The genetic contribution to severe post-traumatic osteoarthritis.

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by  Valdes, Ana M

Clinical and epidemiological research
CONCISE REPORT
The genetic contribution to severe post-traumatic
osteoarthritis
Ana M Valdes,1,2 Sally A Doherty,1 Kenneth R Muir,3,4 Margaret Wheeler,1
Rose A Maciewicz,5 Weiya Zhang,1 Michael Doherty1
HandlingeditorToreKKvien ABSTRACT and Spector10). Recent genetic association studies
Objective tocomparethecombinedroleofgenetic have identified a number of genetic variants asso-
▸Additionalmaterialis
variantslociassociatedwithriskofkneeorhip ciated with knee or hip OA or with severe large
publishedonlineonly.Toview
pleasevisitthejournalonline osteoarthritis(OA)inpost-traumatic(PT)andnon- joint OA leading to total joint arthroplasty.11–15 To
(http://dx.doi.org/10.1136/ traumatic(NT)casesofclinicallysevereOAleadingto date, 12 independent variants have been reported
annrheumdis-2012-202562). totaljointreplacement. to be associated with risk of hip or knee OA or
1AcademicRheumatology, Methods Atotalof1590controls,2168totalknee related traits with a statistical significance level of
NottinghamCityHospital, replacement(TKR)cases(33.2%PT)and1567totalhip p<1×10−7with(table1).
Nottingham,UK replacement(THR)cases(8.7%PT)from2UKcohortswere The aim of this study was to examine whether
2DepartmentofTwinResearch
&GeneticEpidemiology,King’s genotypedfor12variantspreviouslyreportedtobe PT OA might have a lower genetic contribution
CollegeLondon,StThomas’ reproduciblyassociatedwithriskofkneeorhipOA.A than non-traumatic (NT) idiopathic large joint OA.
Hospital,London,UK geneticriskscorewasgeneratedandtheassociationwithPT We investigatedthecombined roleofthepublished
3HealthSciencesResearch andNTTKRandTHRwasassessedadjustingforcovariates. OA-riskgenetic variants in twocase controlstudies
Institute,WarwickMedical Results ForTHR,eachadditionalgeneticriskvariant from the UK focusing on severe OA leading to
School,UniversityofWarwick,
conferredlowerriskamongPTcases(OR=1.07,95%CI totalkneereplacement (TKR)andtotalhipreplace-
Coventry,UK
4InstituteofPopulationHealth, 0.96to1.19;p=0.24)thanNTcases(OR1.11,95%CI ment (THR).
UniversityofManchester, 1.06to1.17;p=1.55×10−5).Incontrast,forTKR,each
Manchester,UK riskvariantconferredslightlyhigherriskamongPTcases PATIENTS AND METHODS
5Respiratory&Inflammation (OR1.12,95%CI1.07to1.19;p=1.82×10−5)than Studycohorts
ResearchArea,AstraZeneca,
CharnwoodR&D, amongNTcases(OR1.08,95%CI1.03to1.1; THR and TKR cases were recruited from two case-
Loughborough,Leicestershire, p=0.00063). controlstudiesinNottingham, UK: theNottingham
UK Conclusions BasedonthevariantsreportedtodatePT OACase-Control and the Genetics of Osteoarthritis
TKRcaseshaveatleastashighageneticcontributionas and Lifestyle (GOAL) study. Controls were obtained
Correspondenceto
NTcases. fromboththesestudies.
DrAnaMValdes,Department
ofTwinResearch&Genetic
Epidemiology,KingsCollege PTOAdefinition
London,StThomasHospital INTRODUCTION PT THR was defined as THR in the presence of
campus,LondonSE17EH,UK;
[email protected] Large joint osteoarthritis (OA) is a common hip injury and PT TKR as TKR in the presence of
complex disorder with multiple genetic, constitu- knee injury as described in the online supplemen-
Received24August2012 tional and environmental risk factors and marked tarymethodssection.
