Polymorphisms of IL-1, IL-1Ra, and TNF- Genes: A Nested Case-Control Study of Their Association With Risk for Stroke Jasmina Trifunovic Cvetkovic, MSci,* Per Gunnar Wiklund, MD,† Ejaz Ahmed, MD,* Lars Weinehall, MD, PhD,‡ Göran Hallmans, MD, PhD,§ and Ann Kari Lefvert, MD, PhD* Certain alleles of cytokine genes interleukin-1 beta (IL-1), interleukin-1 receptor antagonist (IL-1Ra), and tumor necrosis factor alpha (TNF-) are correlated with increased production of the proteins. The aim of this study was to investigate polymorphisms of these genes and their possible correlation with the development of stroke. This matched case-control study was nested within the population-based Västerbotten Intervention Program (VIP) cohort and the Northern Sweden World Health Organization MONICA (Multinational Monitoring of Trends and Determi- nants in Cardiovascular Diseases) cohort, based on individuals who were free from cardiovascular events when the cohorts were established. After an average period of 34.1 months, 113 individuals developed stroke and to each case 2 individuals not suffering from cardiovascular events were matched to serve as controls. Polymer- ase chain reaction amplification was used to analyze genetic polymorphisms. There was no association between polymorphic sites of the IL-1 and IL-1Ra genes and stroke. Carriage of haplotype A2 + IL-1/A2 + IL-1Ra was significantly increased in normotensive cases (23.1%) compared with normotensive controls (8.9%) (odds ratio [OR] = 3.07; P = .045). In hypertensive male cases, there was an association between the A1A1 genotype of TNF- and risk of stroke (OR = 2.46; P = .034). Our findings indicate an association between allele A1 of the TNF- NcoI polymor- phism and stroke in hypertensive male cases, as well as an association between haplotype A2 + IL-1/A2 + IL-1Ra and stroke in normotensive cases. Key Words: Rheumatoid arthritis—IL-1—TNF—IL-1Ra— genetic polymorphisms. © 2005 by National Stroke Association To date, genetic studies of stroke have focused mainly on the genes involved in the regulation of blood pres- sure, because hypertension is a leading risk factor for this condition. 1 Investigations have been performed on the angiotensin-converting enzyme (ACE) insertion/ deletion polymorphism of the gene (ACE D/I poly- morphism), 2 and on the polymorphisms in the genes of angiotensinogen and angiotensin II type 1 receptor gene. 3 Studies of ACE D/I polymorphism in the Fra- mingham Heart Study showed association of the DD genotype with increased diastolic blood pressure in men, but not in women. 4 Stroke is related to the development of atherosclero- sis, a process that has been increasingly recognized as having immune/inflammatory components. Patients with inflammatory disorders, such as rheumatoid ar- thritis, have a high incidence of premature cardiovas- From *The Immunological Research Unit, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden and Sections of †Medicine, ‡Epidemiology, and §Nutritional Research, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden. Received September 22, 2004; accepted October 14, 2004. Supported by grants from the Swedish Heart-Lung Foundation (grant 71337, to A.K.L.), Swedish Medical Research Council (grant 27Y-12689-02B, to G.H.), the Stroke Fund, the Joint Committee of the Northern Sweden Health Care Region, the Norrbotten and Väster- botten County Councils, the King Gustaf Vth 80-years Foundation and Queen Victoria’s Foundation, the Åke Wiberg Foundation, the Nanna Svartz Foundation, and the Magnus Bergwall Foundation. Address reprint requests to Ann Kari Lefvert, MD, PhD, Immu- nological Research Unit, CMM L8/03, Karolinska Hospital, 171 76 Stockholm, Sweden. E-mail: Ann.Kari.Lefvert@cmm.ki.se. 1052-3057/$—see front matter © 2005 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2004.10.004 Journal of Stroke and Cerebrovascular Diseases, Vol. 14, No. 1 (January-February), 2005: pp 29 –35 29