approximately 80% in Europeans.44 As damage, invariably leading to CKD and
shown in Figure 1, UMOD shows the BIOLOGIC RELEVANCE OF THE renal failure.34 Most of the UMOD mu-
largest OR for CKD compared with all UMOD LOCUS tations described thus far are missense
other loci in nearly all ethnicities. The changes that often replace or delete one
OR for CKD is 1.24 (95% confidence in- The prior knowledge about uromodulin of the conserved cysteine residues of
terval [95% CI], 1.19 to 1.29) per copy of paralleled by genetic evidence involving the protein, affecting its folding and
the UMOD risk allele,26 rising up to 1.35 UMOD in rare kidney diseases and by trafficking to the plasma membrane.
(95% CI, 1.18 to 1.54) if eGFRcrea,45 translational studies has sustained the This effect has been shown in vitro,61
ml/min per 1.73 m 2 is considered. 20 biologic relevance of the association of whereas analysis of patient biopsies has
UMOD is, to date, the only locus associ- UMOD with renal function and CKD. shown typical accumulation of mutant
ated with incident CKD at a genome-wide Uromodulin has a long history (Fig- uromodulin in the endoplasmic reticu-
level of significance, with an OR of about ure 2). First described by Rovida48 as a lum, showing that ADTKD-UMOD is,
1.3 per copy of the risk allele, which re- wax-like material in kidney tubules, the in fact, an endoplasmic reticulum storage
mained unchanged after baseline eGFR- protein was isolated from the urine in disease.62,63
crea adjustment.43 Furthermore, UMOD 1950 by Tamm and Horsfall49 from the The fact that the top UMOD GWAS
is also associated with incident ESRD.43 If Rockefeller Institute in New York. The variants are in perfect linkage disequilib-
all eGFRcrea loci together explain nearly Tamm–Horsfall protein, as it was named rium in the promoter of the gene pro-
4% of the trait variance,31 .1% is ex- from there, was found to be the most vided an important clue for their biologic
plained by UMOD alone. Accordingly, abundant protein in normal human relevance.44 Indeed, population studies
UMOD accounts for 25% of the eGFRcrea urine, characterized by a mass of ap- established that the UMOD promoter var-
variability explained by genetic factors. proximately 85 kD, a high carbohydrate iants are strongly associated with urinary
Recent studies show that the effect of content (approximately 30% of the mo- levels of uromodulin, each (major) risk al-
the UMOD eGFRcrea-lowering allele is lecular mass), 48 cysteine residues, and a lele increasing the urinary excretion of ur-
double in diabetic individuals compared tendency to form aggregates. After the omodulin in a dose-dependent fashion.47,64
with nonpatients with diabetes (approx- demonstration of an immunoregulatory In fact, homozygous carriers of the risk al-
imately 22.7% versus 21.5% eGFRcrea activity in vitro, the protein was renamed lele had twofold-higher indexed uromodulin
per copy of the risk allele in patients with “uromodulin.”50 Uromodulin is exclu- levels than the homozygous carriers of the
diabetes versus nonpatients with diabe- sively produced in the kidney—by the (minor) protective allele.47 Along with eGFR
tes, respectively; P value for difference cells lining the thick ascending limb and sodium excretion, the UMOD genotype
=0.02). 26 However, it is possible that (TAL) of the loop of Henle.51,52 Studies at rs4293393 was one of the independent
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Figure 1. Genetic loci for CKD have small effects. ORs for CKD at the loci showing genome-wide significant association with CKD un-
derlying traits. The ORs are reported along with their 95% CIs. The underlying trait that led to uncover each specific locus is identified with
a different color: eGFRcrea (blue), albuminuria (red), BUN (green), and uric acid (orange). (A) OR for CKD in the general population of
European ancestry at loci reported by the CKDGen Consortium GWAS.26,31 Given that no GWAS of CKD was performed by Gorski et al.31
for these loci and the albuminuria locus cubilin (CUBN),39 ORs for CKD were obtained by a lookup of the GWAS results published in the
work by Pattaro et al.26 Given the different genetic imputation platforms (HapMap versus 1000 Genomes), not all loci were available. (B)
OR for CKD in the general population of Asian ancestry as reported by the AGEN Consortium.22 *Genome-wide significance for CKD. (C)
OR for CKD, defined as eGFRcrea,60 or ESRD, in a general mixed population of European, African, Asian, and Hispanic ancestry.28
predictors of urinary uromodulin levels in a promoter in vitro reflected by twofold- modeled in a transgenic Umod mouse over-
Canadian population.65 Further studies higher UMOD transcript levels in human expressing wild-type uromodulin (TgUmodwt):
showed that the risk variants exert a robust kidney biopsies and a higher level of uromo- with aging, the kidneys of these mice showed
influence on the activity of the UMOD dulin in urine.44 The human situation was focal lesions and increased expression of
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Figure 2. Milestones in the discovery of Tamm–Horsfall/uromodulin protein and the UMOD gene from the XIXth to the XXIst century. ER,
endoplasmic reticulum.
