ARTICLE Effect of the SORT1 low-density lipoprotein cholesterol locus is sex-specific in a fit, Canadian young-adult population Angela Karlos, Jane Shearer, Elizabeth Gnatiuk, Chiatogu Onyewu, Gina Many, Eric P. Hoffman, and Dustin S. Hittel Abstract: The SORT1 locus was originally identified by genome-wide association studies of low-density lipoprotein cholesterol (LDL-C) in adults. Although the effect sizes of this locus are relatively small, we hypothesized that a younger population would show a greater genetic effect because of fewer confounding variables. As such, we investigated the association between the SORT1 locus and LDL-C in a group of healthy young adults. Subjects (n = 122, mean age = 23.2 years) were recruited from the University of Calgary. Lipid measures and genomic DNA were collected from peripheral blood after an overnight fast. Blood pressure, percent body fat (%BF), and maximal oxygen consumption were also measured. Associations between genotype and LDL-C were investigated using linear regression. Nearly one half (42.9%) of the female and 21.7% of the male subjects had a %BF that was above a healthy range. More than one quarter of the subjects had LDL-C values that were considered nonoptimal. Although the association was not significant when both sexes were combined, a significant association was observed between the SORT1 locus (GG: 2.46 ± 0.11 mmol·L −1 vs. GT–TT: 2.06 ± 0.12 mmol·L −1 , p = 0.016) and LDL-C in male subjects, with genotype explaining 3.0% of the variability in LDL-C. A high prevalence of nonoptimal LDL-C exists in this young population even though it is otherwise fit and healthy. A significant association was found between LDL-C and the minor SORT1 allele in male subjects, with an effect size larger than previously reported in older populations. SORT1 is a valuable target for identifying individuals who would most benefit from early interventions to prevent cardiovascular disease. Key words: SORT1, LDL cholesterol, cardiovascular disease, prevention. Résumé : Le locus du SORT1 a été originellement identifié dans les études d'associations pangénomiques du cholestérol LDL (LDL-C) et chez les adultes. Bien que l'ampleur des effets de ce locus soit relativement faible, nous avançons l'hypothèse selon laquelle l'impact génétique est plus grand sur une population plus jeune, et ce, a ` cause du moins grand nombre de variables de confusion. Ainsi donc, nous analysons l'association entre le locus du SORT1 et le LDL-C chez de jeunes adultes en bonne santé. Les sujets (n = 122, âge moyen = 23,2 ans) sont recrutés a ` l'Université de Calgary. Après un jeûne d'une nuit, on prélève des échantillons de sang en périphérie pour analyser les lipides et l'ADN génomique. On évalue aussi la pression artérielle, le pourcentage de gras (%BF) et le consommation maximale d'oxygène. On évalue les associations entre le génotype et le LDL-C au moyen d'une analyse de régression linéaire. Près de la moitié des femmes (42,9 %) et du quart des hommes (21,7 %) présentent un %BF supérieur a ` la norme santé. Plus d'un quart des sujets présentent des valeurs de LDL-C dites non optimales. Même si l'association n'est pas significative après la combinaison des deux sexes, on observe une association significative entre le locus du SORT1 (GG: 2,46 ± 0,11 mmol·L –1 versus GT/TT: 2,06 ± 0,12 mmol·L –1 , p = 0,016) et le LDL-C chez les hommes; le génotype explique 3,0 % de la variation de LDL-C. On observe une forte prévalence de LDL-C dit non optimal même si cette jeune population est en santé et en bonne condition physique. On observe une association significative entre le LDL-C et l'allèle mineur du SORT1 chez les hommes et l'ampleur de l'effet est plus prononcée que celle rapportée dans les populations plus âgées. Le gène SORT1 est une cible de choix a ` retenir pour pointer les sujets qui profiteraient d'interventions précoces pour la prévention de maladies cardiovasculaires. [Traduit par la Rédaction] Mots-clés : SORT1, LDL-cholestérol, maladie cardiovasculaire, prévention. Introduction Cardiovascular disease (CVD) has been reported to be the over- all leading cause of death and disability globally (Mendis et al. 2011) and is the second-leading cause of death in Canada (Statistics Canada 2011). CVD places the greatest economic burden on the Canadian health care system, with direct and indirect estimates of up to $22 billion annually (Manuel et al. 2003; Genest et al. 2009). Absolute mortality rates of CVD have declined over the past 50 years because of more efficacious primary and secondary pre- vention measures (Genest et al. 2009; Roger et al. 2011). However, the rate of this decline in CVD mortality has slowed and morbidity associated with CVD remains high (Genest et al. 2009; Roger et al. 2011). Among the risk factors (RFs) for CVD, low-density lipoprotein cho- lesterol (LDL-C) concentration remains one of the strongest and is currently the primary target of risk management and reduction in both Canada and the United States (National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) 2002; Genest et al. 2009). Over the past 30 years, a substantial body of evidence has also shown that atherosclerosis and the development of CVD begin in childhood (Loria et al. 2007; Juonala et al. 2010; Pletcher et al. 2010). Therefore, given the plateau in the rate of decline in CVD mortality and the sustained high morbidity, novel CVD prevention strategies are needed that halt or reverse the development of athero- sclerosis much earlier in the disease pathogenesis. Received 19 June 2012. Accepted 18 July 2012. A. Karlos, J. Shearer, E. Gnatiuk, and D.S. Hittel. Faculty of Kinesiology, University of Calgary, 2500 University Drive, Calgary, AB T2N 1N4, Canada. C. Onyewu, G. Many, and E.P. Hoffman. Children's National Medical Center, Research Center for Genetic Medicine, 111 Michigan Ave. NW, Washington, DC, 20010, USA. Corresponding author: Dustin S. Hittel (e-mail: dhittel@kin.ucalgary.ca). 188 Appl. Physiol. Nutr. Metab. 38: 188–193 (2013) dx.doi.org/10.1139/apnm-2012-0231 Published at www.nrcresearchpress.com/apnm on 1 November 2012. Appl. Physiol. Nutr. Metab. Downloaded from www.nrcresearchpress.com by UNIV CALGARY on 02/26/13 For personal use only.