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ORIGINAL ARTICLE
A coding polymorphism in NALP1 confers risk for
autoimmune Addison’s disease and type 1 diabetes
NF Magitta
1,2,3
, AS Bøe Wolff
1,4,5
, S Johansson
1,2,6
, B Skinningsrud
7,8
, BA Lie
9
, K-M Myhr
2,10
,
DE Undlien
7,8
, G Joner
11,12
, PR Njølstad
2,13
, TK Kvien
14
, Ø Førre
15
, PM Knappskog
1,2,16
and ES Husebye
4,5,16
1
Centre of Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway;
2
Institute of Clinical Medicine,
University of Bergen, Bergen, Norway;
3
Department of Biochemistry, Muhimbili University of Health and Allied Sciences, Dar es
Salaam, Tanzania;
4
Department of Medicine, Haukeland University Hospital, Bergen, Norway;
5
Institute of Medicine, University of
Bergen, Bergen, Norway;
6
Institute of Biomedicine, University of Bergen, Bergen, Norway;
7
Institute of Medical Genetics, University
of Oslo, Oslo, Norway;
8
Department of Medical Genetics, Ulleva
˚l University Hospital, Oslo, Norway;
9
Institute of Immunology,
Rikshospitalet-Radiumhospitalet University Hospital, Oslo, Norway;
10
Department of Neurology, Haukeland University Hospital,
Bergen, Norway;
11
Department of Paediatrics, Ulleva
˚l University Hospital, Oslo, Norway;
12
Institute of Health Management and Health
Economics, University of Oslo, Oslo, Norway;
13
Department of Paediatrics, Haukeland University Hospital, Bergen, Norway;
14
Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway and
15
Department of Rheumatology, Rikshospitalet-
Radiumhospitalet University Hospital, Oslo, Norway
Variants in the gene encoding NACHT leucine-rich-repeat protein 1 (NALP1), an important molecule in innate immunity, have
recently been shown to confer risk for vitiligo and associated autoimmunity. We hypothesized that sequence variants in this
gene may be involved in susceptibility to a wider spectrum of autoimmune diseases. Investigating large patient cohorts from six
different autoimmune diseases, that is autoimmune Addison’s disease (n ¼333), type 1 diabetes (n ¼1086), multiple sclerosis
(n ¼502), rheumatoid arthritis (n ¼945), systemic lupus erythematosus (n ¼156) and juvenile idiopathic arthritis (n ¼505),
against 3273 healthy controls, we analyzed four single nucleotide polymorphisms (SNPs) in NALP1. The major allele of the
coding SNP rs12150220 revealed significant association with autoimmune Addison’s disease compared with controls
(OR ¼1.25, 95% CI: 1.06–1.49, P ¼0.007), and with type 1 diabetes (OR ¼1.15, 95% CI: 1.04–1.27, P ¼0.005). Trends
toward the same associations were seen in rheumatoid arthritis, systemic lupus erythematosus and, although less obvious,
multiple sclerosis. Patients with juvenile idiopathic arthritis did not show association with NALP1 gene variants. The results
indicate that NALP1 and the innate immune system may be implicated in the pathogenesis of many autoimmune disorders,
particularly organ-specific autoimmune diseases.
Genes and Immunity (2009) 10, 120–124; doi:10.1038/gene.2008.85; published online 23 October 2008
Keywords: adrenal insufficiency; type 1 diabetes mellitus; NALP1; NLRP1; autoimmunity; single nucleotide
polymorphism
Introduction
NACHT leucine-rich-repeat protein 1 (NALP1) or NLR
family, pyrin domain containing 1 (NLRP1), is a member
of the nucleotide oligomerization domains (NOD)-like
receptors (NLRs) family, which are cytoplasmic proteins
that sense endogenous microbial products and metabolic
stresses, thereby stimulating innate immunity. In
humans, NLRs include several members of the NALP
family, interleukin-1b(IL-1b)-converting enzyme pro-
tease activating factors, neuronal apoptosis inhibitory
factors, major histocompatibility complex class II trans-
activator and five members of the NOD subfamily. NLRs
associate with other proteins forming multiprotein
cytoplasmic complexes that mediate the activation of
inflammatory caspases, which can further activate pro-
inflammatory cytokines and promote inflammation.