damage markers, including lipocalin-2 function.17,20 Other potentially deleterious the association of UMOD variants with
and Kim-1. These changes, which were factors could be the metabolic demand of hypertension44 and completes the link
not observed in control mice, occurred uromodulin production in TAL cells, the between renal tubular transport of
in absence of renal failure. Similar focal chronic activation of salt reabsorption sys- NaCl and BP regulation.66
lesions were seen in kidney biopsies from tems, or the effects of increased uromodulin
individuals ages .65 years old, and their levels in the lumen of the distal nephron or
area was significantly increased in indi- in the circulation.33 PROGNOSTIC VALUE: GENOTYPE
viduals homozygous for UMOD risk var- In addition to renal damage and aging VERSUS BIOMARKER
iants relative to those carrying protective lesions, the transgenic Umod mice dis-
variants.44 Taken together, these results played salt-sensitive hypertension due The UMOD locus is associated with
indicate that increased expression of ur- to activation (phosphorylation) of eGFR and CKD in the general population.
omodulin does not lead to renal failure NKCC2 in the TAL, which was mirrored The promoter SNPs constituting the risk
per se. Instead, they support a second hit by increased response to furosemide. An haplotype drive increased transcriptional
model, in which high uromodulin pro- increased response to furosemide was activity and higher levels of uromodulin
duction over time predisposes to kidney also observed in hypertensive individu- in kidney and urine and in blood.44,67
damage induced by additional comorbid- als homozygous for the UMOD risk al- Accordingly, one could expect that higher
ities.44 This model is, in fact, supported by lele.44 The gain-of-function mechanism levels of uromodulin would be associated
the strong interaction of age with the asso- associated with higher uromodulin ex- with higher risk of kidney damage in epi-
ciation of UMOD variants with kidney pression in this mouse model supports demiologic studies. However, recent
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Figure 3. Interpretation of the uromodulin biomarker versus UMOD genotype studies. In observational epidemiologic studies, ur-
omodulin levels largely reflect kidney mass at baseline. Higher levels of uromodulin in urine, representing a higher renal functional reserve,
are as such associated with a positive outcome in prospective studies conducted in at-risk individuals. Conversely, decreased levels of
uromodulin reflect decreased production and lower functional reserve at baseline. This situation (i.e., when it is the disease [kidney
damage] that affects the studied risk factor [uromodulin level]) is typical of reverse causation. In turn, reverse causation represents a bias
when evaluating the causality of the UMOD risk haplotype in promoting CKD. Genetic, experimental, and statistical studies in healthy
individuals have shown that the UMOD risk haplotype drives the expression of uromodulin in the kidney and its level in urine. The use of
analytic methods, such as Mendelian randomization, will provide a valuable opportunity to assess the causality of the UMOD genotype
and higher uromodulin levels as a risk factor for CKD. ER, endoplasmic reticulum.
prospective studies showed that higher with eGFR, markers of tubular transport, thus be considered as biomarkers of kidney
levels of uromodulin are protective of kid- and kidney length and volume, suggesting tubule function, with higher levels reflecting
ney damage in at-risk cohorts.67–69 How that urinary uromodulin is a biomarker for higher renal functional mass (Figure 3).
can we explain these seemingly opposite tubular mass and function.72 A fraction of From the above, it can be hypothesized
predictive values of uromodulin levels for uromodulin produced in the TAL is that low urinary uromodulin is a marker of
the risk of kidney disease (Figure 3)? released into the circulation.73 Plasma poorer tubular health: in at-risk individuals
The value of uromodulin as a biomarker uromodulin concentrations, which are ap- (aged and early CKD), decreased levels of
originates from its exclusive production by a proximately 1000 times lower than urinary uromodulin reflect decreased production
tubular segment of the kidney, with sizeable levels (nanograms per milliliter versus mi- (i.e., decreased renal functional reserve).
