Aim Rheumatic heart disease (RHD) is an inflammatory autoimmune disease, occurring as a sequel of exaggerated host immune response to cross reactive group A streptococcal infection in an susceptible host. Natural killer (NK) cells play a crucial role in modulating innate and adaptive immune responses against infection. Since polymorphic killer cell Ig-like receptors (KIR) regulate NK cell response, we investigate if any KIR genes are associated with RHD. Methods Blood samples were collected from 90 RHD patients enrolled in Govt. Rajaji Hospital, Madurai, India, along with their 117 healthy siblings with their consent. Based on echocardiography data, patients were further classified as those with mitral valvular lesions (MVL) (N = 63) or with combined valvular lesions (CVL) (N = 22). Five patients had only rheumatic fever without valvular damage. Genomic DNA was extracted and KIR genes were typed by duplex SSP method. Unusual KIR genotypes were further confirmed by One Lambda rSSO method. Comparisons were made by two-tailed Fisher’s exact probabilities (p), with p Results No difference was observed in the frequencies of any KIR genes between RHD and sibling controls (see Fig). Compared to siblings, a slight decrease was observed in the frequencies of 3DL1 and 2DS4 in RHD patients, and the decrease was statistically significant in CVL subset. Moreover, 80% of CVL patients carried 4 activating KIRs (2DS5, 2DS1, 3DS1, 2DS2), while only 51% of siblings 41% of MVL group carried these activating KIRs. Conclusions A decreased frequency of inhibitory 3DL1 and increased frequency of 4 activating KIRs in CVL group suggest that a dominant activating KIR repertoire may involve in the pathogenesis of CVL phenotype. Further analyses with more CVL patients as well as typing of HLA ligands and 3DL1 and 2DS4 subtypes are necessary to substantiate this clinically relevant genetic association. Download : Download high-res image (409KB) Download : Download full-size image