Cardiovascular Risk Factors and Ischemic Heart Disease: Is the Confluence of Risk Factors Greater Than the Parts? A Genetic Approach.
BACKGROUND
Cardiovascular risk factors tend to aggregate. The biological and predictive value of this aggregation is questioned and genetics could shed light on this debate. Our aims were to reappraise the impact of risk factor confluence on ischemic heart disease (IHD) risk by testing whether genetic risk scores (GRSs) associated with these factors interact on an additive or multiplicative scale, and to determine whether these interactions provide additional value for predicting IHD risk.


RESULTS
We selected genetic variants associated with blood pressure, body mass index, waist circumference, triglycerides, type-2 diabetes mellitus, high-density lipoprotein and low-density lipoprotein cholesterol, and IHD to create GRSs for each factor. We tested and meta-analyzed the impact of additive (synergy index) and multiplicative (βinteraction) interactions between each GRS pair in 1 case-control (n=6042) and 4 cohort studies (n=17 794) and evaluated the predictive value of these interactions. We observed 2 multiplicative interactions: GRSLDL·GRSTriglycerides (βinteraction=-0.096; SE=0.028) and nonpleiotropic GRSIHD·GRSLDL (βinteraction=0.091; SE=0.028). Inclusion of these interaction terms did not improve predictive capacity.


CONCLUSIONS
The confluence of low-density lipoprotein cholesterol and triglycerides genetic risk load has an additive effect on IHD risk. The interaction between low-density lipoprotein cholesterol and IHD genetic load is more than multiplicative, supporting the hazardous impact on atherosclerosis progression of the combination of inflammation and increased lipid levels. The capacity of risk factor confluence to improve IHD risk prediction is questionable. Further studies in larger samples are warranted to confirm and expand our results.
From the Cardiovascular Epidemiology and Genetics, IMIM, Barcelona, Spain (R.E., C.L.-G., I.S., G.L., S.S.-B., J.M.); Epidemiology and Public Health Network (CIBERESP), Barcelona, Spain (I.S.); National Institute for Health and Welfare, Helsinki, Finland (A.H., A.P., V.S.); Estonian Genome Center of Tartu University, Tartu, Estonia (K.L., M.A., K.F.); Research Unit, Nuestra Señora de la Candelaria University Hospital, Santa Cruz de Tenerife, Spain (A.C.d.L.); University of La Laguna, La Laguna, Spain (A.C.d.L.); Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain (M.S.); The New York Academy of Medicine (D.S.); and Skåne University Hospital Clinical Research Center, Malmö, Sweden (O.M.). relosua@imim.es.
Roberto
R
Elosua
From the Cardiovascular Epidemiology and Genetics, IMIM, Barcelona, Spain (R.E., C.L.-G., I.S., G.L., S.S.-B., J.M.); Epidemiology and Public Health Network (CIBERESP), Barcelona, Spain (I.S.); National Institute for Health and Welfare, Helsinki, Finland (A.H., A.P., V.S.); Estonian Genome Center of Tartu University, Tartu, Estonia (K.L., M.A., K.F.); Research Unit, Nuestra Señora de la Candelaria University Hospital, Santa Cruz de Tenerife, Spain (A.C.d.L.); University of La Laguna, La Laguna, Spain (A.C.d.L.); Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain (M.S.); The New York Academy of Medicine (D.S.); and Skåne University Hospital Clinical Research Center, Malmö, Sweden (O.M.).
Carla
C
Lluís-Ganella
From the Cardiovascular Epidemiology and Genetics, IMIM, Barcelona, Spain (R.E., C.L.-G., I.S., G.L., S.S.-B., J.M.); Epidemiology and Public Health Network (CIBERESP), Barcelona, Spain (I.S.); National Institute for Health and Welfare, Helsinki, Finland (A.H., A.P., V.S.); Estonian Genome Center of Tartu University, Tartu, Estonia (K.L., M.A., K.F.); Research Unit, Nuestra Señora de la Candelaria University Hospital, Santa Cruz de Tenerife, Spain (A.C.d.L.); University of La Laguna, La Laguna, Spain (A.C.d.L.); Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain (M.S.); The New York Academy of Medicine (D.S.); and Skåne University Hospital Clinical Research Center, Malmö, Sweden (O.M.).
