UBASH3A and Autoimmune Disease in

Down Syndrome
Richard A. Spritz, M.D.
Professor and Director,
Human Medical Genetics and Genomics Program
University of Colorado Denver School of Medicine
Aurora, CO 80045

Research Supported by a Grand Challenge Grant Award,

Linda Crnic Institute for Down Syndrome
The goals of this research are to:
1. Investigate whether an autoimmunity gene on chromosome 21,
UBASH3A, plays a role in the high frequency of autoimmune diseases in
people with Down Syndrome.
2. If UBASH3A does play a role, investigate how it is involved in causing
autoimmune disease.
Long-term benefits might include pre-symptomatic testing and potentially
preventive treatment of individuals at highest risk.

~50-80 different disorders in which

immune/inflammatory cells recognize and attack
self cells and tissues

Examples: Type 1 diabetes, autoimmune thyroid

disease, vitiligo, celiac disease, rheumatoid arthritis

Complex traits :
caused by multiple genes + environmental triggers
AI diseases rank among top 10 causes of death in

Prevalence of autoimmune diseases greatly elevated

among people with Down Syndrome

High Prevalence of Autoimmune Diseases in

People with Down Syndrome

Syndr.

Autoimmune Thyroid Disease

(Hashimoto Thyroiditis, Graves Disease)
Celiac Disease
Vitiligo
Type 1 Diabetes
Rheumatoid Arthritis
(Juvenile)

General Pop.
~5%
1-2% > 0.1%
0.4%
0.3%
~1%
0.14%

Down
~35%
~5% > 1.4%
3%
~1%
0.87%

Multiple Autoimmune Diseases can occur in

some Patients
1855: Addisons Disease, Vitiligo, Pernicious Anemia

Autoimmune thyroid disease (Hashimotos disease, Graves disease)

Vitiligo
Pernicious anemia
Type 1 diabetes
Systemic lupus erythematosus
Rheumatoid arthritis
Addisons disease
This is also true in people with Down Syndrome

Vitiligo
Specific
Genes,
Triggers
Type 1
Diabetes
Specific
Genes,
Triggers

Autoimmune
Thyroid
Disease
Specific
Genes,
Triggers

Shared
Genes
Chr21
Lupus

Rheumatoid
Arthritis

Addisons
Disease
Pernicious
Anemia

Hypotheses
1. The high frequency of autoimmune diseases in people
with Down Syndrome is due to a gene on chromosome
21; UBASH3A?
2. The high frequency of autoimmune diseases in people
with Down Syndrome suggests there is nothing
special about the version of the UBASH3A gene in
people with Down Syndrome
3. If the problem is 3 copies of UBASH3A, then the
pathogenic mechanism is increased function
4. If the problem is 3 chances to carry the common
UBASH3A high-risk allele, then the pathogenic
mechanism could be either increased function (more
likely) or reduced function (much less likely)
5. The actual situation is probably a combination of 3 & 4.

Genomewide association study (GWAS)

4680 EUR cases vs. 39,586 EUR controls
UBASH3A

Initial SNP rs2839511

With fine-mapping rs12482904
P = 5.84 E-29, OR 1.35, MAF 0.24

Vitiligo
Type 1 diabetes
Rheumatoid arthritis
Autoimmune thyroid disease
Celiac disease
Lupus
Inflammatory bowel disease
Psoriasis
Addison's disease
Alopecia areata

At least in Caucasians, there is a common genetic variation of

UBASH3A that predisposes to many different autoimmune diseases

rs2839511 rs12482904

H3k27Ac marks active enhancers

Pink indicates specifically active in lymphocytes (immune cell)

 Encodes TULA-1/Sts-2
Negative regulator of T-cell receptor TCR signaling
May alter expression of downstream pathway genes,
including PTPN22 and SH2B3 (both generic
autoimmune susceptibility genes)

Hypotheses
1. The high frequency of autoimmune diseases in people
with Down Syndrome is due to a gene on chromosome
21; UBASH3A?
2. The high frequency of autoimmune diseases in people
with Down Syndrome suggests there is nothing
special about the version of the UBASH3A gene in
people with Down Syndrome
3. If the problem is 3 copies of UBASH3A, then the
pathogenic mechanism is increased function
4. If the problem is 3 chances to carry the common
UBASH3A high-risk allele, then the pathogenic
mechanism could be either increased function (more
likely) or reduced function (much less likely)
5. The actual situation is probably a combination of 3 & 4.