1–4
NALP1 provides a scaffold for the assembly of the
inflammasome that activates caspases 1 and 5, which
subsequently promote the processing and maturation of
the inflammatory cytokines, pro-IL-1b, IL-18 and IL-33.
3–7
Apoptosomes are also formed with NALP1, caspase-2
and caspase-9, suggesting a role for NALP1 in the
regulation of apoptosis and cell survival.
8
The strong
expression of NALP1 in immune cells, particularly the
Langerhans cells and T cells, underscores its potential
role in autoimmunity.
A link between NLRs and autoimmunity was recently
provided by Jin and co-workers,
9,10
who showed an
Received 11 July 2008; revised 23 September 2008; accepted 24
September 2008; published online 23 October 2008
Correspondence: Professor ES Husebye, Institute of Medicine,
Haukeland University Hospital, University of Bergen, Bergen
N-5021, Norway.
E-mail: Eystein.Husebye@helse-bergen.no
16
These authors contributed equally to this work.
Genes and Immunity (2009) 10, 120–124
&
2009 Macmillan Publishers Limited All rights reserved 1466-4879/09
$
32.00
www.nature.com/gene
association of polymorphisms in NALP1 and generalized
vitiligo and vitiligo-associated autoimmune disorders.
They suggested the existence of two distinct associated
regions within the NALP1 locus, one spanning the 50part
of the gene, including the promoter, and another locus
covering the 30end of the gene, tagged by rs6502867. To
examine whether the NALP1 gene could play a more
general role in autoimmunity, we tested the associations
of four single nucleotide polymorphisms (SNPs) with a
number of autoimmune diseases. We found associations
with autoimmune Addison’s disease and type 1 diabetes,
and similar trends for multiple sclerosis, rheumatoid
arthritis and systemic lupus erythematosus. Juvenile
idiopathic arthritis was not associated with any of the
tested SNPs in NALP1.
Results
First, we analyzed patients with autoimmune Addison’s
disease (n¼333), type 1 diabetes (n¼1086) and multiple
sclerosis (n¼502) against two groups of healthy controls
(n¼2269) for association with the tag SNPs rs12150220,
rs2670660, rs878329 and rs6502867 in NALP1. All SNPs
were in the Hardy–Weinberg equilibrium in each
stratum, apart from the marker rs6502867 in the multiple
sclerosis patients (Table 2). The two control cohorts were
genotyped at two different centers, but had almost
identical allele frequencies across all SNPs (P40.76),
and were therefore pooled in all analyses presented. The
SNP rs12150220 (p.Leu155His) was significantly asso-
ciated with both autoimmune Addison’s disease
(OR ¼1.27, 95% CI: 1.06–1.49, P¼0.006) and type 1
diabetes (OR ¼1.16, 95% CI: 1.04–1.28, P¼0.006)
(Table 1). The other three SNPs showed trends of
association with Addison’s disease, whereas two of them
(rs2670660 and rs878329) showed trends of association
with type 1 diabetes (Table 1). The subgroup analyses of
Addison’s disease patients divided into isolated Addi-
son’s disease and autoimmune polyendocrine syndrome
type II (APS II, that is Addison’s disease and auto-
immune thyroid disease and/or type 1 diabetes) did not
differ significantly from the total group of Addison’s
disease patients (data not shown). Similarly, when type 1
diabetes patients were stratified into low, neutral,
intermediate or high-risk human leukocyte antigen
haplotypes, the associations were similar to that of the
total group of type 1 diabetes (data not shown). No
NALP1 association with multiple sclerosis was evident
(Table 1), although the frequency distributions were
skewed in the same direction as those for autoimmune
Addison’s disease and type 1 diabetes. Moreover,
haplotype analysis (data not shown) and conditional
analysis (Table 1) suggested that the association within
this region could best be explained by one disease locus
tagged by rs12150220.
