Table 2 Summary of the included articles indicating biomedical risk factors of Achilles tendinopathy in physically active people

Abate et al. (2015) [41]

Cross-sectional study/3

38/38

CON, 69 ± 2.8; AT, 69.6 ± 3.3

CON and AT, 32 M and 6 F in each group

CON, 24.8 ± 2.3; AT, 26.8 ± 3

0

Speed walking, jogging, tennis

Pain at rest or during activities in the AT region, and/or local tenderness or swelling, and/or functional limitation (ankle dorsiflexion and extension)

Diabetes is a contributing factor to the development of AT (p = 0.004).

Abrahams et al. (2013) [23]

Retrospective case-control study/4

160 (81 SA + 79 AUS)/342 (149 SA + 93 AUS)

AT (age of initial injury), 39.8 ± 14.5; CON, 37.7 ± 11.7

AT, 73% M, 27% F; CON, 50.6%M, 49.4% F

AT 25.7 ± 3.8 (147) vs CON 24.2 ± 3.6 (330)

0

Long distance running, squash

As per Mokone et al. (2005)

COL5A1 rs71746744, rs16399 and rs1134170 polymorphisms are independently associated with chronic AT (p = 0.008, OR = 2, 95%CI 1.2–3.3; p = 0.015, OR = 1.7, 95%CI 1.1–2.7; p = 0.014, OR = 1.8, 95%CI 1.1–2.9, respectively). MIR608 rs4919510 polymorphism is associated with chronic AT (p = 0.023, OR = 1.6, 95%CI 1.1–2.5).

Brown et al. (2016) [36]

Retrospective case-control study/4

112 (87 AT and 25 RUP)/130 CON

CON, 41.6 ± 11.6 (123); ATP, 43.9 ± 13.8 (112)

CON, 63.1% M, 36.9% F; ATP, 60.7% M, 39.3% F

CON, 25.9 ± 4.5 (123); ATP, 26.0 ± 4.0 (82)

0

Not specified, physically active people

As per Mokone et al. (2005)

Three inferred allele combinations constructed from COL5A1 rs12722, rs3196378 and rs71746744 increase risk of ATP, RUP and AT (p = 0.023, p = 0.011, p = 0.011). One inferred allele combination constructed from CASP8 rs3834129 and rs1045485 was significantly associated with an increased risk of AT (p = 0.031).

El Khoury et al. (2016) [38]

Retrospective case-control study/4

118 (93 AT and 25 RUP)/130 CON

CON, 41.7 ± 11.6 (124); ATP, 43.7 ± 13.8 (117)

CON, 62.6% M, 37.4% F; ATP, 60.2% M, 39.8% F

CON, 25.9 ± 4.5 (123); ATP, 26.3 ± 4.1 (n = 86)

0

Not specified, physically active people

As per Mokone et al. (2005)

TIMP2 rs4789932 variant is associated with ATP in males (p = 0.038).

MMP3 rs679620 variant is associated with RUP (p = 0.021).

El Khoury et al. (2015) [35]

Retrospective case-control study/4

135 (60 AUS + 75 SA)/239 (143 AUS + 96 SA)

CON, 38.2 ± 11.2 (230); AT, 40.1 ± 14.2 (129)

CON 50.6% M, 49.4% F; AT, 77.4% M, 22.6% F

CON 24.2 ± 3.6 (235); AT 25.7 ± 3.9 (124)

0

Running, high-impact sports

As per Mokone et al. (2005)

FBN2 rs331079 variant is associated with ATP in males (p = 0.035).

No association between ELN rs2071307 variant and ATP (p = 0.795).

El Khoury et al. (2013) [24]

Retrospective case-control study/4

165 (59 AUS + 114 SA)/248 (152 AUS + 96 SA)

AUS CON, 38.5 ± 11.9 (149); SA CON, 37.1 ± 10.0 (91); AUS ATP, 40.3 ± 14.1 (58); SA ATP, 40.2 ± 12.3 (107)

AUS CON, 39.7% M, 60.3% F; SA CON, 66.3% M, 33.7% F; AUS ATP, 67.8% M, 32.2% F; SA ATP, 73% M, 27% F

AUS CON 24.8 ± 4.0 (150); SA CON 23.3 ± 2.8 (93); AUS ATP 26.6 ± 4.1 (57); SA ATP 26.0 ± 3.9 (103)

20 Controls

Long distance running, squash

As per Mokone et al. (2005)

TIMP2 rs4789932 variant is associated with ATP in combined SA and AUS populations (p = 0.016, OR = 1.58, 95% CI 1.03–2.43)

None of the selected variants within the ADAMTS2, ADAMTS5, ADAMTS14 and ADAM12 genes were associated with risk of ATP in the two populations investigated (p = 0.316, p = 0.323, p = 0.849, p = 0.633, respectively).