levels being detected in normal urine.70,71 crograms per milliliter, respectively), corre- The latter hypothesis is supported by the
Observational studies carried out in the late positively with urinary uromodulin studies of Garimella et al.,68 which mea-
general population showed that urinary ur- excretion and creatinine clearance in patients sured urinary uromodulin levels in 192
omodulin levels are positively associated with CKD.74,75 The levels of uromodulin can participants of the Cardiovascular Health
718 Journal of the American Society of Nephrology J Am Soc Nephrol 29: 713–726, 2018
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Study over 9 years. Each one SD increase high prevalence of the ancestral allele kidney stones, UTIs, and myeloma cast ne-
in urinary uromodulin was associated could reflect some evolutionary advan- phropathy.44,82
with a 23% lower odds of eGFR decline tage.77 In fact, the ancestral allele shows a The opposite effects on BPobserved in
and a 10% lower risk of mortality. Similarly, global correlation with bacterial diversity transgenic and knockout uromodulin
lower preoperative urinary uromodulin (the Human Genome Diversity Project) mouse models44,83 and the observation
levels were associated with higher risk of and the prevalence of antibiotic resistance of an increased response to furosemide
postoperative AKI.69 In these at-risk indi- in Gram-negative uropathogens (i.e., areas in hypertensive individuals homozygous
viduals, decreased levels of uromodulin with higher prevalence of UTIs). The levels for the UMOD risk allele44 raise perspec-
reflect decreased functional reserve. The of uromodulin in urine also correlated tives for a personalized medical approach.
latter situation is typical of reverse causa- with urinary leukocytes and nitrites in the For example, the possibility to use a long-
tion (i.e., when it is the disease [kidney population.77 Furthermore, high urinary acting loop diuretic (torasemide) in patients
damage] that affects the studied risk factor levels of uromodulin were also associated with resistant hypertension who harbor
[uromodulin level]) (Figure 3). Such a sit- with lower risk for UTI in older adults UMOD promoter risk variants is currently
uation would then constitute a bias when from the Cardiovascular Health Study, in- being tested in a prospective study.84
evaluating the causality of the UMOD ge- dependent of traditional UTI risk factors.78
notype and the uromodulin levels in rela- Taken together, these studies suggest that Limitations and Hope for GWAS
tion to the outcome. The use of analytic the ancestral UMOD allele has been kept The small effect of each individual GWAS
methods, such as Mendelian randomiza- at a high frequency due to its protective locus reflects the polygenic theory that
tion, will provide a valuable opportunity effect against UTIs, which mainly affect complex diseases are driven by a blend of
to assess the causality of higher uromodulin young women and have important conse- different pathways, each one responsible
levels as a risk factor for CKD.76 Further- quences in terms of fitness and reproduc- of a minimal fraction of the risk of the dis-
more, even if the UMOD variants show tion. The salt-retaining effect of this variant ease.85,86 This does not mean that genetic
the largest effect size among all known could also confer an advantage in patients findings have little clinical relevance. In
loci for eGFRcrea and CKD, their effect with severe infection, particularly children.79 fact, as already reported by Köttgen
is clearly age dependent and contributing The persistent high frequencies of the et al.,15 a genetic risk score on the basis of
only to a small part of the overall risk of ancestral UMOD allele in areas with the first 20 loci identified was associated
kidney damage, together with many stronger selective pressure for its protec- with the doubling of CKD prevalence
other genetic and environmental factors. tive effect follow the model of selection from about 5% to about 10% in the general
Especially regarding age and CKD status, on standing variation,80 as observed for population. In addition, regardless of the
Mendelian randomization studies should the ancestral -3826A allele in UCP1, that effect size, each gene identified shed light
take the stratification of study subjects has been kept at higher frequencies in on a particular pathway. Each of these
into account to depict a conclusive pic- populations exposed to low solar radia- pathways has the potential to become a
ture of the causal relation between uro- tion.81 Of note, the UMOD situation dif- therapeutic target to prevent CKD as illus-
modulin levels and disease risk. Also, one fers from the ancestral susceptibility model trated in the field of coronary artery disease,
should keep in mind the possibility that that is applicable when salt retention is the where large-scale genetic investigations
the UMOD SNPs may still have addi- primary motor for evolutionary selection paved the way to release of targeted therapies
tional effects, unrelated to the production (e.g., variants in the salt-retaining genes into the market.87 In line with such a “blend”
of uromodulin, involved in the associa- CYP3A5 and AGT)77,79 and the selection theory is the observation that eGFRcrea is
tion with renal disease. at the APOL1 locus, where the derived al- not the only phenotype that should be used
lele rather than the ancestral allele confers a to uncover genetic loci for CKD: Okada
selective advantage against a pathogen.3 et al.22 showed that loci associated with
PERSPECTIVES uric acid and BUN may be associated with
Uromodulin as a Target for CKD at a similar magnitude as eGFRcrea
Evolution and Selection Treatment loci. Also, larger meta-GWASs of uromodulin
The lead UMOD risk variant (allele T at If the causal relation between uromodulin levels may be useful to uncover mechanisms
rs4293393) associated with CKD and hy- production and the risk of developing CKD involved in uromodulin production and/or
pertension is the ancestral allele, and its is substantiated by MR, the possible benefit release from TAL cells. In turn, these factors
prevalence ranges from 70% to 80% in of regulating uromodulin production in the may be viewed as additional traits reflecting
Africans and Europeans to .90% in East TAL by dietary or pharmacologic interven- renal tubular health.