We next extended the analyses by genotyping
rs6502867 and rs12150220 in patients affected with three
other autoimmune diseases, that is rheumatoid arthritis,
systemic lupus erythematosus and juvenile idiopathic
arthritis, and an additional set of healthy controls.
Although a trend for association in the same direction
as autoimmune Addison’s disease and type 1 diabetes
was seen in rheumatoid arthritis and systemic lupus
erythematosus for rs12150220, it did not reach statistical
significance. Juvenile idiopathic arthritis was not asso-
ciated with either of the NALP1 SNPs (Table 2).
Linkage disequilibrium (LD) analysis showed the
existence of strong LD between the exon 3 SNP
rs12150220 and the two SNPs upstream of the gene
(rs2670660 and rs878329), whereas very little LD seemed
to extend to rs6502867 located in the 30part of the gene
Table 1 NALP1 allelic association results; a comparison of patients from three groups of autoimmune diseases and 2269 healthy controls
SNP bp Alleles Genotype (%) Patient groups Genotype (%) OR L95 U95 P-value Conditional
on rs12150220
P-value
rs6502867 5361052 C/T 5.2, 34.9, 59.9 AAD (n¼333) 6.1, 39.9, 54.0 0.83 0.68 1.01 0.06 0.3
TID (n¼1084) 5.6, 35.6, 58.9 0.96 0.85 1.09 0.51 0.8
MS (n¼502)
a
7.3, 30.4, 62.3 1.01 0.84 1.20 0.94 0.5
AAD+TID 5.7, 36.6, 57.7 0.93 0.83 1.04 0.19 0.8
rs12150220 5426091 T/A 21.5, 51.3, 27.2 AAD (n¼333) 15.4, 52.0, 32.6 1.27 1.06 1.49 0.006 —
TID (n¼1084) 18.9, 49.2, 31.9 1.16 1.04 1.28 0.006 —
MS (n¼502) 20.5, 49.7, 29.9 1.08 0.93 1.23 0.30 —
AAD+TID 18.1, 49.9, 32.0 1.18 1.08 1.30 0.0007 —
rs2670660 5459730 G/A 20.7, 49.7, 29.6 AAD (n¼333) 13.9, 55.4, 30.7 1.18 0.99 1.39 0.06 0.2
TID (n¼1084) 17.6, 49.7, 32.7 1.14 1.02 1.27 0.02 0.8
MS (n¼502) 18.4, 50.2, 31.4 1.09 0.94 1.25 0.23 0.4
AAD+TID 16.7, 51.0, 32.3 1.15 1.04 1.27 0.007 0.5
rs878329 5493974 C/G 20.9, 49.4, 29.7 AAD (n¼333) 16.0, 50.9, 33.0 1.18 1.00 1.39 0.05 0.6
TID (n¼1084) 18.4, 49.9, 31.8 1.10 0.99 1.22 0.08 0.7
MS (n¼502) 20.3, 48.7, 31.1 1.04 0.90 1.19 0.59 1.0
AAD+TID 17.8, 50.1, 32.1 1.11 1.01 1.23 0.03 0.6
Abbreviations: AAD, autoimmune Addison’s disease; bp, nucleotide position; L95, lower boundary of the 95% confidence region;
MS, multiple sclerosis OR, odds ratio; SNP, single nucleotide polymorphism; TID, type 1 diabetes; U95, upper boundary of the 95%
confidence region.
a
Not in the Hardy–Weinberg equilibrium.
NALP1 and autoimmunity
NF Magitta et al
121
Genes and Immunity
(Supplementary Table 1). These LD observations were
consistent with the LD pattern generated from genotype
data from HapMap samples (CEU) (http://www.
hapmap.org/index.html), which showed that intron 3
marks the boundary between two distinct blocks of LD
with very little LD in between (Supplementary Figure 1).
Discussion
NALP1 is believed to mediate inflammation and auto-
immunity partly due to its ability to associate with the
adapter protein ASC, caspase-1 and caspase-5, to form
inflammasomes that are central in the activation of pro-
inflammatory IL-1b.
3,5,8
Polymorphisms of NALP1 have been reported to
confer risk for vitiligo and/or extended autoimmune/
inflammatory disorders in Caucasian patients from the
United Kingdom and the United States,
9
and more
recently from Romania.