Gaida et al. (2009) [43]

Cross-sectional study/3

60/60

CON, 47 ± 10; AT, 48 ± 9

CON, 53% M, 47% F; AT 53% M, 47% F

CON, 25 ± 3; AT, 25 ± 3

0

Not specified

Individuals with chronic Achilles tendon pain were diagnosed with midportion Achilles tendinopathy were included in the study.

AT subjects showed evidence of underlying dyslipidemia. They had higher triglyceride (TG), lower %HDL-C levels, apolipoprotein concentrations and higher TG/HDL-C ratio are associated with AT (p = 0.039, p = 0.016, p = 0.017, p = 0.036, respectively).

Gaida et al. (2010) [44]

Cross-sectional study/3

25/273

CON M 36.3 ± 11.3; CON F, 36.0 ± 10.3; AT M, 50.9 ± 10.4; AT F, 47.4 ± 10.0

CON, 40.3% M, 59.7% F; AT, 68% M, 32% F

CON M, 25.5 (3.5); CON F, 23.8 (3.2); AT M, 26.4 (3.2) AT F, 22.6 (2.6)

0

Not specified

Achilles tendons were examined by the ultrasound. Each tendon was classified as having a normal or abnormal internal structure. A tendon was classified as abnormal if any of the three following conditions were met: (1) one or more focal hypoechoic regions visible in both the longitudinal and transverse scans, (2) diffuse hypoechogenicity associated with bowing of the anterior tendon border or (3) diffuse hypoechogenicity associated with generalised thickening of the tendon in comparison with the contralateral tendon.

Older age and greater waist/hip ratio (WHR), higher android/gynoid fat mass ratio and higher upper-body/lower body fat mass ratio in men are associated with ATP (p < 0.001, 0.039, p = 0.014, p = 0.013, respectively). Men older than 40 years with a waist circumference >83 cm had the greatest prevalence of tendon pathology (33%). Older age, less total fat, less trunk fat, less android fat and lower central/peripheral fat mass ratio are associated with ATP in women (p = 0.008, p = 0.009, p = 0.003, p = 0.005, p = 0.004, respectively).

Gibbon et al. (2016) [37]

Retrospective case-control study/4

153 (99 AUS + 74 SA)/296 (199 AUS + 97 SA)

SA cohort from Mokone et al. (2005), AUS from Raleigh et al. (2009)

SA cohort from Mokone et al. (2005), AUS from Raleigh et al. (2009)

SA cohort from Mokone et al. (2005), AUS from Raleigh et al. (2009)

0

Not specified, physically active people

As per Mokone et al. (2005)

MMP3 rs679620, rs3025058 inferred variants are associated with AT within the SA group (p = 0.012; OR 2.88; 95% CI 1.4 to 6.1).

Hay et al. (2013) [25]

Retrospective case-control study/4

184 (78 AUS + 106 SA)/338 (177 AUS +161 SA)

AUS CON, 39.4 ± 12.3 (174); SA CON, 36.4 ± 10.8 (154); AUS AT, 40.7 ± 14.5 (77); SA AT, 40.9 ± 14.8 (92)

AUS CON, 40.3% M, 59.7% F; SA CON, 63.8% M, 36.2 F ; AUS AT, 71.8% M, 28.2% F; SA AT, 67.6% M, 32.4% F

AUS CON 24.7 ± 3.9 (175); SA CON 23.6 ± 2.8 (151); AUS AT 26.2 ± 3.5 (75); SA AT 24.8 ± 3.3 (81)

0

Long distance running, squash

As per Mokone et al. (2005)

None of COL11A1 rs3753841, rs1676486 and COL11A2 rs1799907 variants are independently associated with AT (p = 0.108, p = 0.35, p = 0.154, respectively). TCT-inferred pseudohaplotype, constructed from the three studied polymorphisms is associated with an increased risk of AT (p = 0.006).

Longo et al. (2009) [42]

Cross-sectional study/3

85/93

CON, 52.4 ± 12.0; AT, 54.9 ± 11.8

No data

No data

0

Running, hurdle, jumping

VISA_A questionnaire was filled out by the participants in order to identify the presence of AT. If the score was less than 100, then they were examined by an orthopaedic surgeon to ascertain whether the AT diagnosis was appropriate.