Revised6December2012 variabilityinphenotype.12
Accepted29December2012
OA is divided into ‘primary’ OA, considered to Laboratorymethods
PublishedOnlineFirst
26January2013 result mainly from genetic and constitutional Genomic DNA was extracted from peripheral
factors, and ‘secondary’ OA when there is an blood leukocytes of affected individuals and con-
obvious cause of joint insult.3 A long-recognised trols using standard protocols. Genotyping was
riskfactorforOAisdirectjointinjury,suchasasub- carried out by Kbioscience Ltd, Hertfordshire, UK.
chondral fracture, meniscectomy, anterior cruciate Single nucleotide polymorphisms (SNPs) were gen-
tear or a deforming tibial or femoral fracture that otyped using the Kompetitive Allele Specific PCR
resultsinpooralignmentorleglengthshortening.45 (KASPar)chemistry.
An estimated 12% of symptomatic OA may be
attributedtoapost-traumatic(PT)cause6anddiffer- Statisticalanalysis
ences in radiographic patterns have been reported Geneticscore
betweenprimaryandPTkneeOAcases.7However, Thesumofriskalleles(whichcantakevalues0,1or
two studiesthat examined the relationship between 2foreachvariant)asdefinedintable1overallvar-
hand OA and the risk of developing knee OA fol- iants was computed for each study participant.
OpenAccess lowing meniscectomy found that the presence of Individualswithmorethan1missinggenotypeforall
Scantoaccessmore
freecontent hand OA associated with a higher frequency and 12 variants were excluded, otherwise the genotype
radiographic severity of post-meniscectomy OA,8 9 was imputed using the allele frequency in the
demonstrating that development of OA following a population.
meniscaltearandsubsequentsurgeryarenotneces- Logistic regressions using TKR or THR as out-
Tocite:ValdesAM,
DohertySA,MuirKR,etal. sarilyofsecondaryorigin. comes and including age, gender, (BMI) and knee
AnnRheumDis Genetic factors are known to influence risk of genetic risk score (for TKR) or hip genetic risk
2013;72:1687–1690. hip OA, knee OA and generalised OA (see Valdes score (for THR) were performed. Analyses were
ValdesAM,etal.AnnRheumDis2013;72:1687–1690.doi:10.1136/annrheumdis-2012-202562 1687
Clinical and epidemiological research
Table1 Geneticvariantsusedtogeneratethegeneticriskscore
DNA pValuein RAFcontrols Risk Hip Knee
Gene SNP change Reference Traitassociated Caucasians (%) allele gene gene
GDF5 rs143383 T/C Valdesetal11 KneeOA 8×10–9 61.9 T − +
COG5* rs4730250 A/G Evangelouetal12 KneeOA 9×10–9 19.3 G − +
MCFL2 rs11842874 A/G Day-Williamsetal13 HiporkneeOA 9.2×10−9 91.5 A + +
PTHLH* rs10492367 A/C arcOGEN14 HipOA 1.5×10−8 21.0 A + −
SUPT3H rs10948172 G/A arcOGEN14 HiporkneeOAinmen 7.9×10−8 28.6 G + +
TP63 rs12107036 A/G arcOGEN14 TKRinwomen 6.7×10−8 53.6 G − +
FILIP1* rs9350591 C/T arcOGEN14 THR 2·42×10−9 10.9 T + −
GLN3* rs11177 A/G arcOGEN14 HiporkneeOA 7.24×10−11 39.0 A + +
DOT1L rs12982744 C/G Castaño-Betancourt Minimumjointspace 1.1×10−11 60.2 G + −
etal15 width†
ASTN2 rs4836732 C/T arcOGEN14 THR 6.1×10−10 49.7 C + −
FTO rs8044769 C/T arcOGEN14 TKRinwomen 6.8×10−8 51.3 C + +
CHST11 rs835487 A/G arcOGEN14 THR 1.6×10−8 34.0 G + −
*Forconcisenessonlyoneofthegenesintheregionisshown.rs4730250mapstoaclusterofgenesthatcomprisesCOG5,HBP1,GPR22,PRKAR2B,DUS4LandBCAP29.rs10492367
mapsbetweenPTLHLandKLHDC5.rs9350591mapsbetweenFILIP1andSENP6.rs11177mapstoanamino-acidchangewithinGLN3butisinstronglinkagedisequilibrium(LD)with
variantsintheGLT8D1gene.
