Investigating the association of genetic variants, previously identified by a genome-wide association study, with ACL rupture risk in multiple cohorts

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dc.contributor.advisorCollins, Malcolm
dc.contributor.advisorLaguette, Mary-Jessica
dc.contributor.advisorSeptember, Alison
dc.contributor.authorPhipson, Caryn
dc.date.accessioned2026-08-11T11:33:18Z
dc.date.available2026-08-11T11:33:18Z
dc.date.issued2026
dc.date.updated2026-08-11T11:32:28Z
dc.description.abstractINTRODUCTION Genetic variance is an important risk factor for many musculoskeletal soft tissue injuries, including ACL ruptures. Several direct-to-consumer genetic tests have emerged that claim to be able to test for susceptibility to such injuries. Only a single company uses injury-specific markers in their tests based on the findings of genome-wide association studies (GWAS), an arguably more robust and scientifically reliable approach than the candidate gene study approach traditionally used. The genetic markers identified by GWAS used to determine ACL rupture risk include rs144051132 (T/A), rs186727643 (C/T), and rs188099931 (A/G). However, their viability as reliable markers of injury risk has yet to be critically and scientifically evaluated in independent cohorts. Thus, the aim of this study was to determine whether rs144051132, rs186727643, and rs188099931 are associated with ACL rupture across multiple population groups. METHODS A genetic association study, comprising cases clinically diagnosed with ACL rupture (ACL), a subset of cases who had sustained an ACL rupture via a non-contact mechanism (ACL-NC), and a control group (CON), was conducted whereby participants from four cohorts of European ancestry; South African (CON=229, ACL=242, ACL-NC=161), Australian (CON=82, ACL=330, ACL-NC=149), Swedish (CON=116, ACL=95, ACL-NC=79), and Polish (CON=147, ACL=142, ACL-NC=56), as well as a South African mixed ancestry cohort (CON=105, ACL=98, ACL-NC=58), were genotyped for the three variants using TaqMan™ Genotyping assays. Genotype distributions were compared between the ACL and CON groups, as well as between the ACL-NC and CON groups. The functional effects of each variant were also analysed using multiple bioinformatics tools. RESULTS No significant associations between the three variants and ACL rupture risk were reported. Furthermore, several genotypes were either absent or rare. Specifically, the rs144051132 AA, rs186727643 TT, and rs188099931 GG genotypes were not detected. Twelve rs144051132 TA [CON(0.7%, n=4) vs ACL(1.0%, n=8), p=0.770; CON vs ACL-NC(0.9%, n=4), p=0.819], one rs186727643 CT [ACL(0.1%, n=1), p=1.000], and six rs188099931 AG [CON(0.2%, n=1) vs ACL(0.6%, n=5), p=0.410; CON vs ACL-NC(0.7%, n=3), p=0.448] genotypes were identified across the European cohorts. In the South African mixed ancestry cohort, three rs144051132 TA [CON(0.9%, n=1) vs ACL(2.0%, n=2), p=0.611; CON vs ACL-NC(2.0%, n=1), p=0.489], eight rs186727643 CT [CON(2.8%, n=3) vs ACL(5.1%, n=5), p=0.486; CON vs ACLNC(2.0%, n=1), p=0.092], and one rs188099931 AG [CON(0.9%, n=1), p=1.000] genotypes were identified. All three heterozygote genotypes were absent from the Swedish cohort, while rs186727643 CT and rs188099931 AG were absent from the Polish cohort. The rs186727643 CT genotype was also absent from the South African cohort of European ancestry. CONCLUSION In line with these results, the scientific evidence is too weak to support an association between ACL rupture risk and rs144051132, rs186727643, and rs188099931. The observed rarity of the effect allele suggests that the use of these variants as reliable markers of ACL rupture risk is not yet viable, and this dissertation does not support their inclusion as markers of injury risk in a direct-to-consumer genetic test.