Sex, age, weight, height and track and field specialty are not associated with AT (p = 0.14, p = 0.20, p = 0.21, p = 0.46, p = 0.032, respectively).

Mokone et al. (2005) [27]

Retrospective case-control study/4

114 (72 AT and 42 RUP)/127

CON, 40.4 ± 10.8 (120); ATI, 39.8 ± 13.3 (112)

CON, 63.5% M, 36.5% F; ATI, 72.8% M, 27.2% F

CON, 23.3 ± 2.7 (120); ATI, 26.0 ± 4.0 (112)

0

Running, squash

The clinical diagnostic criteria for chronic Achilles tendinopathy were gradual progressive pain over the posterior lower limb in the Achilles tendon area for greater than 6 months, together with at least one out of the following six criteria: (1) early morning pain over the Achilles tendon area, (2) early morning stiffness over the Achilles tendon area, (3) a history of swelling over the Achilles tendon area, (4) tenderness to palpation over the Achilles tendon, (5) palpable nodular thickening over the affected Achilles or (6) movement of the painful area in the Achilles tendon with plantar-dorsi-flexion (positive “shift” test).

TNC 12 and 14 GT repeats variants frequencies were significantly higher in the symptomatic subjects, whereas the frequencies of 13 and 17 GT repeats variants were significantly higher in the asymptomatic control subjects (p = 0.001). 13 or 17 GT repeats were associated with 6.2 times lower risk of AT (OR = 6.2, 95%CI 3.5–11, p < 0.001).

Mokone et al. (2006) [27]

Retrospective case-control study/4

111 (72 AT + 39 RUP)/129

CON, 40.3 ± 11.0 (122); ATP, 40.1 ± 14.0 (108); AT, 39.7 ± 15.3 (69); RUP, 40.8 ± 11.3 (39)

CON, 61.7% M, 28.3% F; ATP, 73% M, 27% F; AT, 73.5 M, 26.5% F; RUP 79.5% M, 20.5% F

CON, 23.2 ± 2.7 (121); ATP, 25.9 ± 3.9 (108); AT, 24.7 ± 3.3 (69); RUP, 28.1 ± 4.1(39)

0

Running, recreational sports

As per Mokone et al. (2005)

Three alleles produced by the BstUI RFLP within the 3′-UTR of the COL5A1 alleles produced by BstUI RFLP within the 3′-UTR are associated with ATP and AT (p = 0.006, p = 0.0009, respectively).

Nell et al. (2012) [28]

Retrospective case-control study/4

166 (87 SA + 79 AUS)/358 (159 SA + 199 AUS)

No data

No data

No data

0

Running, recreational sports

As per Mokone et al. (2005)

CASP8 rs3834129 variant is associated with AT (p = 0.0294, OR = 1.67; 95% CI 1.08–2.60)

Owens et al. (2013) [40]

Descriptive epidemiology study/3

450/77,092

Cohort was divided into groups by year born; mean age was not calculated.

CON, 70.3% M, 29.7% F; AT, 69.33% M, 30.67% F

CON, underweight/normal 44.76%, overweight 46.54%, obese 8.7%; AT, underweight/normal 35.11%, overweight 51.33%, obese 13.56%

0

Military training

International Classification of Diseases, 9th Revision (ICD-9) represents tendinopathies that may have been caused by acute injury or the result of chronic pathology.

Overweight, obesity and moderate alcohol consumption are associated with AT (AOR = 1.29, 95% CI 1.04–1.59; AOR = 1.59, 95% CI 1.16–2.17; AOR = 1.33, 95% CI 1–1.76, respectively).

Posthumus et al. (2010) [29]

Retrospective case-control study/4

171 (59 AUS + 73 SA)/235 (142 AUS + 96 SA)

AUS CON, 39.0 ± 12.1 (140); AUS ATP, 40.3 ± 14.1 (59); SA CON, 36.9 ± 9.9 (89); SA ATP, 40.2 ± 13.5 (107)

AUS CON, 40.2% M, 59.8% F; AUS ATP, 67.8% M, 32.2% F; SA CON, 66.3% M, 33.7% F; SA ATP, 73% M, 27% F

AUS CON, 24.9 ± 4.0 (141); AUS ATP, 26.6 ± 4.1 (57); SA CON, 23.3 ± 2.8 (93); SA ATP, 26.0 (103)

0

Running, recreational sports

As per Mokone et al. (2005)

GDF5 rs143383 variant is associated with AT in AUS population and combined AUS and SA populations (p = 0.011, OR = 2.24, 95%CI 1.21–4.16; p = 0.004, OR = 1.82, 95%CI 1.23–2.74, respectively).