Asians. Furthermore, this risk variant di- tions should be investigated—keeping in The fact that all loci reported so far
rectly increases the expression of uro- mind the age effect associated with the only explain approximately 4% of the
modulin in a dose-dependent fashion, UMOD risk variant.17,44 Another approach total variance of eGFRcrea,31 whereas
and it causes salt-sensitive hypertension could be to modulate the biochemical the genetic heritability of the trait is be-
and kidney damage in mice and hu- properties of uromodulin in the urine, tween 30% and 50%88 means that most of
mans.44 Recent studies suggest that the which could offer some perspectives for the genetic heritability of eGFRcrea remains
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Nelson GW, Vanhollebeke B, Winkler CA,
least to 1%, hopefully to 0.5%, MAF means UMOD mutations (stop gained, missense Kopp JB, Pays E, Pollak MR: Association of
getting larger effects and thus, stronger pre- involving cysteine residues, or frameshift). trypanolytic ApoL1 variants with kidney dis-
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Bockenhauer D, Kottgen A, Dragomirescu L,
only. To gain insight into kidney function Considering that the top UMOD variants Voinescu C, Patel N, Pearce K, Hubank M,
biology, it would be important to expand show pleiotropic effects on multiple Stephens HA, Laundy V, Padmanabhan S,
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renal function before aging-related comor- clinical associations94 and reveal biologic Stengel B, Powis SH, Brenchley P, Feehally J,
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normal renal activity, which may be attrac- phropathy. N Engl J Med 364: 616–626, 2011
tive targets. Before large sequencing studies 5. Kiryluk K, Li Y, Scolari F, Sanna-Cherchi S,
become available, increased precision in ACKNOWLEDGMENTS Choi M, Verbitsky M, Fasel D, Lata S, Prakash
S, Shapiro S, Fischman C, Snyder HJ, Appel
genotyping can be achieved with denser
G, Izzi C, Viola BF, Dallera N, Del Vecchio L,
and better imputed genetic maps as illus- We thank Guido Barbujani, Anthony Bleyer,
Barlassina C, Salvi E, Bertinetto FE, Amoroso
trated by the discovery of rare variants Murielle Bochud, Kai-Uwe Eckardt, Caroline A, Savoldi S, Rocchietti M, Amore A,
(MAF,2%) associated with serum creati- S. Fox, Barry Freedman, Anna Köttgen, François Peruzzi L, Coppo R, Salvadori M, Ravani P,
nine and CKD in an Icelandic cohort.38 By Madore, Eric Olinger, Belen Ponte, Menno Magistroni R, Ghiggeri GM, Caridi G, Bodria
Pruijm, Luca Rampoldi, Rajesh V. Thakker, M, Lugani F, Allegri L, Delsante M, Maiorana
focusing on markers located in the coding
M, Magnano A, Frasca G, Boer E, Boscutti G,
regions of the genes, exome chip analysis Stephane Troyanov, Peter Vollenweider, Gérard
Ponticelli C, Mignani R, Marcantoni C, Di
has the potential to discover rare variants Waeber, and Sonia Youhanna for fruitful Landro D, Santoro D, Pani A, Polci R, Feriozzi
more likely to have a functional value as discussions. S, Chicca S, Galliani M, Gigante M, Gesualdo
recently shown by Li et al.29 By exploiting O.D. is supported by the Swiss National Centre L, Zamboli P, Battaglia GG, Garozzo M,
of Competence in Research Kidney Control of Maixnerová D, Tesar V, Eitner F, Rauen T,
the value of next generation sequencing
Floege J, Kovacs T, Nagy J, Mucha K,
technologies, future studies should con- Homeostasis program, Swiss National Science
Pączek L, Zaniew M, Mizerska-Wasiak M,
sider fine mapping of top GWAS loci, be- Foundation grant 31003A_169850, and the Rare Roszkowska-Blaim M, Pawlaczyk K, Gale D,
cause it was shown that such loci may carry DiseaseInitiativeZurich(Radiz),aclinicalresearch Barratt J, Thibaudin L, Berthoux F, Canaud G,
multiple independent rare variants that priority program of the University of Zurich. Boland A, Metzger M, Panzer U, Suzuki H,
Goto S, Narita I, Caliskan Y, Xie J, Hou P, Chen
substantially increase the amount of ex-
N, Zhang H, Wyatt RJ, Novak J, Julian BA,
plained heritability.93 Feehally J, Stengel B, Cusi D, Lifton RP,
In conclusion, UMOD has been identi- DISCLOSURES Gharavi AG: Discovery of new risk loci for IgA
fied as one of the most outstanding loci None. nephropathy implicates genes involved in
720 Journal of the American Society of Nephrology J Am Soc Nephrol 29: 713–726, 2018
www.jasn.org BRIEF REVIEW
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