Isaac
I
Subirana
From the Cardiovascular Epidemiology and Genetics, IMIM, Barcelona, Spain (R.E., C.L.-G., I.S., G.L., S.S.-B., J.M.); Epidemiology and Public Health Network (CIBERESP), Barcelona, Spain (I.S.); National Institute for Health and Welfare, Helsinki, Finland (A.H., A.P., V.S.); Estonian Genome Center of Tartu University, Tartu, Estonia (K.L., M.A., K.F.); Research Unit, Nuestra Señora de la Candelaria University Hospital, Santa Cruz de Tenerife, Spain (A.C.d.L.); University of La Laguna, La Laguna, Spain (A.C.d.L.); Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain (M.S.); The New York Academy of Medicine (D.S.); and Skåne University Hospital Clinical Research Center, Malmö, Sweden (O.M.).
Aki
A
Havulinna
From the Cardiovascular Epidemiology and Genetics, IMIM, Barcelona, Spain (R.E., C.L.-G., I.S., G.L., S.S.-B., J.M.); Epidemiology and Public Health Network (CIBERESP), Barcelona, Spain (I.S.); National Institute for Health and Welfare, Helsinki, Finland (A.H., A.P., V.S.); Estonian Genome Center of Tartu University, Tartu, Estonia (K.L., M.A., K.F.); Research Unit, Nuestra Señora de la Candelaria University Hospital, Santa Cruz de Tenerife, Spain (A.C.d.L.); University of La Laguna, La Laguna, Spain (A.C.d.L.); Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain (M.S.); The New York Academy of Medicine (D.S.); and Skåne University Hospital Clinical Research Center, Malmö, Sweden (O.M.).
Kristi
K
Läll
From the Cardiovascular Epidemiology and Genetics, IMIM, Barcelona, Spain (R.E., C.L.-G., I.S., G.L., S.S.-B., J.M.); Epidemiology and Public Health Network (CIBERESP), Barcelona, Spain (I.S.); National Institute for Health and Welfare, Helsinki, Finland (A.H., A.P., V.S.); Estonian Genome Center of Tartu University, Tartu, Estonia (K.L., M.A., K.F.); Research Unit, Nuestra Señora de la Candelaria University Hospital, Santa Cruz de Tenerife, Spain (A.C.d.L.); University of La Laguna, La Laguna, Spain (A.C.d.L.); Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain (M.S.); The New York Academy of Medicine (D.S.); and Skåne University Hospital Clinical Research Center, Malmö, Sweden (O.M.).
Gavin
G
Lucas
From the Cardiovascular Epidemiology and Genetics, IMIM, Barcelona, Spain (R.E., C.L.-G., I.S., G.L., S.S.-B., J.M.); Epidemiology and Public Health Network (CIBERESP), Barcelona, Spain (I.S.); National Institute for Health and Welfare, Helsinki, Finland (A.H., A.P., V.S.); Estonian Genome Center of Tartu University, Tartu, Estonia (K.L., M.A., K.F.); Research Unit, Nuestra Señora de la Candelaria University Hospital, Santa Cruz de Tenerife, Spain (A.C.d.L.); University of La Laguna, La Laguna, Spain (A.C.d.L.); Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain (M.S.); The New York Academy of Medicine (D.S.); and Skåne University Hospital Clinical Research Center, Malmö, Sweden (O.M.).