dc.identifier.apacitationPhipson, C. (2026). <i>Investigating the association of genetic variants, previously identified by a genome-wide association study, with ACL rupture risk in multiple cohorts</i>. (). University of Cape Town ,Faculty of Health Sciences ,Department of Human Biology. Retrieved from http://hdl.handle.net/11427/43708en_ZA
dc.identifier.chicagocitationPhipson, Caryn. <i>"Investigating the association of genetic variants, previously identified by a genome-wide association study, with ACL rupture risk in multiple cohorts."</i> ., University of Cape Town ,Faculty of Health Sciences ,Department of Human Biology, 2026. http://hdl.handle.net/11427/43708en_ZA
dc.identifier.citationPhipson, C. 2026. Investigating the association of genetic variants, previously identified by a genome-wide association study, with ACL rupture risk in multiple cohorts. . University of Cape Town ,Faculty of Health Sciences ,Department of Human Biology. http://hdl.handle.net/11427/43708en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Phipson, Caryn AB - INTRODUCTION Genetic variance is an important risk factor for many musculoskeletal soft tissue injuries, including ACL ruptures. Several direct-to-consumer genetic tests have emerged that claim to be able to test for susceptibility to such injuries. Only a single company uses injury-specific markers in their tests based on the findings of genome-wide association studies (GWAS), an arguably more robust and scientifically reliable approach than the candidate gene study approach traditionally used. The genetic markers identified by GWAS used to determine ACL rupture risk include rs144051132 (T/A), rs186727643 (C/T), and rs188099931 (A/G). However, their viability as reliable markers of injury risk has yet to be critically and scientifically evaluated in independent cohorts. Thus, the aim of this study was to determine whether rs144051132, rs186727643, and rs188099931 are associated with ACL rupture across multiple population groups. METHODS A genetic association study, comprising cases clinically diagnosed with ACL rupture (ACL), a subset of cases who had sustained an ACL rupture via a non-contact mechanism (ACL-NC), and a control group (CON), was conducted whereby participants from four cohorts of European ancestry; South African (CON=229, ACL=242, ACL-NC=161), Australian (CON=82, ACL=330, ACL-NC=149), Swedish (CON=116, ACL=95, ACL-NC=79), and Polish (CON=147, ACL=142, ACL-NC=56), as well as a South African mixed ancestry cohort (CON=105, ACL=98, ACL-NC=58), were genotyped for the three variants using TaqMan™ Genotyping assays. Genotype distributions were compared between the ACL and CON groups, as well as between the ACL-NC and CON groups. The functional effects of each variant were also analysed using multiple bioinformatics tools. RESULTS No significant associations between the three variants and ACL rupture risk were reported. Furthermore, several genotypes were either absent or rare. Specifically, the rs144051132 AA, rs186727643 TT, and rs188099931 GG genotypes were not detected. Twelve rs144051132 TA [CON(0.7%, n=4) vs ACL(1.0%, n=8), p=0.770; CON vs ACL-NC(0.9%, n=4), p=0.819], one rs186727643 CT [ACL(0.1%, n=1), p=1.000], and six rs188099931 AG [CON(0.2%, n=1) vs ACL(0.6%, n=5), p=0.410; CON vs ACL-NC(0.7%, n=3), p=0.448] genotypes were identified across the European cohorts. In the South African mixed ancestry cohort, three rs144051132 TA [CON(0.9%, n=1) vs ACL(2.0%, n=2), p=0.611; CON vs ACL-NC(2.0%, n=1), p=0.489], eight rs186727643 CT [CON(2.8%, n=3) vs ACL(5.1%, n=5), p=0.486; CON vs ACLNC(2.0%, n=1), p=0.092], and one rs188099931 AG [CON(0.9%, n=1), p=1.000] genotypes were identified. All three heterozygote genotypes were absent from the Swedish cohort, while rs186727643 CT and rs188099931 AG were absent from the Polish cohort. The rs186727643 CT genotype was also absent from the South African cohort of European ancestry. CONCLUSION In line with these results, the scientific evidence is too weak to support an association between ACL rupture risk and rs144051132, rs186727643, and rs188099931. The observed rarity of the effect allele suggests that the use of these variants as reliable markers of ACL rupture risk is not yet viable, and this dissertation does not support their inclusion as markers of injury risk in a direct-to-consumer genetic test. DA - 2026 DB - OpenUCT DP - University of Cape Town KW - ACL rupture KW - genome study LK - https://open.uct.ac.za PB - University of Cape Town PY - 2026 T1 - Investigating the association of genetic variants, previously identified by a genome-wide association study, with ACL rupture risk in multiple cohorts TI - Investigating the association of genetic variants, previously identified by a genome-wide association study, with ACL rupture risk in multiple cohorts UR - http://hdl.handle.net/11427/43708 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/43708
dc.identifier.vancouvercitationPhipson C. Investigating the association of genetic variants, previously identified by a genome-wide association study, with ACL rupture risk in multiple cohorts. []. University of Cape Town ,Faculty of Health Sciences ,Department of Human Biology, 2026 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/43708en_ZA
dc.language.isoen
dc.language.rfc3066eng
dc.publisher.departmentDepartment of Human Biology
dc.publisher.facultyFaculty of Health Sciences
dc.publisher.institutionUniversity of Cape Town
dc.subjectACL rupture
dc.subjectgenome study
dc.titleInvestigating the association of genetic variants, previously identified by a genome-wide association study, with ACL rupture risk in multiple cohorts
dc.typeThesis / Dissertation
dc.type.qualificationlevelMasters
dc.type.qualificationlevelMSc(Med)
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