We explored the associations of three variants in the uncoupling protein 2 (UCP2) gene, one variant in the UCP2-UCP3 intergenic region and five variants in the uncoupling protein 3 (UCP3) gene with obesity and diabetes related traits in subjects with impaired glucose tolerance participating in Finnish Diabetes Prevention Study. Altogether 507 overweight individuals (body mass index: 31.2 +/- 4.5 kg/m2, age: 55 +/- 7 years) for whom DNA was available were randomized to either an intensified diet and physical activity group or to a conventional care control group.

We explored the associations of three variants in the uncoupling protein 2 (UCP2) gene, one variant in the UCP2-UCP3 intergenic region and five variants in the uncoupling protein 3 (UCP3) gene with obesity and diabetes related traits in subjects with impaired glucose tolerance participating in Finnish Diabetes Prevention Study. Altogether 507 overweight individuals (body mass index: 31.2 +/- 4.5 kg/m2, age: 55 +/- 7 years) for whom DNA was available were randomized to either an intensified diet and physical activity group or to a conventional care control group.

We explored the associations of three variants in the uncoupling protein 2 (UCP2) gene, one variant in the UCP2-UCP3 intergenic region and five variants in the uncoupling protein 3 (UCP3) gene with obesity and diabetes related traits in subjects with impaired glucose tolerance participating in Finnish Diabetes Prevention Study. Altogether 507 overweight individuals (body mass index: 31.2 +/- 4.5 kg/m2, age: 55 +/- 7 years) for whom DNA was available were randomized to either an intensified diet and physical activity group or to a conventional care control group.

We explored the associations of three variants in the uncoupling protein 2 (UCP2) gene, one variant in the UCP2-UCP3 intergenic region and five variants in the uncoupling protein 3 (UCP3) gene with obesity and diabetes related traits in subjects with impaired glucose tolerance participating in Finnish Diabetes Prevention Study. Altogether 507 overweight individuals (body mass index: 31.2 +/- 4.5 kg/m2, age: 55 +/- 7 years) for whom DNA was available were randomized to either an intensified diet and physical activity group or to a conventional care control group.

The marked clinical and genetic heterogeneity seen in hypertrophic (HCM) and dilated cardiomyopathies (DCM) suggests involvement of disease modifiers and environmental factors in the pathophysiology of these diseases. In the current study, we examined association of single nucleotide polymorphisms (SNPs) of three candidate genes, ACE2 (rs6632677), TNNI3K (rs49812611) and CALM3 (rs13477425) with clinical phenotypes of HCM and DCM patients of North Indian ethnicity. Prevalence of ACE2 (7160726 C>G) variant genotypes (CG and GG) was significantly higher in DCM subjects as compared to controls. Prevalence of TNNI3K (3784 C>T) and CALM3 (-34T>A) variant homozygous genotype were significantly higher in HCM and DCM subjects as compared to controls. DCM patients with CT genotype showed significant decrease in LVEF as compared to CC genotype (p<0.03). There was significant gene-gene interaction between these SNPs and three-way SNP combination of ACE2 C>G, TNN13K C>T, CALM3 A>T gene variants and was associated with high risk of HCM and DCM. Presence of ACE2 (7160726 C>G) and CALM3 (-34T>A) variant genotypes in HCM Patients with mutations (sarcomeric or non sarcomeric genes) was associated with increased mean septal thickness, further suggesting a role of these gene variants in modifying disease phenotype. Our results suggest that ACE2, TNNI3K and CALM3 polymorphisms are associated with increased risk of HCM and DCM and may act as disease modifiers of these diseases.

We investigated the individual and combined effect of functional TNFA -308G/A and IL10 -1082G/A single nucleotide polymorphisms (SNPs) and their genotypes on the susceptibility to systemic lupus erythematosus (SLE) in a Bulgarian population.

