Sex-Specific Effects of Adiponectin on Carotid Intima-Media Thickness and Incident Cardiovascular Disease.
BACKGROUND
Plasma adiponectin levels have previously been inversely associated with carotid intima-media thickness (IMT), a marker of subclinical atherosclerosis. In this study, we used a sex-stratified Mendelian randomization approach to investigate whether adiponectin has a causal protective influence on IMT.


RESULTS
Baseline plasma adiponectin concentration was tested for association with baseline IMT, IMT progression over 30 months, and occurrence of cardiovascular events within 3 years in 3430 participants (women, n=1777; men, n=1653) with high cardiovascular risk but no prevalent disease. Plasma adiponectin levels were inversely associated with baseline mean bifurcation IMT after adjustment for established risk factors (β=-0.018, P<0.001) in men but not in women (β=-0.006, P=0.185; P for interaction=0.061). Adiponectin levels were inversely associated with progression of mean common carotid IMT in men (β=-0.0022, P=0.047), whereas no association was seen in women (0.0007, P=0.475; P for interaction=0.018). Moreover, we observed that adiponectin levels were inversely associated with coronary events in women (hazard ratio 0.57, 95% CI 0.37 to 0.87) but not in men (hazard ratio 0.82, 95% CI 0.54 to 1.25). A gene score of adiponectin-raising alleles in 6 loci, reported recently in a large multi-ethnic meta-analysis, was inversely associated with baseline mean bifurcation IMT in men (β=-0.0008, P=0.004) but not in women (β=-0.0003, P=0.522; P for interaction=0.007).


CONCLUSIONS
This report provides some evidence for adiponectin protecting against atherosclerosis, with effects being confined to men; however, compared with established cardiovascular risk factors, the effect of plasma adiponectin was modest. Further investigation involving mechanistic studies is warranted.
Division of Cardiovascular Medicine, Department of Clinical Sciences, Karolinska Institutet, Danderyd University Hospital, Stockholm, Sweden (J.P., B.G., P.L.).
Jonas
J
Persson
Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden (R.J.S., O.M.L., K.G., A.S., B.S., M.S.L., J., A.H.).
Rona J
RJ
Strawbridge
Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden (R.J.S., O.M.L., K.G., A.S., B.S., M.S.L., J., A.H.).
Olga
O
McLeod
Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden (R.J.S., O.M.L., K.G., A.S., B.S., M.S.L., J., A.H.).
Karl
K
Gertow
Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden (R.J.S., O.M.L., K.G., A.S., B.S., M.S.L., J., A.H.).
Angela
A
Silveira
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy (D.B., E.T.) Centro Cardiologico Monzino, IRCCS, Milan, Italy (D.B., F.V., E.T.).
Damiano
D
Baldassarre
Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, United Kingdom (N.V.Z., A.D.M., C.A.P.).
Natalie
N
Van Zuydam
University College London Genetics Institute, University College London, London, United Kingdom (S.S.) Diamantina Institute and Queensland Brain Institute, University of Queensland, Australia (S.S.).
Sonia
S
Shah
Division of Internal Medicine C, Department of Medicine, Hospital "Policlinico G.B Rossi", University of Verona, Italy (C.F.) Clinical Research Center, Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Sweden (C.F., B.H., O.M.).
Cristiano
C
Fava
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden (S.G., E.I.).
Stefan
S
Gustafsson
Centro Cardiologico Monzino, IRCCS, Milan, Italy (D.B., F.V., E.T.).
Fabrizio
F
Veglia
Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden (R.J.S., O.M.L., K.G., A.S., B.S., M.S.L., J., A.H.) Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden (B.S.).
Bengt
B
Sennblad
IFM Bioinformatics, Linköping University, Linköping, Sweden (M.L.).
Malin
M
Larsson
Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden (R.J.S., O.M.L., K.G., A.S., B.S., M.S.L., J., A.H.).
Maria
M
Sabater-Lleal
Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (K.L., B.G., U.F.).
