Lipoprotein (a) concentrations, apolipoprotein (a) phenotypes, and peripheral arterial disease in three independent cohorts.
OBJECTIVE
The relevance of lipoprotein(a) [Lp(a)] concentrations and low-molecular-weight (LMW) apo(a) phenotypes in peripheral arterial disease (PAD) has only been investigated by few studies. Therefore, we analysed this association in three independent cohorts and performed a Mendelian Randomization approach using instrumental variable regression.


RESULTS
Lp(a) concentrations, apo(a) phenotypes, and one SNP in the LPA gene (rs10455872) were measured in the CAVASIC study, including 241 male patients with intermittent claudication and 246 age- and diabetes-matched controls as well as in the two population-based studies KORA F3 (n = 3184) and KORA F4 (n = 3080). In KORA F3/F4, 109/80 persons suffered from intermittent claudication, 200/144 from PAD, and 128/103 showed an ankle-brachial index (ABI) <0.9. In CAVASIC, adjusted logistic regression analyses revealed significant associations between an increase of log-Lp(a) per one standard deviation (SD) (OR = 1.28, P = 0.02) as well as LMW apo(a) phenotypes and symptomatic PAD (OR = 1.65, P = 0.03). Linear regression models with continuous ABI showed a significant association in the combined analyses of KORA F3/F4: an increase in log-Lp(a) per one SD (β = -0.006, P = 0.005) and the presence of LMW apo(a) phenotypes (β = -0.011, P = 0.02) or the minor allele of rs10455872 (ß = -0.016, P = 0.03) were associated with a decrease in ABI in the fully adjusted linear and instrumental variable regression models.


CONCLUSIONS
Analyses in three independent populations showed significant associations of Lp(a) concentrations, LMW apo(a) phenotypes, and rs10455872 with PAD. This points to a causal relationship between Lp(a) and PAD since the genetically determined apo(a) phenotypes and SNP alleles are indeed associated with PAD.
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Schöpfstr. 41, A-6020 Innsbruck, Austria.
Anja
A
Laschkolnig
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Schöpfstr. 41, A-6020 Innsbruck, Austria.
Barbara
B
Kollerits
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Schöpfstr. 41, A-6020 Innsbruck, Austria.
Claudia
C
Lamina
Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Institute of Epidemiology II, Neuherberg, Germany.
Christa
C
Meisinger
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Schöpfstr. 41, A-6020 Innsbruck, Austria Department of Vascular Surgery, Innsbruck Medical University, Innsbruck, Austria.
Barbara
B
Rantner
Third Medical Department of Metabolic Diseases and Nephrology, Hietzing Hospital, Vienna, Austria.
Marietta
M
Stadler
Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Institute of Epidemiology II, Neuherberg, Germany.
Annette
A
Peters
Department of Internal Medicine II - Cardiology, University of Ulm Medical Center, Ulm, Germany.
Wolfgang
W
Koenig
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Schöpfstr. 41, A-6020 Innsbruck, Austria.
Andrea
A
Stöckl
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Schöpfstr. 41, A-6020 Innsbruck, Austria.
Doreen
D
Dähnhardt
Department of Internal Medicine II, University Medical Center Regensburg, Regensburg, Germany.
Carsten A
CA
Böger
Vth Department of Medicine, University Medicine Mannheim, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany.
Bernhard K
BK
Krämer
Department of Vascular Surgery, Innsbruck Medical University, Innsbruck, Austria.
Gustav
G
Fraedrich
Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Institute of Genetic Epidemiology, Neuherberg, Germany Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Institute of Medical Informatics, Munich, Germany.
Konstantin
K
Strauch
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Schöpfstr. 41, A-6020 Innsbruck, Austria florian.kronenberg@i-med.ac.at.
Florian
F
Kronenberg
D000328:Adult; D000368:Aged; D055109:Ankle Brachial Index; D053241:Apoprotein(a) / Q000097:blood* / Q000737:chemistry / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007383:Intermittent Claudication / Q000097:blood / Q000235:genetics / Q000503:physiopathology; D016014:Linear Models; D017270:Lipoprotein(a) / Q000097:blood* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008970:Molecular Weight; D058729:Peripheral Arterial Disease / Q000097:blood* / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
D017270:Lipoprotein(a); D053241:Apoprotein(a)
Ankle-brachial index; Apolipoprotein(a) phenotypes; Causality; Lp(a) concentrations; Mendelian randomization; Peripheral arterial disease