BRIEF COMMUNICATION Association of the lymphotoxin-a gene Thr26Asn polymorphism with severity of coronary atherosclerosis R Laxton 1 , E Pearce 1 , T Kyriakou 1 and S Ye 1 1 Human Genetics Division, School of Medicine, University of Southampton, Southampton, UK A recent large-scale, genome-wide association study of single nucleotide polymorphisms showed a strong association between susceptibility to myocardial infarction and the Thr26Asn polymorphism in the lymphotoxin-a (LTA) gene. In the present study, we investigated whether the LTA Thr26Asn polymorphism was associated with the extent of coronary atherosclerosis in a large cohort (n ¼ 1082) of well-documented coronary artery disease patients. Thr26Asn genotypes showed a significant different distribution in male patients, when stratified according to the number of diseased coronary arteries, with an odds ratio of 1.98 (95% CI 1.22–3.22) for multiple-vessel disease in patients of the Asn/Asn genotype, compared with patients of the Thr/Thr or Thr/Asn genotype (P ¼ 0.006). Thus, further to the recent finding that LTA gene variation is associated with susceptibility to coronary heart disease, the present study provides evidence of an association between LTA genotype and the extent of coronary atherosclerosis. Genes and Immunity (2005) 6, 539–541. doi:10.1038/sj.gene.6364236; published online 23 June 2005 Keywords: lymphotoxin-d; genetics; polymorphism; atherosclerosis Twin studies have indicated a significant genetic influence on the development of coronary artery disease (CAD). 1 The genetic basis for several Mendelian dis- orders that can lead to early-onset CAD has been elucidated, exemplified by familial hypercholesterolae- mia which is caused by mutations in the low-density lipoprotein receptor gene. 2,3 However, these Mendelian disorders only account for a small percentage of CAD patients. In the majority of cases, the disease is a result of the combined effect of multiple genetic and environ- mental factors, where each of the genetic factors makes a moderate contribution. 2–5 Recently, a large-scale, genome-wide association study of 65 671 gene-based single nucleotide polymorphisms in relation to myocardial infarction, a severe condition of CAD, was performed in a large group of Japanese cases (n ¼ 1133) and two control groups (n ¼ 1006 and 872, respectively). The study showed a strong association between susceptibility to myocardial infarction and polymorphisms in a 50 kb genomic region on chromosome 6p21 that contains the lymphotoxin-a (LTA) gene. 6 Among the polymorphisms examined, 804C4A (Thr26Asn) in exon 3 of the LTA gene showed the strongest association with the disease. 6 The association of the Thr26Asn polymorphism with susceptibility to CAD has been confirmed in a recent study of 400 Caucasian trio families, using the transmission disequilibrium test (TDT) method. 7 Inflammation plays important roles in both the development and progression of atherosclerosis, the vascular lesion underlying the majority of CAD. 8,9 LTA is an important proinflammatory cytokine and is expressed in atherosclerotic lesions. 10 It has been shown that LTA can induce the expression of a number of adhesion molecules and cytokines that are involved in atherogenesis. 6 Studies in mice fed an atherogenic diet showed that the area of atherosclerosis lesion in the aorta was significantly reduced (three-fold less) in LTA / mice than in LTA wild-type mice. 10 In this study, we examined the LTA gene Thr26Asn polymorphism in a cohort (n ¼ 1082) of Caucasian patients with angiographically confirmed coronary atherosclerosis and investigated whether this genetic variation was associated with the extent of coronary atherosclerosis. The study was approved by the local research ethics committee, and all subjects gave written consent. The characteristics of these patients have been described previously. 11 Coronary angiograms were ana- lyzed by a consultant cardiologist. The coronary arteries, divided into 16 segments, were examined for the presence of stenosis. Of the 1082 patients, 445 had 450% stenosis in one coronary artery (one vessel disease), 356 had 450% stenosis in two coronary arteries (two vessel disease), and 272 had 450% stenosis in three coronary arteries (three vessel disease). DNA was extracted from peripheral blood samples using the ‘salting out’ method, and the LTA gene 804C4A (Thr26Asn) polymorphism genotyped using the Ampli- fluor single nucleotide polymorphism genotyping sys- tem. Statistical analyses were carried in the sample as a whole, and then separately in male patients and female Received 20 April 2005; revised 17 May 2005; accepted 18 May 2005; published online 23 June 2005 Correspondence: Dr S Ye, Human Genetics Division, Duthie Building MP 808, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK. E-mail: sy1@soton.ac.uk Genes and Immunity (2005) 6, 539–541 & 2005 Nature Publishing Group All rights reserved 1466-4879/05 $30.00 www.nature.com/gene