10
The current report provides further evidence of the
involvement of NALP1 in the pathophysiology of
autoimmune diseases. The association of a polymorph-
ism in NALP1 with autoimmune Addison’s disease and
type 1 diabetes, combined with the lack of significant
association with the systemic autoimmune disorders
systemic lupus erythematosus and juvenile idiopathic
arthritis, may indicate a specific role in organ-specific
autoimmunity. However, the lack of statistical signifi-
cance for an association between genetic variants in
NALP1 and the systemic diseases tested here might also
be a result of the lack of statistical power.
We found that the major allele of rs12150220 in NALP1
was associated with increased risk of disease, whereas
the earlier reported risk of vitiligo and complex
autoimmunity was associated with the minor allele.
9
Our result was verified by sequencing eight samples
(data not shown), to ensure that here we report the
correct association. The discrepancy may be due to
population differences in allele frequencies, well known
from studies of the major histocompatibility complex
(MHC).
11
Contrary to our results, a recent genome-wide
association study of type 1 diabetes and rheumatoid
arthritis implicated neither chromosome 17 nor the
NALP1 gene.
12,13
However, none of the SNPs tested were
highly correlated with the SNP that we have found to be
associated with autoimmunity. Actual genotyping of
rs12150220 in a Wellcome Trust Case Control Consortium
(WTCCC) 15 K scan (British population) revealed no
significant statistical differences between patients with
multiple sclerosis and controls (http://www.wtccc.
org.uk/info/summary_stats.shtml). The relatively weak
effect of the association in addition to ethnic variations of
the studied cohorts could explain some of the divergence
of the data. It can be noted that the minor allele
frequencies for the control groups observed in the
WTCCC study varied slightly compared with this study.
Despite the relatively large number of cases and
controls ascertained in this study we do not have
sufficient power to reach genome-wide significance.
The P-values are presented without correction for
multiple comparisons. Using a classical conservative
Bonferroni correction for the primary analysis would set
the study-wide significance threshold to Po0.004
(N¼12, four SNPs and three phenotypes), which is
slightly lower than the P-values detected for AAD and
T1D separately, i.e. 0.007 and 0.005, respectively (Table 2).
However, a Bonferroni correction might be too conser-
vative given that three of the four SNPs tested are highly
correlated. We also argue that the general trend for
increased risk in all but one of the disease groups studied
combined with the P-value of 0.0005 for the pooled
autoimmune Addison’s disease and type 1 diabetes
samples suggest that the results might reflect a biological
effect rather than a type 1 error.
More studies of well-characterized patients with
various autoimmune diseases should be performed to
gain more information on the involvement of the NALP1
Table 2 NALP1 allelic association results; a comparison of patients from six groups of autoimmune diseases and 3273 healthy controls
Controls (n¼3273) Cases Allelic test
SNP Alleles Genotype MAF Patient groups Genotype MAF OR L95 U95 P-value
rs6502867 C/T 161/1075/1888 0.78 AAD (n¼333) 19/124/168 0.74 0.82 0.68 0.99 0.04
TID (n¼1084) 58/372/615 0.77 0.94 0.84 1.06 0.35
MS (n¼502)
a
30/125/256 0.77 0.99 0.83 1.18 0.92
RA (n¼945) 43/328/549 0.77 0.99 0.88 1.12 0.90
SLE (n¼156) 10/52/88 0.76 0.91 0.69 1.19 0.51
JIA (n¼505) 32/159/295 0.77 0.97 0.83 1.14 0.69
Addison+TID (n¼1417) 77/496/783 0.76 0.91 0.82 1.02 0.10
rs12150220 T/A 688/1611/878 0.53 AAD (n¼333) 49/166/104 0.59 1.25 1.06 1.49 0.007
TID (n¼1084) 202/525/340 0.56 1.15 1.04 1.27 0.005
MS (n¼502) 98/238/143 0.55 1.08 0.93 1.23 0.32
RA (n¼945) 181/418/270 0.55 1.09 0.98 1.20 0.11
SLE (n¼156) 28/73/51 0.58 1.20 0.95 1.52 0.12
JIA (n¼505) 109/251/138 0.53 1.00 0.87 1.14 0.96
AAD+TID (n¼1417) 251/691/444 0.57 1.18 1.08 1.28 0.0005
Abbreviations: AAD, autoimmune Addison’s disease; JIA, juvenile idiopathic arthritis; L95, lower boundary of the 95% confidence region;
MAF, major allele frequency; MS, multiple sclerosis; OR, odds ratio; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SNP, single
nucleotide polymorphism; TID, type 1 diabetes; U95, upper boundary of the 95% confidence region.
