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

Phipson, Caryn

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

Thesis / Dissertation

2026

Publisher

University of Cape Town

Department

Department of Human Biology

Faculty

Faculty of Health Sciences

Abstract

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.

Keywords

ACL rupture

genome study

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