1. Compare UBASH3A SNP genotypes in:

a. 100 DS cases with AI disease vs. 400 DS
cases without AI disease
b. 100 DS cases with AI disease vs. 1100
population-matched controls without AI
disease

Is high-risk UBASH3A SNP rs2839511 associated

with autoimmune disease in people with DS?
Genotyped rs2839511 A/G in:
140 EUR DS cases
91 with AI
(64 with AITD)
(27 with AI, without AITD)
49 with no AI
2260 EUR controls with no AI

MAF
.28
.27
.27
.20
.22

P = .10

P = .05

1.Yes; the AI disease high-risk SNP rs2839511-A is significantly (though

marginally) associated with AI disease in DS
2.Limited number of DS cases limits power
3.Unreliable self-reported dx of AI by DS parents (esp. hypothyroidism)
4.Most DS cases children; may be pre-symptomatic for AI disease

Hypotheses
1. The high frequency of autoimmune diseases in people
with Down Syndrome is due to a gene on chromosome
21; UBASH3A?
2. The high frequency of autoimmune diseases in people
with Down Syndrome suggests there is nothing
special about the version of the UBASH3A gene in
people with Down Syndrome
3. If the problem is 3 copies of UBASH3A, then the
pathogenic mechanism is increased function
4. If the problem is 3 chances to carry the common
UBASH3A high-risk allele, then the pathogenic
mechanism could be either increased function (more
likely) or reduced function (much less likely)
5. The actual situation is probably a combination of 3 & 4.

 NextGen sequenced UBASH3A in 114 familial vitiligo cases;

identified common multi-variant haplotypes:

An elevated frequency of some of these uncommon variations

might render UBASH3A alleles special

Do UBASH3A genotypes account for elevated

autoimmune disease in people with DS?
Initial SNP rs2839511

P-values for Comparison of Genotype Frequencies of other SNPs

SNP

DS-AI (n=91) versus DS-no AI (n=49)

rs2277798 (S18G)
rs2277800 (L28F)
rs141421753 (V111M)
rs13048049 (R324Q)
rs17114930 (D466E)
rs148149121 (I658V)

P = 0.15
P = 0.41
P = 1.00
P = 1.00
P = 0.50
P = 0.26

(P = 4.70E-05 in GWAS)

1.None of these SNPs are relevant (though sample size very small)
2.There is probably nothing special about chromosomes 21 in DS
patients with autoimmune disease

Hypotheses
1. The high frequency of autoimmune diseases in people
with Down Syndrome is due to a gene on chromosome
21; UBASH3A?
2. The high frequency of autoimmune diseases in people
with Down Syndrome suggests there is nothing
special about the version of the UBASH3A gene in
people with Down Syndrome
3. If the problem is 3 copies of UBASH3A, then the
pathogenic mechanism is increased function
4. If the problem is 3 chances to carry the common
UBASH3A high-risk allele, then the pathogenic
mechanism could be either increased function (more
likely) or reduced function (much less likely)
5. The actual situation is probably a combination of 3 & 4.

2. Quantitative mRNA expression analysis of

UBASH3A in DS patients who carry high-risk vs.
low-risk UBASH3A genotypes

If UBASH3A rs2839511-A causes increased AI

frequency in DS,
is it due to:
1. 1.5X elevated dosage/expression of that gene in people with
2. Three copies of chr21 means higher chance of carrying
genotypes (whatever the downstream mechanism)
3. Both

DS?
high-risk

Genotype counts for rs2839511

DS +AI (n=91)
DS -AI (n=49)

AAA
0
0

GAA
GGA
GGG
23 (.25) 29 (.32)
39 (.43)
6 (.12) 17 (.35)
26 (.53)

P = 0.18

Controls
AA
124

AG
758

GG
1378

AI disease in DS relates to the rs2839511-A allele, not just 3 copies of chr21

Conclusions
1. UBASH3A AI disease high-risk SNP rs2839511-A is
associated with AI disease in DS versus non-DS
controls with no AI disease
2. There is nothing else special about the version of
UBASH3A in DS patients with AI; similar to patients
in general population with AI disease.
3. It is not just that AI disease risk in DS results from
three copies of chr21 and thus elevated function of
UBASH3A. It is clear that AI disease risk relates to
the 1.5X risk of carrying high-risk AI alleles, and
probably both.

Thanks to
Linda Crnic Institute for Down Syndrome for
funding
Sheri Riccardi
Tracey Ferrara
Songtao Ben
Ellen Elias
Stephanie Santorico
Especially, thanks to DS patients and their
parents