†AssociationwithhipOAreportedisp<1.1×10−4.
OA,osteoarthritis;RAF,riskallelefrequency;SNP,singlenucleotidepolymorphism;THR,totalhipreplacement;TKR,totalkneereplacement.
carried out including all TKR (or THR) cases, only PT cases werealsocomputedexcludingindividualswithmissinggenotypes
(PT-TKRorPT-THR)andonlyNTcases(NT-TKRorNT-THR). (see onlinesupplementary tableS2)and are verysimilar to those
Results are reported as OR and corresponding 95% CI for the usingimputedgenotypesformissingdata.
GOAL and Nottingham cohorts separately. ORs were also
meta-analysed for both cohorts using a fixed effects analysis. DISCUSSION
AnalyseswereperformedusingRV.2.13.1(http://www.r-project. In this study we report for the first time the role of genetic
org/). factors in PTclinically severe OA requiring total joint replace-
ment and compare it to the role that these same genetic factors
play among ‘primary’ cases. Our hypothesis was that primary
RESULTS cases would carry a larger number of genetic risk variants than
The listof variants investigated in this study is shown in table 1 PT OA cases. However, the ORestimates for hip and knee risk
along with the best-reported p value in the literature. The role scores are not significantly different between PTand NT sub-
of injuryas a risk factor was assessed in the GOAL study where jects. Among TKR cases PT cases appear to carry a non-
history of trauma was recorded for cases and controls. After significantly larger proportion of risk variants. Among THR
adjustment for age, sex and BMI the risk estimates found were casesalowercontributionofgeneticriskfactorswasseeninPT
OR=3.27, (95 % CI 2.51 to 4.25; p<1.1×10(−18)) for TKR casesthatdidnotachievestatisticalsignificance.
and OR=5.08 (95 % CI 3.05 to 8.47; p<4.2×10(−10)) for
THR. The combined genetic and descriptive statistics risks in
each cohort are shown in table 2. These factors were analysed
Table2 Descriptivestatisticsinthetwostudycohorts
in each cohort to assess their role in defining risk of THR and
TKRfollowingtraumaorintheabsenceofinjury. Factor Controls TKR THR
The mean of each of these risk factors stratified by injury
status shows, as expected, a significantly younger age and a Nottinghamcasecontrol,n: 711 1305 629
Female,% 57.0% 55.2% 57.9%
higher proportion of men in the post-trauma category (see
Age(SD) 66.29(8.97) 69.75(9.21) 70.39(8.75)
onlinesupplementarytableS1).
BMI(SD) 26.57(3.93) 30.15(5.61) 28.83(4.88)
The knee genetic risk score for TKR and the hip genetic risk
score for THR are both significantly related to riskof total joint Kneegenescore(SD) 6.88(1.62) 7.17(1.68) 6.90(1.74)
Hipgenescore(SD) 6.14(1.62) 6.10(1.57) 6.41(1.69)
replacement (table 3). The average ORcontributed byeach add-
Hipinjury,% NA 5.2% 10.8%
itional variant carried is similar to those reported in the studies
thatidentifiedthesegeneticvariants(1.11forhipOAriskvariants Kneeinjury,% NA 33.6% 17.0%
GOALstudy,n: 879 863 938
and1.09forkneeOArisk).Ageandsexcontributedifferentlyto
Female,% 48.2% 47.4% 52.6%
riskofPT-TKRandNT-TKR(seeonlinesupplementarytableS1).
