Familial aggregation of red blood cell membrane fatty acid composition: the Kibbutzim Family Study Rozenn N. Lemaitre a, ⁎ , David S. Siscovick a,b , Elliot M. Berry c , Jeremy D. Kark d , Yechiel Friedlander d a Department of Medicine, Cardiovascular Health Research Unit, University of Washington, Seattle, WA 98101, USA b Department of Epidemiology, University of Washington, Seattle, WA 98101, USA c Department of Human Nutrition and Metabolism, Hebrew University-Hadassah School of Public Health, Jerusalem d Unit of Epidemiology, Hebrew University-Hadassah School of Public Health, Jerusalem Received 16 October 2007; accepted 12 December 2007 Abstract The fatty acid composition of membranes plays an important role in health and diseases. Whether genetic factors play a role in interindividual variability in membrane fatty acid levels has received limited attention. Using variance decomposition methods, we estimated the heritability of red blood cell (RBC) membrane fatty acids in an unselected population sample of 80 families (205 male and 212 female subjects) living in kibbutz settlements in Israel. Fatty acid levels were measured by gas chromatography. We estimated that polygenes explained 40% to 70% of the sex- and age-adjusted interindividual variability in all RBC fatty acids: saturated, monounsaturated, and polyunsaturated. The heritability estimates remained very similar after further adjustment for smoking, alcohol consumption, physical activity, lipoproteins, body mass index, waist to hip ratio, education, and religiosity. In bivariate genetic analyses, we observed positive genetic correlations for the fatty acid pairs 20:4n6-22:6n3 and 20:5n3-22:6n3, and negative genetic correlations for the pairs 16:0-20:4n6, 16:0-22:6n3, 18:1n9-20:3n6, 18:2n6-20:4n6, 18:2n6-24:0, and 20:3n6-20:4n6, suggesting that shared effects of the same sets of loci account for 12% to 30% of the additive genetic variance in these pairs of fatty acids. This study suggests a considerable polygenic component for all RBC membrane fatty acids and provides evidence that shared genetic effects account for the additive genetic variance in various fatty acid pairs. Future studies are needed to map the genes underlying the interindividual variation in these inherited phenotypes. © 2008 Elsevier Inc. All rights reserved. There is increasing evidence for the importance of the fatty acid composition of membranes in health and disease. For example, higher membrane levels of long-chain n-3 fatty acids from fatty fish are associated with lower risk of sudden cardiac arrest [1], preeclampsia [2], and cognitive decline [3,4]; higher membrane levels of trans isomers of linoleic acid are associated with higher risk of sudden cardiac arrest [5]; and several membrane fatty acids appear to influence the risk of breast cancer [6]. The influence of diet on specific membrane fatty acids is well known. In particular, membrane fatty acids that derive from the dietary intake of polyunsaturated fat exclusively (eg, linoleic acid) or mostly (eg, long-chain n-3 fatty acids) are markers of dietary intake [7-9]. In addition, we recently demonstrated that total fat intake influences the overall membrane fatty acid composition [10]. Whether genetic factors also play a role in interindividual variability in membrane fatty acid composition has received limited attention [11]. Our interest in this question comes in part from the observation of familial aggregation of sudden cardiac arrest [12,13] and the search for candidate genes that might account for this cluster within families. If heritability of membrane fatty acids can be demonstrated, it might explain in part the familial component of sudden cardiac arrest and help direct the search for new candidate genes. We took advantage of a family study conducted in a setting with limited dietary variation and with measures of cell membrane fatty acid composition, the Kibbutzim Family Study, to investigate the heritability of red blood cell (RBC) membrane fatty acid composition. Available online at www.sciencedirect.com Metabolism Clinical and Experimental 57 (2008) 662 – 668 www.metabolismjournal.com ⁎ Corresponding author. Cardiovascular Health Research Unit, Uni- versity of Washington, Seattle, WA 98101, USA. Tel.: +1 206 287 2780; fax: +1 206 287 2662. E-mail address: rozenl@u.washington.edu (R.N. Lemaitre). 0026-0495/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.metabol.2007.12.011