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Evidence for an Inherited Predisposition Contributing to the Risk for Rotator Cuff Disease
Robert Z. Tashjian, MD1; James M. Farnham, MS2; Frederick S. Albright, PhD3; Craig C. Teerlink, MS2; Lisa A. Cannon-Albright, PhD2
1 University of Utah Orthopaedic Center, 590 Wakara Way, Salt Lake City, UT 84108. E-mail address: Robert.Tashjian@hsc.utah.edu
2 Genetic Epidemiology, Department of Biomedical Informatics, University of Utah School of Medicine, 26 South 2000 East, Room 5775 HSEB, Salt Lake City, UT 84112
3 Department of Pharmacotherapy, University of Utah College of Pharmacy, 30 South 2000 East, Room 258, Salt Lake City, UT 84112
View Disclosures and Other Information
Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from the National Institutes of Health-National Library of Medicine (NLM R01 LM009331). Partial support (less than $10,000) for all datasets within the Utah Population Database was provided by the University of Utah Huntsman Cancer Institute. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.
Investigation performed at the University of Utah School of Medicine, Salt Lake City, Utah

The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2009 May 01;91(5):1136-1142. doi: 10.2106/JBJS.H.00831
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Abstract

Background: A genetic predisposition has been suggested to contribute to the risk for development of rotator cuff disease on the basis of observed family clusters of close relatives. We used a population-based resource combining genealogical data for Utah with clinical diagnosis data from a large Utah hospital to test the hypothesis of excess familial clustering for rotator cuff disease.

Methods: The Utah Population Database contains combined health and genealogical data on over two million Utah residents. Current Procedural Terminology, Fourth Revision, codes (29827, 23412, 23410, and 23420) and International Classification of Diseases, Ninth Revision, codes (726.1, 727.61, and 840.4) entered in patient records were used to identify patients with rotator cuff disease. We tested the hypothesis of excess familial clustering using two well-established methods (the Genealogical Index of Familiality test and the estimation of relative risks in relatives) in the overall study group (3091 patients) and a subgroup of the study group diagnosed before the age of forty years (652 patients).

Results: The Genealogical Index of Familiality test in patients diagnosed before the age of forty years showed significant excess relatedness for individuals with rotator cuff disease in close and distant relationships (as distant as third cousins) (p = 0.001). The relative risk of rotator cuff disease in the relatives of patients diagnosed before the age of forty years was significantly elevated for second degree (relative risk = 3.66, p = 0.0076) and third degree (relative risk = 1.81, p = 0.0479) relatives.

Conclusions: We analyzed a set of patients with diagnosed rotator cuff disease and a known genealogy to describe the familial clustering of affected individuals. The observations of significant excess relatedness of patients and the significantly elevated risks to both close and distant relatives of patients strongly support a heritable predisposition to rotator cuff disease.

Clinical Relevance: A better understanding of the familial risk of rotator cuff disease could lead to the identification of candidate genes predisposing individuals to rotator cuff disease. Gene identification will possibly allow the development of improved treatments, including biologic augmentations of rotator cuff repairs, which may improve tendon healing and repair outcomes.

Level of Evidence: Prognostic Level III. See Instructions to Authors for a complete description of levels of evidence.

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    References

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    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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    Robert Z. Tashjian, MD
    Posted on June 23, 2009
    Drs. Tashjian and Cannon-Albright respond to Drs. Jain and Higgins
    Department of Orthopaedics, University of Utah School of Medicine, Salt Lake City, Utah

    We appreciate the interest Dr. Jain and Dr. Higgins had in our recent work investigating a possible genetic predisposition for rotator cuff disease. We will attempt to address each of the concerns of Drs. Jain and Higgins in the following response.

    ICD-9 Codes: As Drs. Jain and Higgins point out, we have recognized the limitations of using ICD-9 coding in this study and have attempted to underscore these concerns to the reader by discussing them. We agree with Drs. Jain and Higgins that an accurate diagnosis is paramount in every study. As described, we have restricted our phenotype definition to those individuals with rotator cuff repair surgery or with a diagnosis of rotator cuff disease. This restriction limits our sample size, and thus our power, but does not result in any bias. All individuals with hospital data, including relatives of cases and relatives of matched controls, are similarly censored. Only a bias specific to relatives of controls that increased censoring of their affected relatives, or a bias specific to relatives (both close and distant) of cases that decreased censoring of their affected relatives could be invoked to support the claim that the results are affected by our use of ICD-9 and CPT coding. Because we can assume uniform censoring of phenotype data, the statistics presented are robust, and very likely only conservatively estimate the true extent of the genetic predisposition to rotator cuff disease.

