Shared and non-shared familial susceptibility of coronary heart disease, ischemic stroke, peripheral artery disease and aortic disease ☆ Susanna Calling a, 1 , Jianguang Ji a, 1 , Jan Sundquist a, b, 1 , Kristina Sundquist a, b, 1 , Bengt Zöller a, ⁎ , 1 a Center for Primary Health Care Research, Lund University/Region Skåne, Malmö, Sweden b Stanford Prevention Research Centre, Stanford University School of Medicine, Stanford, CA, USA abstract article info Article history: Received 8 June 2012 Received in revised form 14 March 2013 Accepted 30 March 2013 Available online 30 April 2013 Keywords: Coronary heart disease Ischemic stroke Peripheral artery disease Aortic disease Genetics Background: Little is known about whether the four main manifestations of arterial vascular disease (coronary heart disease = CHD, ischemic stroke, peripheral artery disease = PAD, and aortic (i.e. atherosclerosis/aneurysm) disease = AD) share familial susceptibility. The aim of this nationwide study was to determine the familial risks of concordant (same disease in proband and exposed relative) and discordant (different disease in proband and ex- posed relative) cardiovascular disease (CVD). Methods: Data from the Swedish Multigeneration Register on individuals aged 0–76 years were linked to Swedish Hospital Discharge Register data for the period 1964–2008. Standardized incidence ratios (SIRs) for CHD (n = 140,708 cases), ischemic stroke (n = 73,771), PAD (n = 18,982) and AD (n = 7879) were calculated for siblings of individuals hospitalized due to CHD, stroke, PAD or AD compared to those of unaffected siblings. The procedure was repeated for parent–offspring and spouses. Results: All concordant and discordant sibling risks were increased for both males and females. Concordant risks were generally higher than discordant risks. The highest sibling risks were observed for premature concordant disease (b 55 years for males and b 65 years for females): SIR for CHD = 1.93 (95% CI: 1.90–1.96), SIR for ische- mic stroke = 1.45 (1.39–1.50), SIR for PAD = 2.76 (2.54–3.00), and SIR for AD = 6.36 (5.28–7.59). Premature parent–offspring transmission followed the same pattern. The disease risk was modestly increased in spouses, highest for AD (SIR = 1.48 (1.28–1.69)) and PAD (SIR = 1.27 (1.21–1.32)). Conclusions: The four main manifestations of CVD share familial susceptibility, but unique site-specific familial factors may exist. © 2013 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Atherosclerotic arterial vascular disease and its complications in the form of subsequent coronary, cerebral, aortic and peripheral arte- rial disease are major causes of death and disability globally [1–3]. Atherosclerotic cardiovascular diseases (CVD) has a complex etiology [1–3]. In addition to lifestyle and environmental risk factors, genetic factors contribute to the risk of atherosclerotic disease [1–3]. Familial aggregation has been reported for coronary heart disease (CHD) [4], ischemic stroke [5–7], aortic (atherosclerosis/aneurysm) disease (AD) [8–10], peripheral arterial disease (PAD) [11,12], and overall CVD [13,14]. Atherosclerosis is regarded as a generalized disease [15,16]. For instance, stroke, PAD and CHD are all associated with each other. In most individuals with atherosclerosis, several anatomic sites are af- fected [15,16]. However, in some individuals, only a few parts of the arterial system are affected [15,16]. Genome-wide association studies (GWASs) have shown that genetic variants on chromosome 9p21 are associated not only with coronary artery disease (CAD), but also stroke, abdominal aortic aneurysm and PAD [17]. The pathogenetic mechanisms are incompletely understood. Other gene variants are associated with CHD, but not with stroke [17]. Thus, it is possible that different gene variants may selectively predispose individuals to certain atherosclerotic manifestations. However, little is known about whether shared familial susceptibility to arterial vascular dis- ease is different for different locations in the arterial system. It has International Journal of Cardiology 168 (2013) 2844–2850 Abbreviations: AD, aortic disease; CAD, coronary artery disease; CI, confidence interval; CHD, coronary heart disease; CVD, cardiovascular disease; GWAS, genome-wide association study; ICD, international classification of diseases; PAD, peripheral artery disease; SIR, standardized incidence ratios. ☆ Research support: This work was supported by grants to Bengt Zöller from the Swedish Heart and Lung Foundation and Region Skåne (REGSKANE-124611), to Dr Kristina Sundquist from the Swedish Research Council (K2009-70X-15428-05-3; K2012-70X- 15428-08-3), to Dr Jan Sundquist from the Swedish Council for Working Life and Social Re- search (2007-1754) and the Swedish Freemasons Foundation as well as ALF funding from Region Skåne awarded to Bengt Zöller, Jan Sundquist and Kristina Sundquist. No funding bodies played any role in the design, writing or decision to publish this manuscript. ⁎ Corresponding author at: Center for Primary Health Care Research, CRC, Building 28, Entrance 72, Floor 11, Skåne University Hospital, S-205 02 Malmö, Sweden. Tel.: +46 40 391954, +46 70 6691476 (mobile); fax: +46 40 391370. E-mail address: bengt.zoller@med.lu.se (B. Zöller). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.03.149 Contents lists available at ScienceDirect International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard