Association study of inflammatory genes with rheumatic heart disease in North Indian population: A multi-analytical approach.
Rheumatic heart disease (RHD) is an inflammatory, autoimmune disease; occurring as a consequence of group A streptococcal infection complicated by rheumatic fever (RF). An inappropriate immune response is the central signature tune to the complex pathogenesis of RHD. However, some of those infected develop RHD, and genetic host susceptibility factors are thought to play a key role in diseasedevelopment. Therefore, the present study was designed to explore the role of genetic variants in inflammatory genes in conferring risk of RHD. The study recruited total of 700 subjects, including 400 RHD patients and 300 healthy controls. We examined the associations of 8 selected polymorphisms in seven inflammatory genes: IL-6 [rs1800795G/C], IL-10 [rs1800896G/A], TNF-A [rs1800629G/A], IL-1β [rs2853550C/T], IL-1VNTR [rs2234663], TGF-β1 [rs1800469C/T]; [rs1982073T/C], and CTLA-4 [rs5742909C/T] with RHD risk. Genotyping for all the polymorphisms was done using PCR-ARMS/PCR/RFLP methods. Multifactor dimensionality reduction and classification and regression tree approaches were combined with logistic regression to discover high-order gene-gene interactions in studiedgenes involved in RHD susceptibility.In univariate logistic regression analysis, we found significant association of variant-containing genotypes (CT&TT) of TGF-β1 869T/C [rs1982073]; [p=0.0.004 & 0.001, OR (95% CI)=1.65 (1.2-2.3) & 2.25 (1.4-3.6) respectively], variant genotype (CC) of IL-1β -511C/T [rs2853550]; [p=0.001, OR (95% CI)=2.33 (1.4-3.8)] and IL-1 VNTR [rs2234663]; [p=0.03, OR (95% CI)=5.25 (1.2-23.4)] SNPs with RHD risk. CART analysis revealed that individuals with the combined genotypes of TGF-β1T/C_ rs1982073 (CT/TT) and IL-1 β_ rs2853550 (CC) had significantly higher susceptibility for RHD [p=0.0005, OR (95% CI)=5.91 (2.9-12.5)]. In MDR analysis, TGF-β1 869T>C yielded the highest testing accuracy of 0.562. In conclusion, using multi-analytical approaches, our study revealed important role of TGF-β1 869T/C [rs1982073] in RHD susceptibility.
Department of Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow, India.
Usha
U
Gupta
Department of Bioengineering, Integral University, Lucknow, India.
Snober S
SS
Mir
Department of Cardiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow, India.
Naveen
N
Garg
Department of Cardiovascular and Thoracic Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow, India.
Surendra K
SK
Agarwal
Department of Cardiovascular and Thoracic Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow, India.
Shantanu
S
Pande
Department of Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow, India. Electronic address: balraj@sgpgi.ac.in.
Balraj
B
Mittal
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D002648:Child; D016207:Cytokines / Q000235:genetics; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007194:India; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012214:Rheumatic Heart Disease / Q000235:genetics* / Q000378:metabolism; D012737:Sex Factors; D044465:White People / Q000235:genetics*; D055815:Young Adult
D016207:Cytokines
Indian population; Inflammatory genes; RHD; TGF-β1 gene