    With regards to CPT surgical coding, we agree with Drs. Jain and Higgins that identification of patients using the presence of a rotator cuff repair surgery would be optimal. As presented, we identified 244 individuals with a history of rotator cuff surgery. Although this is a small sample size to use for the GIF analysis, we did perform it. The mean case GIF was 3.12 and the mean control GIF was 2.75; respective p-values were not significant (p = 0.24 and 0.51), but we observed an excess of relationships of distance 2, 4, 6, and 8 (second cousins), supporting the hypothesis of more distant relationships between these cases than expected.

    With regards to the comments on degenerative rotator cuff tearing, we did not make the assumption that degenerative rotator cuff tears have a genetic predisposition. Therefore, we agree with Drs. Jain and Higgins that this cannot be supported by the data and we have in no place in this manuscript made this assumption. Rather we have made the assumption that, “rotator cuff disease”, which likely includes degenerative tears, has a genetic predisposition. While this may be unfamiliar to some researchers, most clinicians, coders and billers will recognize the ICD-9 code 840.4 as a way to classify patients who have a rotator cuff related problem as well as some antecedent history of trauma. Included in this group are patients with likely an underlying degenerative process who had some level (from very low to higher level energy) of injury at various time points (from very acute to very remote). Consequently, inclusion of these patients does not preclude the possibility of a degenerative process. More importantly, we are not attempting to define the familial patterns of a degenerative process, rather a genetic process. Consequently, we believe it is just as important to include the patients with the 840.4 code as those coded with a rotator cuff tear. Patients may have an underlying genetic profile that predisposes them to a rotator cuff injury that requires treatment that other individuals without an underlying genetic predisposition may not sustain despite the same level of trauma. We are attempting to capture this population of patients at risk for rotator cuff related injury, therefore inclusion of the 840.4 patients was justified.

    We agree with Drs. Jain and Higgins that the best evidence for a genetic predisposition would be available in early onset tears, which we have presented. Although the numbers of affected relatives observed is small, as the Drs. Jain and Higgins note, the significance of the statistical test performed supports our conclusion.

    Information on missing data: As described in our manuscript, we did not screen any relatives for this study. We relied on the existence of hospital diagnosis data for approximately 1 million patients who also have at least 3 generations of genealogy data. As noted, we recognize that there is censorship of any relative who is not in the genealogy data and/or who was not a patient at the University of Utah after 1994. However, this censorship applies uniformly to relatives of both cases and to the relatives of their matched controls and does not introduce any bias, but rather leads to conservative estimates of risk.

    Age of participants: We agree with Drs. Jain and Higgins that increasing age in various generations has an impact on risk of rotator cuff disease. For this reason, as discussed, we estimated expected numbers of cases by age (and sex), using 5 year birth year cohorts.

    Conclusion: The suggestion that these results represent, “a familial association with shoulder pain visits” might be reasonable if we only saw an excess in first-degree, or maybe even in second-degree relatives. However, invoking a, ”familial association” in the face of significant excess risk in third-degree relatives would require the assumption that individuals with affected relatives as distant as first cousins (third degree in the RR analysis) or second cousins (genetic distance = 8 in the GIF analysis) are more likely to visit a clinic regarding shoulder pain because their relative did this. The significant excess clustering we observed in close and distant relatives strongly supports much more than a, “familial association with shoulder pain visits”.

    In conclusion, we agree with Drs. Jain and Higgins that more detailed studies will help clarify the genetic predisposition to rotator cuff disease that we have strongly supported in this study. Screening studies of high-risk Utah pedigrees are planned.

