Shar Pei AutoInflammatory Disease

(SPAID)

Shar Pei AutoInflammatory Disease (SPAID) is a heritable syndrome defined by recurrent episodes of fever and inflammation with no known pathogenic or autoimmune cause. SPAID is characterised by five signs of inflammation;

  1. Familial Shar-Pei Fever (FSF) 

  2. Cutaneous Hyaluranosis (HCH) – Formerly “Cutaneous Mucinosis”

  3. Amyloidosis (Can only be diagnosable post death)

  4. Arthritis

  5. Recurrent Otitis 

For an in depth genetic explanation on SPAID see the article below from Dr Jeff Vidt's website.

SPAID Test

A validated genetic test is available to measure the copy number variant (CNV) linked to Shar Pei AutoInflammatory Disease (SPAID). The SPAID Test identifies Shar Pei most likely to be affected by SPAID during their lifetime. The result can be used by owners two-fold:

  1. As a health tool to suggest a dog should be watched more carefully for signs of SPAID. 

  2. As a breeding tool with the aim of reducing the presence of SPAID in the worldwide Shar Pei population.

The table below shows the SPAID Test result groups, CNV numbers, outcome and explanation:

SPAID Test Result Groups

The two locations that test and measure the CNV linked to SPAID are;

  1. SLU in Sweden

  2. Cornell in the USA

The blood sample required for testing must be extracted by a vet. SLU state the blood should be collected in 2 EDTA tubes (~4ml / tube) and 1 serum-tube (~4 ml). This amount is sufficient for testing and future research.

For puppies; the blood sample can be extracted as early as 4 weeks. SLU prefer at least 1-2 ml of EDTA-blood for puppies, but if it is not possible they can do the test with less (however such a small amount would not be sufficient for future research).

The image below depicts the puppy CNV outcome from a SPAID tested parent mating;

SPAID CNV RESULTS

Notes:

SPAID testing is a linkage test. It is a useful health tool for breeders, but it is not a guarantee certificate for life.

There is also an alternative SPAID test available from laboratories such as Laboklin & Pet Genetics Lab in Europe. Again, this is a ‘Linkage Test’.

 

Even though this particular test has the same objective in principle as the CNV test that is to look for the likelihood of the dog suffering from any of the 5 inflammatory signs of SPAID they are indeed different test looking for different gene mutations.

This alternative test looks for the mutation MTBP:g.19383758G>A. This is located at position 69870 of Sequence id 1 or position 2623 of Sequence id 2.

Sequence 1 is the genomic sequence & sequence 2 is the cDNA sequence.

 

The test sample is obtained either by the owner or by a vet and can be taken by Bucal Swab or EDTA Blood sample (the latter must be obtained by a vet). There are three possible test results:

  • N/N (Clear) which means that the dog does not carry the mutation and it has no increased risk of developing the disease.

  • N / SPAID (Carrier): the dog carries one copy of the mutation and it has an increased risk of developing the disease although may not develop the disease.

  • SPAID / SPAID (Affected): the dog carries two copies of the mutation and it has a high risk of developing the disease.

All our breeding stock are SPAID tested.

For more information on the SPAID Test, refer to the links at the bottom of this page.  

 

SPAID Article

The following information has been obtained online from the Dr. Jeff Vidt's website;

SPAID is a term to describe the spectrum of clinical signs due to systemic and persistent inflammation in Chinese Shar Pei.

 

All the signs in SPAID are auto inflammatory in nature and are related elevated levels of hyaluronan, a molecule which functions as a danger signal (a DAMP) that triggers the inflammatory response.

 

SPAID resembles human AID (auto inflammatory disease) that also presents with multiple inflammatory signs. Many Shar Pei with SPAID also receive relief from disease by the use of IL-1â inhibitors which suggests a cytokine-driven inflammation and a dysregulation of the innate immune response.

 

SPAID definitely is linked to increased levels of LMW-HA (low molecular weight hyaluronan) which appears to be a breed characteristic related to strong selective breeding for the heavily wrinkled phenotype.

It Involves a genetic defect in the innate immune system caused by a mutation in a regulatory gene upstream of the HA2S gene on chromosome 13.  The mutation occurs in two forms: the so-called “traditional” and “meatmouth” mutation.  The mutation is a duplication resulting in a Copy Number Variation (CNV).  This mutation is responsible for the increase in hyaluronan levels seen in this breed.  The mutation appears to involve a regulatory gene for the Hyaluronan Synthase 2 gene (HAS2) which produces hyaluronan (HA).  It appears HAS2 over-expression is driving the amplified production of hyaluronan and in turn, driving the canine AID state. The amount of HA is responsible for the variation in the “wrinkling” phenotype which is unique to the Shar-Pei.  A higher copy number is also significantly associated with the risk of experiencing recurrent fever attacks as well as chronic recurrent otitis, hock swelling/arthritis, vesicular hyaluronosis (HCH), inflammatory bowel disease and amyloidosis).  This seems to hold true only for the “meatmouth duplication and doesn’t occur with the “traditional duplication”.

