Linkage and Association Analysis Identifies TRAF1 Influencing Common Carotid Intima-Media Thickness

Nicole Heßler; Marie Henrike Geisel; Stefan Coassin; Raimund Erbel; Stefanie Heilmann; Frauke Hennig; Barbara Hoffmann; Karl-Heinz Jöckel; Susanne Moebus; Susanna Moskau-Hartmann; Gudrun Nürnberg; Peter Nürnberg; Maren Vens; Thomas Klockgether; Florian Kronenberg; André Scherag; Andreas Ziegler

doi:10.1161/STROKEAHA.116.013943

Linkage and Association Analysis Identifies TRAF1 Influencing Common Carotid Intima-Media Thickness

Stroke. 2016 Dec;47(12):2904-2909. doi: 10.1161/STROKEAHA.116.013943. Epub 2016 Nov 8.

Authors

Nicole Heßler¹, Marie Henrike Geisel¹, Stefan Coassin¹, Raimund Erbel¹, Stefanie Heilmann¹, Frauke Hennig¹, Barbara Hoffmann¹, Karl-Heinz Jöckel¹, Susanne Moebus¹, Susanna Moskau-Hartmann¹, Gudrun Nürnberg¹, Peter Nürnberg¹, Maren Vens¹, Thomas Klockgether¹, Florian Kronenberg¹, André Scherag¹, Andreas Ziegler²

Affiliations

¹ From the Institute of Medical Biometry and Statistics (IMBS), University of Lübeck, University Medical Center Schleswig-Holstein, Campus Lübeck, Germany (N.H., M.V., A.Z.); Clinical Epidemiology, Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Germany (M.H.G., A.S.); Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University of Duisburg-Essen, Germany (M.H.G., R.E., K.-H.J., S.M.); Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Austria (S.C., F.K.); Institute of Human Genetics (S.H.) and Department of Epileptology (S.M.-H.), University of Bonn, Germany; Department of Genomics, Life & Brain Research Center, Bonn, Germany (S.H.); Institute of Occupational, Social and Environmental Medicine, Center for Health and Society, Faculty of Medicine, University of Düsseldorf, Germany (F.H., B.H.); Department of Neurology, University Hospital Bonn, Germany (S.M.-H., T.K.); Cologne Center of Genomics, University of Cologne, Germany (G.N., P.N.); Department of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Germany (M.V.); Center for Clinical Trials, University of Lübeck, Germany (A.Z.); and School of Mathematics, Statistics and Computer Science, University of KwaZulu-Natal, Pietermaritzburg, South Africa (A.Z.).
² From the Institute of Medical Biometry and Statistics (IMBS), University of Lübeck, University Medical Center Schleswig-Holstein, Campus Lübeck, Germany (N.H., M.V., A.Z.); Clinical Epidemiology, Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Germany (M.H.G., A.S.); Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University of Duisburg-Essen, Germany (M.H.G., R.E., K.-H.J., S.M.); Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Austria (S.C., F.K.); Institute of Human Genetics (S.H.) and Department of Epileptology (S.M.-H.), University of Bonn, Germany; Department of Genomics, Life & Brain Research Center, Bonn, Germany (S.H.); Institute of Occupational, Social and Environmental Medicine, Center for Health and Society, Faculty of Medicine, University of Düsseldorf, Germany (F.H., B.H.); Department of Neurology, University Hospital Bonn, Germany (S.M.-H., T.K.); Cologne Center of Genomics, University of Cologne, Germany (G.N., P.N.); Department of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Germany (M.V.); Center for Clinical Trials, University of Lübeck, Germany (A.Z.); and School of Mathematics, Statistics and Computer Science, University of KwaZulu-Natal, Pietermaritzburg, South Africa (A.Z.). ziegler@imbs.uni-luebeck.de.

PMID: 27827325
DOI: 10.1161/STROKEAHA.116.013943

Abstract

Background and purpose: Carotid intima-media thickness is a marker for subclinical atherosclerosis that predicts subsequent clinical cardiovascular events. The aim of this study was to identify chromosomal loci with linkage or association to common carotid intima-media thickness.

Methods: Nuclear families were recruited using the single parental proband sib-pair design. Genotype data were available for 546 individuals from 132 nuclear families of the Bonn IMT Family Study using the Affymetrix GeneChip Human Mapping 250K Sty chip. Multipoint logarithm of the odds (LOD) scores were determined with the quantitative trait locus statistic implemented in multipoint engine for rapid likelihood. Linkage analysis and family-based association tests were conducted. Data from 2471 German participants from the HNR (Heinz Nixdorf Recall) Study were used for subsequent replication.

Results: Two new genomic regions with suggestive linkage (LOD>2) were identified on chromosome 4 (LOD=2.26) and on chromosome 17 (LOD=2.01). Previously reported linkage findings were replicated on chromosomes 13 and 14. Fifteen single nucleotide polymorhisms, located on chromosomes 4, 6, and 9, revealed P<10^-4 in the family-based association analyses. One of these signals was replicated in HNR (rs2416804, 1-sided P=1.60×10^-3, located in the gene TRAF1).

Conclusions: This study presents the first genome-wide linkage and association study of common carotid intima-media thickness in the German population. Alleles of rs2416804 in TRAF1 were identified as being linked and associated with carotid intima-media thickness. Further studies are needed to evaluate the contribution of this locus to the development of atherosclerosis.

Keywords: association analysis; atherosclerosis; intima–media thickness; linkage; replication.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Atherosclerosis / genetics*
Carotid Intima-Media Thickness*
Female
Genetic Linkage
Genome-Wide Association Study
Germany
Humans
Male
Middle Aged
Nuclear Family
TNF Receptor-Associated Factor 1 / genetics*

Substances

TNF Receptor-Associated Factor 1