Wedidnotobserveasignificantdifferenceintheriskconferredby Age(SD) 62.90(8.50) 69.05(6.82) 67.83(6.96)
BMI(SD) 27.23(4.44) 31.37(5.31) 29.31(5.25)
kneegeneticriskfactors,buttheORisslightlyhigherforPT-TKR
Kneegenescore(SD) 6.73(1.67) 6.98(1.70) 6.94(1.73)
cases (OR=1.12) than for non-traumatic cases (OR=1.08). For
THR only the gender composition is significantly different Hipgenescore(SD) 5.93(1.62) 6.10(1.62) 6.24(1.64)
Hipinjury,% 1.8% 3.4% 7.4%
betweenNTandPTcases(seeonlinesupplementarytableS1).The
genetic risk conferred does not achieve statistical significance Kneeinjury,% 15.7% 32.7% 16.5%
among PT-THR cases and is lower (OR=1.07) than among BMI,bodymassindex;GOAL,GeneticsofOsteoarthritisandLifestyle;NA,not
NT-THR cases (OR=1.11) where it is highly significant. Results applicable;THR,totalhipreplacement;TKR,totalkneereplacement.
1688 ValdesAM,etal.AnnRheumDis2013;72:1687–1690.doi:10.1136/annrheumdis-2012-202562
Clinical and epidemiological research
Table3 Age,sex,BMIandgeneticriskscoresasriskfactorsforpost-traumatic(PT)andnon-traumatic(NT)totaljointreplacementintwo
studycohorts
Riskfactor Studycohort All pValue PT pValue NT pValue
TKR:
Age GOAL 1.13(1.12to1.15) 1.10(1.08to1.12) 1.16(1.13to1.18)
Nottingham 1.07(1.06to1.08) 1.04(1.02to1.05) 1.09(1.07to1.1)
Summary 1.09(1.08to1.1) 4.88E-73 1.06(1.05to1.07) 5.17E-20 1.11(1.10to1.12) 7.05E-75
Sex GOAL 0.99(0.78to1.24) 0.61(0.45to0.84) 1.41(1.08to1.83)
Nottingham 0.76(0.62to0.93) 0.49(0.37to0.63) 1.00(0.79to1.25)
Summary 0.85(0.73to0.99) 0.039 0.53(0.44to0.65) 1.39E-09 1.16(0.97to1.37) 0.098
BMI GOAL 1.24(1.21to1.27) 1.20(1.16to1.25) 1.26(1.22to1.29)
Nottingham 1.21(1.18to1.24) 1.20(1.16to1.23) 1.22(1.19to1.25)
Summary 1.22(1.2to1.24) 9.8E-106 1.20(1.17to1.23) 4.2E-55 1.24(1.21to1.26) 1.35E-93
KneeOA GOAL 1.08(1.01to1.16) 1.14(1.06to1.23) 1.07(1.01to1.14)
Risk Nottingham 1.09(1.03to1.16) 1.10(1.02to1.2) 1.10(1.03to1.17)
Genes Summary 1.09(1.04to1.14) 0.00025 1.12(1.07to1.19)* 1.82E-05 1.08(1.03to1.13)* 0.00063
THR:
Age GOAL 1.1(1.08to1.11) 1.06(1.03to1.09) 1.10(1.08to1.11)
Nottingham 1.07(1.05to1.08) 1.08(1.05to1.11) 1.06(1.05to1.08)
Summary 1.08(1.07to1.09) 3.87E-57 1.07(1.05to1.09) 1.11E-09 1.08(1.07to1.09) 1.02E-54
Sex GOAL 1.38(1.13to1.69) 1.04(0.62to1.75) 1.45(1.18to1.78)
Nottingham 1.03(0.82to1.3) 1.33(0.78to2.26) 0.99(0.78to1.26)
Summary 1.22(1.05to1.42) 0.011 1.17(0.81to1.7) 0.40 1.23(1.05to1.44) 0.0092
BMI GOAL 1.11(1.09to1.14) 1.13(1.08to1.19) 1.11(1.09to1.14)
Nottingham 1.15(1.12to1.18) 1.15(1.08to1.22) 1.15(1.12to1.19)
Summary 1.13(1.11to1.15) 2.78E-42 1.14(1.1to1.18) 5.71E-11 1.13(1.11to1.15) 4.83E-40
HipOA GOAL 1.13(1.06to1.21) 1.06(0.91to1.23) 1.14(1.07to1.21)
Risk Nottingham 1.08(1.01to1.16) 1.08(0.92to1.27) 1.08(1to1.16)
Genes Summary 1.11(1.06to1.16) 1.2E-05 1.07(0.96to1.19)* 0.24 1.11(1.06to1.17)* 1.55E-05
*ThedifferencebetweenthePTandNTORsdidnotreachstatisticalsignificance(p>0.05)forTKRandTHR.