Sergi
S
Sayols-Baixeras
From the Cardiovascular Epidemiology and Genetics, IMIM, Barcelona, Spain (R.E., C.L.-G., I.S., G.L., S.S.-B., J.M.); Epidemiology and Public Health Network (CIBERESP), Barcelona, Spain (I.S.); National Institute for Health and Welfare, Helsinki, Finland (A.H., A.P., V.S.); Estonian Genome Center of Tartu University, Tartu, Estonia (K.L., M.A., K.F.); Research Unit, Nuestra Señora de la Candelaria University Hospital, Santa Cruz de Tenerife, Spain (A.C.d.L.); University of La Laguna, La Laguna, Spain (A.C.d.L.); Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain (M.S.); The New York Academy of Medicine (D.S.); and Skåne University Hospital Clinical Research Center, Malmö, Sweden (O.M.).
Arto
A
Pietilä
From the Cardiovascular Epidemiology and Genetics, IMIM, Barcelona, Spain (R.E., C.L.-G., I.S., G.L., S.S.-B., J.M.); Epidemiology and Public Health Network (CIBERESP), Barcelona, Spain (I.S.); National Institute for Health and Welfare, Helsinki, Finland (A.H., A.P., V.S.); Estonian Genome Center of Tartu University, Tartu, Estonia (K.L., M.A., K.F.); Research Unit, Nuestra Señora de la Candelaria University Hospital, Santa Cruz de Tenerife, Spain (A.C.d.L.); University of La Laguna, La Laguna, Spain (A.C.d.L.); Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain (M.S.); The New York Academy of Medicine (D.S.); and Skåne University Hospital Clinical Research Center, Malmö, Sweden (O.M.).
Maris
M
Alver
From the Cardiovascular Epidemiology and Genetics, IMIM, Barcelona, Spain (R.E., C.L.-G., I.S., G.L., S.S.-B., J.M.); Epidemiology and Public Health Network (CIBERESP), Barcelona, Spain (I.S.); National Institute for Health and Welfare, Helsinki, Finland (A.H., A.P., V.S.); Estonian Genome Center of Tartu University, Tartu, Estonia (K.L., M.A., K.F.); Research Unit, Nuestra Señora de la Candelaria University Hospital, Santa Cruz de Tenerife, Spain (A.C.d.L.); University of La Laguna, La Laguna, Spain (A.C.d.L.); Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain (M.S.); The New York Academy of Medicine (D.S.); and Skåne University Hospital Clinical Research Center, Malmö, Sweden (O.M.).
Antonio
A
Cabrera de León
From the Cardiovascular Epidemiology and Genetics, IMIM, Barcelona, Spain (R.E., C.L.-G., I.S., G.L., S.S.-B., J.M.); Epidemiology and Public Health Network (CIBERESP), Barcelona, Spain (I.S.); National Institute for Health and Welfare, Helsinki, Finland (A.H., A.P., V.S.); Estonian Genome Center of Tartu University, Tartu, Estonia (K.L., M.A., K.F.); Research Unit, Nuestra Señora de la Candelaria University Hospital, Santa Cruz de Tenerife, Spain (A.C.d.L.); University of La Laguna, La Laguna, Spain (A.C.d.L.); Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain (M.S.); The New York Academy of Medicine (D.S.); and Skåne University Hospital Clinical Research Center, Malmö, Sweden (O.M.).
Mariano
M
Sentí
From the Cardiovascular Epidemiology and Genetics, IMIM, Barcelona, Spain (R.E., C.L.-G., I.S., G.L., S.S.-B., J.M.); Epidemiology and Public Health Network (CIBERESP), Barcelona, Spain (I.S.); National Institute for Health and Welfare, Helsinki, Finland (A.H., A.P., V.S.); Estonian Genome Center of Tartu University, Tartu, Estonia (K.L., M.A., K.F.); Research Unit, Nuestra Señora de la Candelaria University Hospital, Santa Cruz de Tenerife, Spain (A.C.d.L.); University of La Laguna, La Laguna, Spain (A.C.d.L.); Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain (M.S.); The New York Academy of Medicine (D.S.); and Skåne University Hospital Clinical Research Center, Malmö, Sweden (O.M.).