a
Not in the Hardy–Weinberg equilibrium.
NALP1 and autoimmunity
NF Magitta et al
122
Genes and Immunity
locus in autoimmunity, but there are several lines of
evidence that lends support to this notion. NALP1
belongs to the CATERPILLER family of protein char-
acterized by nucleotide-binding and leucine-rich
domains
14
with functions in controlling immune and
inflammatory responses. Maybe the best-studied mem-
ber of this group is the MHC class II transactivator
(MHC2TA) crucial for the expression of MHC class II
molecules. Mutations in the MHC2TA gene gives rise to
the bare lymphocyte syndrome, a fatal condition where
patients succumb in bacterial, viral, fungal and proto-
zoan infections.
14
Intriguingly, polymorphisms in the
MHC2TA locus is associated with a number of auto-
immune diseases, among them Addison’s diseases.
15
Mutations in another gene of this family known as
caspase recruitment domain 15 (CARD 15)orNOD2 is
associated with Crohn’s disease,
16
early-onset sarcoidosis
and Blau syndrome characterized by granulomatous
synovitis, non-granulomatous uveitis and cranial neuro-
pathies.
14,17
Mutations in NALP3 coding for cryopyrin are
causative for the auto-inflammatory diseases, such as
familial cold autoinflammatory syndrome, the Muckle-
Wells syndrome and neonatal-onset multisystem inflam-
matory disease.
14
The three diseases are now considered
to be a continuum referred to as cryopyrin-associated
periodic syndrome. Most of the mutations are found in
the NACHT domain, close to where rs12150220 in
NALP1 is located. This indirectly supports that the
Leu/His amino acid variation at position 155 modulates
NALP1 function and the way inflammasomes processes
microbial products.
IL-1b, one of the mediators of inflammasome activa-
tion, has been shown to be cytotoxic to insulin-producing
islet cells in vitro.
18
Possibly, variation in the inflamma-
some activation could influence antigen presentation and
subsequently tolerance to self. Functional studies of
NALP1 variants and association studies with other
disorders are needed to further elucidate NALP1’s
possible role in autoimmune diseases.
Patients and methods
Patients and controls
All together, 333 Norwegian patients with autoimmune
Addison’s disease were recruited from a national
registry of organ-specific autoimmune diseases. The
diagnosis was based either on a low basal serum cortisol
and high adrenocorticotropic hormone or on a patholo-
gical adrenocorticotropic hormone stimulation test. A
total of 145 patients had type 1 diabetes and/or thyroid
diseases in addition to Addison’s disease, that is APS II.
The cohort of patients with type 1 diabetes consisted of
1086 individuals with disease onset before 17 years of
age, recruited from the nationwide Norwegian Child-
hood Diabetes Registry from 2002, as detailed else-
where.
19
They were all diagnosed according to the
EURODIAB criteria.
20
The human leukocyte antigen
haplotypes for type 1 diabetes were grouped as high
risk, intermediate risk, neutral risk and low risk.
19
Furthermore, a total of 502 patients with definite multi-
ple sclerosis,
21
945 patients with rheumatoid arthritis, 156
systemic lupus erythematosus patients and 505 juvenile
idiopathic arthritis patients were included. All rheuma-
toid arthritis and lupus patients fulfilled the American
College of Rheumatology criteria,
22,23
and the juvenile
idiopathic arthritis patients were classified according to
the International League of Associations for Rheumatol-
ogy criteria.