BMI,bodymassindex;GOAL,GeneticsofOsteoarthritisandLifestyle;OA,osteoarthritis;THR,totalhipreplacement;TKR,totalkneereplacement.
One possible explanation for the lack of differences between strong significant differences in age and gender between PTOA
PTand primary cases is that the genome-wide association study and NT cases, as reported in other studies.3 4 Moreover, the
(GWAS) analyses that identified these variants have not made a questionnaire applied identified a very high risk due to injury
distinction between the two types of patients. Given that PT for TKR (OR=3.27) and THR (OR=5.08) in the case control
cases constitute a substantial proportion of all knee OA cases, design.Suchrisks are muchhigher than all genetic factors com-
any genetic risk factors identified are likely to be implicated in bined. Thus, in spite of the caveats, the population classified as
both types of patients. This is possible since in the case of hip PT based on questionnaire data appears enriched for true PT
OA the prevalence of hip injury is much lower and the hip OA cases. Another limitation is that the results apply to UK
geneticriskloadamongPTTHRcasesislowerthan inprimary populations and may not generalise to other ethnic groups, but
cases. However the effect of knee risk variants is as strong or the genetic variants used are only those reported in Caucasians
even strongeramong PT TKRcases indicating that the genes so ashavingaroleinriskofOA.
far identified to influence risk of knee OA play a role in the In conclusion, PT hip OA cases appear to have a lower
pathogenesis of severe PT knee OA. However, the OR for hip geneticriskloadthanNTcases,whereasPTkneeOAcaseshave
genes in the PT group is not significantly different from 1 and at least as high a genetic contribution as NTcases. These data
with the current sample size and the effect size observed the support the perspective of OA as common complex condition
study is not powered to determine if PT THR has a modest and further challenge a clear separation between ‘primary’ and
geneticcomponent. ‘secondary’formsofOA.
Recentresearchsupportstheviewthatacutejointdamagethat
occurs at the time ofaninjury initiates a sequence ofeventsthat
Contributors Allauthorscontributedtothestudydesign,datainterpretationand
canleadtoprogressivearticularsurfacedamage.Determinationof thefinalmanuscript.Inaddition,AMVanalysedandinterpretedthedataand
theriskfactors affectingjointtissuesand their respective rolesin preparedmanuscript.SADandMDevaluatedstudysubjects.AMVandMD
disease progression is critical to advances in the treatment of PT supervisedthestudy.
OA.4 Our data indicate that among the risk factors to take into Funding SupportedbyEC-FP7programmegrant200800TREAT-OAand277849
accountinPTkneeOAaregeneticinfluences. EurHEALTHAgeing.AstraZenecaUKfundedtheGOALstudysampleanddata
collection.
There are some limitations to this study. Prior injuries were
self-reported rather than based on medical records, and may be Competinginterests RAMisanemployeeofAstrazenecaplc.
open to recall bias. Also some of the cases classified as PT OA Ethicsapproval theresearchethicscommitteesofNottinghamCityHospitaland
mayactuallybe‘primary’casesduetothetypeofinjuryexperi- NorthNottinghamshire.
enced. Nevertheless, using the current definitions we found Provenanceandpeerreview Notcommissioned;externallypeerreviewed.
ValdesAM,etal.AnnRheumDis2013;72:1687–1690.doi:10.1136/annrheumdis-2012-202562 1689
Clinical and epidemiological research
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