David
D
Siscovick
From the Cardiovascular Epidemiology and Genetics, IMIM, Barcelona, Spain (R.E., C.L.-G., I.S., G.L., S.S.-B., J.M.); Epidemiology and Public Health Network (CIBERESP), Barcelona, Spain (I.S.); National Institute for Health and Welfare, Helsinki, Finland (A.H., A.P., V.S.); Estonian Genome Center of Tartu University, Tartu, Estonia (K.L., M.A., K.F.); Research Unit, Nuestra Señora de la Candelaria University Hospital, Santa Cruz de Tenerife, Spain (A.C.d.L.); University of La Laguna, La Laguna, Spain (A.C.d.L.); Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain (M.S.); The New York Academy of Medicine (D.S.); and Skåne University Hospital Clinical Research Center, Malmö, Sweden (O.M.).
Olle
O
Mellander
From the Cardiovascular Epidemiology and Genetics, IMIM, Barcelona, Spain (R.E., C.L.-G., I.S., G.L., S.S.-B., J.M.); Epidemiology and Public Health Network (CIBERESP), Barcelona, Spain (I.S.); National Institute for Health and Welfare, Helsinki, Finland (A.H., A.P., V.S.); Estonian Genome Center of Tartu University, Tartu, Estonia (K.L., M.A., K.F.); Research Unit, Nuestra Señora de la Candelaria University Hospital, Santa Cruz de Tenerife, Spain (A.C.d.L.); University of La Laguna, La Laguna, Spain (A.C.d.L.); Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain (M.S.); The New York Academy of Medicine (D.S.); and Skåne University Hospital Clinical Research Center, Malmö, Sweden (O.M.).
Krista
K
Fischer
From the Cardiovascular Epidemiology and Genetics, IMIM, Barcelona, Spain (R.E., C.L.-G., I.S., G.L., S.S.-B., J.M.); Epidemiology and Public Health Network (CIBERESP), Barcelona, Spain (I.S.); National Institute for Health and Welfare, Helsinki, Finland (A.H., A.P., V.S.); Estonian Genome Center of Tartu University, Tartu, Estonia (K.L., M.A., K.F.); Research Unit, Nuestra Señora de la Candelaria University Hospital, Santa Cruz de Tenerife, Spain (A.C.d.L.); University of La Laguna, La Laguna, Spain (A.C.d.L.); Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain (M.S.); The New York Academy of Medicine (D.S.); and Skåne University Hospital Clinical Research Center, Malmö, Sweden (O.M.).
Veikko
V
Salomaa
From the Cardiovascular Epidemiology and Genetics, IMIM, Barcelona, Spain (R.E., C.L.-G., I.S., G.L., S.S.-B., J.M.); Epidemiology and Public Health Network (CIBERESP), Barcelona, Spain (I.S.); National Institute for Health and Welfare, Helsinki, Finland (A.H., A.P., V.S.); Estonian Genome Center of Tartu University, Tartu, Estonia (K.L., M.A., K.F.); Research Unit, Nuestra Señora de la Candelaria University Hospital, Santa Cruz de Tenerife, Spain (A.C.d.L.); University of La Laguna, La Laguna, Spain (A.C.d.L.); Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain (M.S.); The New York Academy of Medicine (D.S.); and Skåne University Hospital Clinical Research Center, Malmö, Sweden (O.M.).
Jaume
J
Marrugat
D001794:Blood Pressure / Q000235:genetics; D015992:Body Mass Index; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics; D050171:Dyslipidemias / Q000097:blood* / Q000453:epidemiology / Q000235:genetics*; D056726:Genetic Association Studies; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D006973:Hypertension / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology; D008055:Lipids / Q000097:blood; D017202:Myocardial Ischemia / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D009765:Obesity / Q000453:epidemiology / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D012307:Risk Factors; D055105:Waist Circumference / Q000235:genetics
D005819:Genetic Markers; D008055:Lipids
genetic association studies; genetic variation; regression analysis; risk assessment; risk factors