No association between the functional TGFB1 rs1800469 variant and ATP (p = 0.491).

Raleigh et al. (2009) [31]

Retrospective case-control study/4

114 (75 AT and 39 RUP)/ 98

CON, 36.8 ± 9.9 (91); AT, 40.5 ± 13.7 (70); RUP, 40.7 ± 11.5 (37)

CON, 67% M, 33% F; AT, 73% M, 27% F; RUP 73% M, 27% F

CON, 23.3 ± 2.8 (95); AT, 24.9 ± 3.4 (66); RUP, 27.8 ± 3.7 (37)

0

Not specified, physically active people

As per Mokone et al. (2005)

MMP3 rs679620, rs591058 and rs650108 are associated with AT (p = 0.010, OR = 2.5, 95% CI 1.2–4.9; p = 0.023, OR = 2.3, 95% CI 1.1–4.5; p = 0.043, OR = 4.9, 95% CI 1.0–24.1, respectively). An inferred haplotype of these three SNPs is significantly under-represented in AT cases and may be protective against the development of AT (p = 0.038).

Rickaby et al. (2015) [39]

Retrospective case-control study/4

131/131

CON, 41.3 ± 11.3 (122); ATP, 54.1 ± 14.2 (127)

CON, 62.6% M, 37.4% F; ATP, 61.8% M, 38.1% F

CON, 25.7 ± 5.1 (122); ATP 26.3 ± 4.1 (94)

0

Not specified, physically active people

As per Mokone et al. (2005)

TNFRSF1A rs4149577 and CASP8 rs3834129 SNPs were not associated with ATP (p = 0.335, p = 0.635, respectively).

Saunders et al. (2013) [30]

Retrospective case-control study/4

179/339

No data

No data

No data

0

Running, recreational sports

As per Mokone et al. (2005)

A haplotype of COL27A1 rs946053, TNC rs13321 and rs2104772 variants is significantly associated with risk of AT in a SA and AUS cohorts (p = 0.019).

September et al. (2008) [34]

Retrospective case-control study/4

137 (93 AT and 44 RUP)/131

CON, 37.1 ± 10.4 (124); ATI 40.0 ± 13.5 (131); AT, 39.1 ± 14.3 (87); RUP, 41.8 ± 11.6 (44)

CON, 64.6 M, 35.4 F; ATI, 73.7% M, 26.3 F; AT, 72% M, 28% F; RUP, 77.3% M, 26.6% F

CON, 23.3 ± 2.7 (126); ATI, 25.8 ± 3.8 (128); AT, 24.8 ± 3.3 (84); RUP, 27.8 ± 4.0 (44)

0

Running, recreational sports

As per Mokone et al. (2005)

No association between COL12A1 rs240736, COL14A1 rs4870723 and AT (p = 0.992, p = 0.232, respectively).

September et al. (2009) [33]

Retrospective case-control study/4

178 (85 AUS + 93 SA)/342 (210 AUS + 132 SA)

AUS CON, 38.5 ± 12.4 (205); AUS AT, 40.4 ± 14.2 (84); SA CON and AT are the same as in Mokone et al. (2006)

AUS CON, 40.2% M, 59.8% F; AUS AT, 72.9% M, 27.1% F

AUS CON, 24.6 ± 3.9 (207); AUS AT, 26.5 ± SD 3.8 (82)

0

Running, recreational sports

As per Mokone et al. (2005)

COL5A1 rs12722 variant is associated with AT in AUS cohort (p = 0.001). COL5A1 rs12722 variant had a significantly decreased risk of AT in AUS and SA cohorts (p = 0.017, OR 0.42, 95% CI 0.20–0.86; p = 0.008, OR 0.38, 95% CI 0.18–0.77, respectively). COL5A1 rs13946 is not associated with AT (p = 0.197).

September et al. (2011) [32]

Retrospective case-control study/4

175 (90 SA + 85 AUS)/369 (161 SA + 208 AUS)

No data

No data

No data

0

Running, recreational sports

As per Mokone et al. (2005)

No association of IL1β (two polymorphisms), IL6 or IL1RN genes and AT (p = 0.380, p = 0.097, p = 0.183, p = 0.779, respectively). The inferred allele combination constructed from the COL5A1 BstUI RFLP – IL1β −31 T → C – IL1β −511C → T – IL6 − 172G → C – IL1RN VNTR is associated with AT (p = 066005) and suggests the potential interactions of these respective sequence variants in modulating the risk profile of developing AT.