Note in the picture below the variants in the Shar Pei appearance from the heavy (overdone) “meatmouth” on the left to the more “traditional” on the far right.

Shar Pei SPAID CNV Genetic Test
 

LMW-HA induces inflammation through two mechanisms:

 

  1. Binding to TLR2 or TLR4 which activates NFƙβ  which leads to an increase in IL-1β

  2. Binding to CD44 which is recognized by NLRP3 and activates the inflammasome leading to the transformation of pro-IL-1β into IL-1β.  IL-1β is the principal cytokine in SPAID.

LMW-HA is recognized as a DAMP (danger-associated molecular pattern)

The autoinflammatory  is now called SPAID and manifests as a number of clinical signs such as:

  • Familial Shar-Pei Fever (FSF)

  • Amyloidosis—due to a potential modifier locus on chromosome 14.

  • Arthritis

  • Recurrent otitis

  • Hereditary Cutaneous Hyaluranosis (HCH) – formerly “cutaneous mucinosis”

Chromosome 13:

  1. 27 Mb duplication determines breed type and dermatitis

  2. 23.5 Mb duplication determines fever, arthritis and amyloidosis

  3. The gene duplication region is located 350 Kb upstream from HAS2.

Bottom line:  Increased LMW-HA is a major risk factor for SPAID

 

Other associations with SPAID?

  • Predisposition to aggressive mast cell disease

  • Allergic dermatitis

  • Cellulitis

  • Streptococcal Toxic Shock Syndrome/Necrotizing Fasciitis

  • Lymphangitis, lymphedema, Lymphangectasia

  • Vasculitis

  • Swollen Hock Syndrome (SHS) with or without pyrexia

  • Inflammatory Bowel Disease (IBD)

HA has a dual role in the inflammatory response.  Low MW HA can serve as a danger associated molecular pattern (DAMP) and activate the inflammasome and the release of pro-inflammatory interleukins (pro-ILs) by two routes.  In one route HA acts on toll-like receptors (TLR2 and TLR4), activating NF-ƙβ to produce immature pro-ILs.  In the second pathway HA binds to the cellular receptor CD-44, followed by hyaluronidase cleavage by HYAL2 at the membrane and HYAL1 in the lysosome.  This produces the small oligosaccharides of HA which actually trigger inflammasome complex formation. BOTH routes must be for active cytokines to be released from the cell.

The distinguishing feature of many of the AIDs is the dysregulated secretion of the inflammatory cytokine interleukin -1β (IL-1β).  HAS2 serves as a rheostat during inflammation.  The pathological outcomes and clinical signs of autoinflammatory disease (AID) result from a dysregulation of the innate immune response.   In Shar-Pei it appears that HAS2 over-expression is driving the amplified production of hyaluronan and, in turn, drives the canine AID state.

There is clear localisation of the genetic signal for breed subtype with the peaks of association for each of the SPAID phenotypes.  There were two signals on chromosome 13, one at ~22-23 Mb and the other between~27-29 Mb.  Genetic duplications in this region, which is upstream from HAS2, result in overproduction of HA which affects the phenotype and predisposition to AID.

Within the larger genomic region in breed subtype differentiation there are two genes involved in collagen production and recognition as well as genes essential for the immune response and kidney function.  These could account for the various disease presentations included in FSF.

There was also noted a signal of association to amyloidosis on chromosome 14.  Continuous, cyclic production of HA can lead to chronic states of inflammation and result in an acute phase response with up to a 1000-fold increase of hepatic serum amyloid A (SAA) production.  SAA is a key modulator of the innate immune response and can provide the two signals required for the inflammasome-mediated release of interleukins.  SAA activates the NF-ƙβ pathway through direct binding with TLR4 similar to HA.  However, its activation of the inflammasome is via binding to the cellular receptor  P2X.

HA and SAA are acting as Danger Associated Molecular Patterns (DAMPs) to trigger formation of the inflammasome.  An individual’s genetic predisposition to DAMP/PAMP stress response may directly impact their susceptibility to amyloidosis.

 

1.  Olsson M, Tintle L, Kierczak M, et al.(2013 “Thorough Investigation of a Canine Autoinflammatory Disease (AID) Confirms One Main Risk Locus and Suggest a Modifier Locus for Amyloidosis”, PLoS Genet. 8(10):e75242.

2.  Olsson M, Meadows JR, Truvè, Rosengren Pielberg G, Puppo F, et al.(2011), “A novel unstable duplication upstream of HAS2 predisposes to a breed-defining skin phenotype and a periodic fever syndrome in Chinese Shar-Pei dogs”. PLoS Genet. 7(3):e1001332.

For more information on SPAID visit;

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