Is frozen shoulder hereditary?! GWAS for shoulder adhesive capsulitis has identified important genetic risk factors

Genome-wide association findings of "important loci" affecting frozen shoulder risk

Shoulder adhesive capsulitis, also known as frozen shoulder or frozen shoulder, is a limited range of motion associated with pain in the shoulder glenoid humeral joint, progressive loss of shoulder motion, and pericapsular fibrosis (scarring or thickening) around the shoulder joint, leading to dyskinesia
.
This pain can develop spontaneously, without obvious damage or irritating events
.
It is most common in women between the ages of 40 and 60, occurs in up to 10% of people at some point in their lives, and is one of
the most common shoulder pathologies.
Treatment of adhesive capsulitis includes intra-articular corticosteroid injections, physical therapy, and surgery
.
Known clinical risk factors for developing adhesive capsulitis include thyroid dysfunction and diabetes and smoking
.
Studies have shown that a history of frozen shoulder is more prevalent in relatives of patients with the disease, such as twin siblings and first-degree relatives, suggesting a possible genetic predisposition
.
However, few studies have assessed this using
population-based unbiased genetics.
A recent study identified 5 potentially important sites in 3 causal genes: MMP14, SFRP4, and WNT7B
.

Dr.
Mark T.
Langhans of New York Specialist Surgery Hospital reports the results of a new genome-wide association study (GWAS), using data from a large UK database, the UK Biobank, to analyze a comparison
between 2142 patients with shoulder adhesive bunsitis compared to undiagnosed patients 。 The study controlled for identified known risk factors such as hypothyroidism and diabetes, and possible genetic associations were adjusted for other factors, including sex, diabetes, thyroid disease, history of shoulder dislocation and smoking, identifying specific locus variants associated with an increased risk of this condition, the article published in the Journal of
Bone and Joint Surgery.
These risk genes were associated with a nearly six-fold increased chance of developing frozen shoulder — a stronger association
with most known clinical risk factors.
The authors believe their findings could provide new insights
into the causes, prevention, and treatment of shoulder adhesive bursitis.

The data comes from a large UK database

Methods: A genome-wide association study (GWAS) was performed using the UK Biobank, which collected approximately 500,000 patients with genetic data and associated ICD-10 [International Classification of Diseases Code, 10th edition]) to compare 2,142 patients with ICD-10 adhesive capsulitis (M750).

A separate GWAS was performed to control 2 known risk factors for capsular adhesions—hypothyroidism and diabetes
.
Logistic regression analysis was performed
for factors including sex, thyroid dysfunction, diabetes, shoulder dislocation, smoking, and genetics.

Results: Three significant associations were identified: WNT7B(rs34315830; odds ratio [OR] = 1.
28; 95% confidence interval [CI], 1.
22 to 1.
39), MAU2(rs2965196; OR = 1.
67; 95% CI, 1.
39 to 2.
00) and POU1F1 (rs1912256; OR = 1.
22; 95% CI, 1.
14 to 1.
31).

After adjusting for thyroid dysfunction and diabetes factors, these three gene associations remain important
.
Together, these three variants had an OR of 5.
81 (95% CI, 4.
08 to 8.
31) for total genetic risk, increasing the odds of developing frozen shoulder by nearly six-fold; Hypothyroidism was 1.
70 (95% CI, 1.
18 to 2.
36) and diabetes was 4.
23 (95% CI, 2.
32 to 7.
05).

Conclusion: The total genetic risk associated with capsular adhesions is significant and similar
to the risks associated with hypothyroidism and diabetes.
Identification of WNT7B, POU1F1, and MAU2 suggests that the Wnt pathway and cell proliferation responses
are involved in the pathogenesis of adhesive capsulitis.

New insights can lead to new developments

These findings may shed new light on
the development of adhesive bunsitis.
In particular, genes located in WNT7B have been shown to be expressed in bone-forming cells (osteoblasts) and involved in regulating fibrosis, among a wide range of other functions
.
Two newly reported locus, POU1F1 and MAU2, are involved in cell division, which may shed light on
the cellular mechanisms of frozen shoulder formation.

The researchers note that their analysis has some key limitations, including the need to further investigate the genetic association
of groups other than the predominantly white British in the UK biobank.

At the same time, the new study found several gene loci that have the ability to
predict clinically relevant risks of frozen shoulder.
Dr Langhans and his colleagues concluded: "Refining genetic risk indicators and incorporating them into a larger clinical model can identify patients at risk for future adhesive bursitis in an effort to prevent, diagnose early, and ultimately improve outcomes
.
"