24
Information on demographic variables of
the patients is summarized in Table 3. A total of 3273
anonymous healthy Norwegian blood donors or donors
from the Norwegian bone marrow donor registry were
used as controls. All patients and controls provided
informed written consent. Relevant medical research
ethics committees approved the study.
SNPs selection and genotyping
On the basis of earlier studies by Jin et al.
9,10
we selected
representative SNPs across the NALP1 gene, tagging the
two autoimmunity-associated regions, SNP rs6502867,
located in intron 15 of the NALP1 gene, and another LD
block tagged by rs12150220 in exon 3 of NALP1, and two
promoter region SNPs (rs2670660 and rs878329). The
SNP rs12150220A/T (p.Leu155His) was also selected due
to its potential functional significances, as it changes a
leucine to histidine in exon 3. Genotyping was per-
formed by commercially available Taqman assays
(Applied Biosystems, Foster City, CA, USA).
TaqMan reactions were set up based on the manufac-
turer’s protocol and the samples were run on an
ABI7900HT II Fast Real-Time instrument. Allelic dis-
crimination was performed as suggested by the manu-
facturer, and analyzed using the SDS software (v. 2.3).
The automated genotype calling was supplemented by
manual inspection by two independent persons and the
results compared.
Sequencing
We sequenced the region covering the rs12150220 A/T
non-synonymous SNP in eight known patient samples to
confirm which strand was detected by the TaqMan assay.
The PCR reactions were set up in a standard manner
and the products were purified using ExoSAP-IT
(USB Corporation, Cleveland, OH, USA). We then
Table 3 Description of the patient cohorts included in the study
Patient groups No. of patients Females (%) Mean age of onset in years (range)
Autoimmune Addison’s disease 333 61 36.1 (12–82)
Type 1 diabetes 1084 47 9.2 (10–17)
Multiple sclerosis 502 64 32.1 (14–58)
Systemic lupus erythematosus 156 84 31.6 (8.1–81.4)
Juvenile idiopathic arthritis (JIA) 505 65 3.2 (0.8–15.3)
a
Rheumatoid arthritis (RA) 945 76 51.4 (23–70)
a
a
The mean ages of the JIA and RA patients were calculated based on 148 and 214 patients, respectively.
NALP1 and autoimmunity
NF Magitta et al
123
Genes and Immunity
sequenced the coding strands of the region surrounding
the SNP using ABI prism BigDye terminator kit v.3.1 and
an ABI3730 DNA analyzer (Applied Biosystems). The
sequences were analyzed using CLC Combined Work-
bench v. 3 (CLS Bio, Cambridge, MA, USA).
Statistical analysis
The Progeny software (Progeny Software Inc., Nova
Scotia, Canada) was used for handling of the genotype
data. The data were transferred to the Plink software
25
in
which all the genetic association tests were performed.
For the conditional analysis, we used logistic regression
with rs12150220 genotypes included as co-variate. The
Haploview software
26
was used to investigate the
linkage LD pattern both in our data set and in HapMap
data. P-values o0.05 were considered significant, and all
P-values were presented without correction for multiple
testing. A formal Bonferroni correction for the number of
tests performed for the primary hypothesis (four SNPs
tested in three diseases) would require a study-wide
significance threshold of Po0.004.
Acknowledgements
We are indebted to each patient and the Norwegian Bone
Marrow Registry for contributing with DNA samples for
healthy controls, and The Norwegian Study Group for
Childhood Diabetes for collection of type 1 diabetes
samples. Vibeke Lilleby and Inge M Gilboe are thanked
for collecting the lupus samples. Berit Flatø and Anne
Marit Selvaag, Rikshospitalet-Radiumhospitalet Medical
Centre, are acknowledged for collecting the juvenile
idiopathic arthritis samples. Furthermore, we thank Siri
Fla
˚m, Rikshospitalet, Sigrid Erdal, Haukeland University
Hospital, and Alice Stormyr and Hanne Akselsen,
Ulleva
˚l University Hospital, for help with genotyping.
The study was supported by grants from The Seventh
Framework Programme ‘Euradrenal,’ The Western and
South-Eastern Regional Health Authorities, the Norwe-
gian Research Council and the University of Bergen.
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