Genetic variants of Klotho have been reported to be associated with human longevity and atherosclerotic vascular events and risk factors. However, very few studies have explored their association with ischemic stroke. We hypothesized that the functional KL-VS and the exonic C1818T variants of Klotho gene may be associated with ischemic stroke in Indian population. We enrolled a total of 460 patients with ischemic stroke and 574 age- and gender-matched controls for the study. Genotyping was done by polymerase chain reaction and restriction fragment length polymorphism. Contrary to other Asian reports, KL-VS variant was polymorphic in our population, with a frequency distribution similar to that of Caucasians. The frequency distribution of the C1818T variant was similar to previously reports in Asians. A differential effect of age on association of Klotho KL-VS variant with ischemic stroke was observed. In subjects aged <= 40 years, the KL-VS homozygotes, 352FF and 352VV, had similar to 1.5-fold (OR = 1.57; 95% CI: 1.02-2.40, p = 0.038) and similar to 3-fold (OR = 3.29; 95%CI: 1.02-10.56, p = 0.046) higher risk of stroke compared to heterozygotes, whereas in the older group (aged > 40 years) no significant association was observed. The C1818T variant was not associated with ischemic stroke. We conclude that KL-VS homozygosity could contribute to early-onset stroke in India. Larger studies in other ethnic populations are warranted to determine the role of these gene variants in the etiology of stroke occurring in the young. (C) 2010 Elsevier Inc. All rights reserved.