BACKGROUND: Cervicitis is one of the major health problems amongst women caused by infection of various pathogens including Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Trichomonas vaginalis (TV) as well as human papillomavirus (HPV), and persistent cervical inflammation is one of the etiologic agents of cervical cancer. Toll-like receptors (TLRs) play an important role in the recognition and subsequent elimination of these pathogens. Variations in the Toll-like receptor genes influence susceptibility to pathogens as well as disease progression independently. METHODS: Ten single nucleotide polymorphisms, five each of TLR4 and TLR9 genes were analyzed among 130 cervicitis patients and 150 controls either using polymerase chain reaction-restriction fragment length polymorphism or allele specific-PCR. RESULTS: T. vaginalis infection was found at the highest frequency (30.7%) as compared to C. trachomatis (1.5%), N. gonorrhoeae (2.3%) and HPV (4.6%) infections in cervicitis patients. TLR4 rs11536889 CC (age-adjusted OR, 2.469 [95% CI, 1.499 to 4.065]; p < 0.001) and TLR9 rs187084 TC (age-adjusted OR, 2.165 [95% CI, 1.267-3.699]; p = 0.005) genotypes showed the higher distribution in cervicitis patients compared to controls. In addition, TLR4 rs11536889 C allele was shown to increase the risk of cervicitis (age-adjusted OR, 1.632 [95% CI, 1.132 to 2.352]; p = 0.009) compared to controls. The TLR4 haplotype GCA (OR, 0.6 [95% CI, 0.38-0.95]; p = 0.0272) and TLR9 haplotype GTA (OR, 1.99 [95% CI, 1.14-3.48]; p = 0.014) were found to be associated with decreased and increased risk of cervicitis respectively. CONCLUSIONS: TLR4 and TLR9 polymorphisms, as well as haplotypes were shown to modulate the cervicitis risk.

BACKGROUND: Cervicitis is one of the major health problems amongst women caused by infection of various pathogens including Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Trichomonas vaginalis (TV) as well as human papillomavirus (HPV), and persistent cervical inflammation is one of the etiologic agents of cervical cancer. Toll-like receptors (TLRs) play an important role in the recognition and subsequent elimination of these pathogens. Variations in the Toll-like receptor genes influence susceptibility to pathogens as well as disease progression independently. METHODS: Ten single nucleotide polymorphisms, five each of TLR4 and TLR9 genes were analyzed among 130 cervicitis patients and 150 controls either using polymerase chain reaction-restriction fragment length polymorphism or allele specific-PCR. RESULTS: T. vaginalis infection was found at the highest frequency (30.7%) as compared to C. trachomatis (1.5%), N. gonorrhoeae (2.3%) and HPV (4.6%) infections in cervicitis patients. TLR4 rs11536889 CC (age-adjusted OR, 2.469 [95% CI, 1.499 to 4.065]; p < 0.001) and TLR9 rs187084 TC (age-adjusted OR, 2.165 [95% CI, 1.267-3.699]; p = 0.005) genotypes showed the higher distribution in cervicitis patients compared to controls. In addition, TLR4 rs11536889 C allele was shown to increase the risk of cervicitis (age-adjusted OR, 1.632 [95% CI, 1.132 to 2.352]; p = 0.009) compared to controls. The TLR4 haplotype GCA (OR, 0.6 [95% CI, 0.38-0.95]; p = 0.0272) and TLR9 haplotype GTA (OR, 1.99 [95% CI, 1.14-3.48]; p = 0.014) were found to be associated with decreased and increased risk of cervicitis respectively. CONCLUSIONS: TLR4 and TLR9 polymorphisms, as well as haplotypes were shown to modulate the cervicitis risk.