Karin
K
Leander
Division of Cardiovascular Medicine, Department of Clinical Sciences, Karolinska Institutet, Danderyd University Hospital, Stockholm, Sweden (J.P., B.G., P.L.) Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (K.L., B.G., U.F.).
Bruna
B
Gigante
Department of Epidemiology and Public Health, University College London, London, United Kingdom (A.T., M.K.) 1st Department of Medicine, Semmelweis University Faculty of Medicine, Semmelweis University, Budapest, Hungary (A.T.).
Adam
A
Tabak
Department of Epidemiology and Public Health, University College London, London, United Kingdom (A.T., M.K.).
Mika
M
Kivimaki
Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland (J.K.).
Jussi
J
Kauhanen
Kuopio Research Institute of Exercise Medicine, Kuopio, Finland (R.R.) Department of Clinical Physiology and Nuclear Medicine, University Hospital of Kuopio, Kuopio, Finland (R.R.).
Rainer
R
Rauramaa
Department of Medicine, University Medical Center Groningen, University of Groningen, The Netherlands (A.J.S.).
Andries J
AJ
Smit
Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Clinical and Experimental Medicine, University of Perugia, Italy (E.M.).
Elmo
E
Mannarino
Assistance Publique - Hopitaux de Paris, Service Endocrinologie-Metabolisme, Groupe Hôpitalier Pitie-Salpetriere, Unités de Prévention Cardiovasculaire, Paris, France (P.G.).
Philippe
P
Giral
Centre for Cardiovascular Genetics, University College London, London, United Kingdom (S.E.H.).
Steve E
SE
Humphries
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy (D.B., E.T.) Centro Cardiologico Monzino, IRCCS, Milan, Italy (D.B., F.V., E.T.).
Elena
E
Tremoli
Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (K.L., B.G., U.F.).
Ulf
U
de Faire
Department of Medical Sciences, Uppsala University, Uppsala, Sweden (L.L.).
Lars
L
Lind
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden (S.G., E.I.).
Erik
E
Ingelsson
Clinical Research Center, Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Sweden (C.F., B.H., O.M.).
Bo
B
Hedblad
Clinical Research Center, Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Sweden (C.F., B.H., O.M.).
Olle
O
Melander
Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, London, United Kingdom (M.K., A.H.).
Meena
M
Kumari
Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, London, United Kingdom (M.K., A.H.).
Aroon
A
Hingorani
Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, United Kingdom (N.V.Z., A.D.M., C.A.P.).
Andrew D
AD
Morris
Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, United Kingdom (N.V.Z., A.D.M., C.A.P.).
Colin N A
CN
Palmer
Division of Cardiovascular Medicine, Department of Clinical Sciences, Karolinska Institutet, Danderyd University Hospital, Stockholm, Sweden (J.P., B.G., P.L.).
Pia
P
Lundman
Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden (R.J.S., O.M.L., K.G., A.S., B.S., M.S.L., J., A.H.).
John
J
Öhrvik
Division of Medicine, Department of Public Health and Clinical Medicine, University of Umeå, Sweden (S.).
Stefan
S
Söderberg
Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden (R.J.S., O.M.L., K.G., A.S., B.S., M.S.L., J., A.H.).
Anders
A
Hamsten
D052242:Adiponectin / Q000097:blood* / Q000235:genetics; D000368:Aged; D015415:Biomarkers / Q000097:blood; D002340:Carotid Artery Diseases / Q000097:blood* / Q000000981:diagnostic imaging* / Q000453:epidemiology / Q000235:genetics; D017536:Carotid Artery, Common / Q000000981:diagnostic imaging*; D059168:Carotid Intima-Media Thickness; D018450:Disease Progression; D005060:Europe / Q000453:epidemiology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011379:Prognosis; D065840:Protective Factors; D018570:Risk Assessment; D012307:Risk Factors; D012737:Sex Factors; D013997:Time Factors
C499918:ADIPOQ protein, human; D052242:Adiponectin; D015415:Biomarkers
Mendelian randomization; adiponectin; atherosclerosis; carotid intima‐media thickness; genetics