    Nitin B. Jain, MD
    Posted on June 10, 2009
    Genetic Predisposition to Rotator Cuff Tears
    Spaulding Rehabilitation Hospital and Harvard Medical School, Boston, Massachusetts

    To the Editor:

    We congratulate Tashjian et al. on their timely study of the genetic epidemiology of rotator cuff disease (1). The authors studied 3,091 patients with rotator cuff disease from the Utah Population Database and concluded that their data “strongly supports a heritable predisposition to rotator cuff disease”. After a careful review of the manuscript, we would like to raise several issues that may impact these conclusions:

    • ICD-9 codes were used to determine cases of rotator cuff disease, a limitation that the authors have acknowledged. However, an accurate diagnosis of rotator cuff disease is of paramount importance for this study. As the readership will appreciate, there still does not exist a standardized methodology for diagnosing rotator cuff tears. It is largely based on expert clinician’s impression and imaging findings. This scenario is further complicated since asymptomatic individuals may have rotator cuff tears on imaging. The prevalence of documented rotator cuff tears on imaging in patients without symptoms is reported to be 40% in subjects >50 years, 54% in those >60 years (2), and 65% in persons over 70 years (3). Often, patients with shoulder pain are diagnosed with rotator cuff tears in primary care settings without supporting clinical and imaging evidence leading to less reliable diagnostic data. It can be argued that, if the bias in diagnosis is non-differential, the results will be biased towards the null. However, the reliability of the outcome variable in this study is a key issue, and is unavailable and likely low. Moreover, the proportion of patients with rotator cuff disease is small as compared to the population sizes (202 of 23,700 patients versus 409 of 117,063 controls in first degree relatives). Hence,if many patients who were deemed to have rotator cuff disease did not,the p-values and relative risks would become statistically non-significant.

    • CPT codes for rotator cuff repair would be a more reliable way to study genetic predisposition since it is unlikely that a patient would be coded as having a repair unless the patient had a rotator cuff tear. The authors do not provide data on genetic predisposition in patients that underwent rotator cuff repair. This would be a valuable addition even if the sample size is small.

    It is plausible that degenerative cuff tears have a genetic predisposition but this assumption cannot be supported the the data. Approximately one-third (n=1,076) of the cases included in the study are based on an ICD-9 code for “rotator cuff traumatic strain”.

    The best evidence for a genetic predisposition would be available from cuff tears in younger individuals who otherwise would not be expected to have a rotator cuff tear (except in cases of trauma). The authors have diligently performed this analysis in patients younger than 40 years. However, small sample sizes (8 cases among 8,266 second degree patient relatives and 11 cases among 41,624 second degree control relatives) make it difficult to reach conclusions based on this analysis.

    • Information on missing data would be useful. Were all first, second, and third degree relatives screened for rotator cuff tear? What about relatives who lived out-of-state but may still have a diagnosis of rotator cuff tear? It is also possible that many patients do not seek medical care despite symptomatic cuff tear. This could be a substantial number of patients. Given the small number of patients with rotator cuff tears from a large population base, even one of these biases, if differential, could alter the results.

    • Finally,the age of participants in first, second, and third degree relatives groups is not presented. Increasing age is associated with increased likelihood of rotator cuff tear (4,5). If the median age of first degree relatives is higher, the prevalence of rotator cuff disease would be expected to be higher in this group.

    In conclusion, the ability to assign a pathoanatomic diagnosis of rotator cuff disease based on the data in this study is limited and uncertain in a percentage of cases. Therefore, the authors have likely shown a familial association with shoulder pain visits, which could indeed reflect genetic associations with rotator cuff disease or impingement. The study raises a range of important questions. More detailed studies that use a more reliable and valid rotator cuff disease diagnosis will be needed to address these questions. The use of genetic biomarkers will also help to quantify the associations objectively.

    The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

    References

    1. Tashjian RZ, Farnham JM, Albright FS, Teerlink CC, Cannon-Albright LA. Evidence for an inherited predisposition contributing to the risk for rotator cuff disease. J Bone Joint Surg Am. 2009;91:1136-42.

    2. Milgrom C, Schaffler M, Gilbert S, van Holsbeeck M. Rotator-cuff changes in asymptomatic adults. The effect of age, hand dominance and gender. J Bone Joint Surg Br. 1995;77:296-8.

    3. Sher JS, Uribe JW, Posada A, Murphy BJ, Zlatkin MB. Abnormal findings on magnetic resonance images of asymptomatic shoulders. J Bone Joint Surg Am. 1995;77:10-5.

    4. Wendelboe AM, Hegmann KT, Gren LH, Alder SC, White GL Jr, Lyon JL. Associations between body-mass index and surgery for rotator cuff tendinitis. J Bone Joint Surg Am. 2004;86-A:743-7.

    5. Yamaguchi K, Ditsios K, Middleton WD, Hildebolt CF, Galatz LM, Teefey SA. The demographic and morphological features of rotator cuff disease. A comparison of asymptomatic and symptomatic shoulders. J Bone Joint Surg Am. 2006;88:1699-704.

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