Cystic fibrosis (CF), the most common lethal single gene disorder in Caucasians, is due to mutations in the CFTR gene. Twin and sibling analysis indicates that modifier genes, rather than allelic variation in CFTR, are responsible for most of the variability in severity of lung disease, the major cause of mortality in CF patients. We used a family-based approach to test for association between lung function and two functional SNPs (rs1800469, '-509' and rs1982073, 'codon 10') in the 5' region of transforming growth factor-beta1 (TGFB1), a putative CF modifier gene. Quantitative transmission disequilibrium testing of 472 CF patient-parent-parent trios revealed that both TGFB1 SNPs showed significant transmission distortion when patients were stratified by CFTR genotype. Although lung function and nutritional status are correlated in CF patients, there was no evidence of association between the TGFB1 SNPs and variation in nutritional status. Additional tagging SNPs (rs8179181, rs2278422, rs8110090, rs4803455 and rs1982072) that capture most of the diversity in TGFB1 were also typed but none showed association with variation in lung function. However, a haplotype composed of the -509 C and codon 10 T alleles along with the C allele of the 3' SNP rs8179181 was highly associated with increased lung function in patients grouped by CFTR genotype. These results demonstrate that TGFB1 is a modifier of CF lung disease and reveal a previously unrecognized beneficial effect of TGFB1 variants upon the pulmonary phenotype.

Cystic fibrosis (CF), the most common lethal single gene disorder in Caucasians, is due to mutations in the CFTR gene. Twin and sibling analysis indicates that modifier genes, rather than allelic variation in CFTR, are responsible for most of the variability in severity of lung disease, the major cause of mortality in CF patients. We used a family-based approach to test for association between lung function and two functional SNPs (rs1800469, '-509' and rs1982073, 'codon 10') in the 5' region of transforming growth factor-beta1 (TGFB1), a putative CF modifier gene. Quantitative transmission disequilibrium testing of 472 CF patient-parent-parent trios revealed that both TGFB1 SNPs showed significant transmission distortion when patients were stratified by CFTR genotype. Although lung function and nutritional status are correlated in CF patients, there was no evidence of association between the TGFB1 SNPs and variation in nutritional status. Additional tagging SNPs (rs8179181, rs2278422, rs8110090, rs4803455 and rs1982072) that capture most of the diversity in TGFB1 were also typed but none showed association with variation in lung function. However, a haplotype composed of the -509 C and codon 10 T alleles along with the C allele of the 3' SNP rs8179181 was highly associated with increased lung function in patients grouped by CFTR genotype. These results demonstrate that TGFB1 is a modifier of CF lung disease and reveal a previously unrecognized beneficial effect of TGFB1 variants upon the pulmonary phenotype.

Cystic fibrosis (CF), the most common lethal single gene disorder in Caucasians, is due to mutations in the CFTR gene. Twin and sibling analysis indicates that modifier genes, rather than allelic variation in CFTR, are responsible for most of the variability in severity of lung disease, the major cause of mortality in CF patients. We used a family-based approach to test for association between lung function and two functional SNPs (rs1800469, '-509' and rs1982073, 'codon 10') in the 5' region of transforming growth factor-beta1 (TGFB1), a putative CF modifier gene. Quantitative transmission disequilibrium testing of 472 CF patient-parent-parent trios revealed that both TGFB1 SNPs showed significant transmission distortion when patients were stratified by CFTR genotype. Although lung function and nutritional status are correlated in CF patients, there was no evidence of association between the TGFB1 SNPs and variation in nutritional status. Additional tagging SNPs (rs8179181, rs2278422, rs8110090, rs4803455 and rs1982072) that capture most of the diversity in TGFB1 were also typed but none showed association with variation in lung function. However, a haplotype composed of the -509 C and codon 10 T alleles along with the C allele of the 3' SNP rs8179181 was highly associated with increased lung function in patients grouped by CFTR genotype. These results demonstrate that TGFB1 is a modifier of CF lung disease and reveal a previously unrecognized beneficial effect of TGFB1 variants upon the pulmonary phenotype.

We have previously demonstrated that betel quid containing safrole induced DNA adducts are highly associated with the development of oral squamous cell carcinoma (OSCC) in Taiwan. Sulfotransferase (SULT) is essential for the formation of these adducts. To elucidate the effects of SULT1A1 haplotypes on OSCC susceptibility, 160 male OSCC cases and 218 age- and sex-matched controls were screened for single-nucleotide polymorphisms within the coding region of SULT1A1 by sequencing. We found that 445C>T (His149Tyr) and 507C>T polymorphisms were significantly associated with increased risk of OSCC. Based on the genotype analysis, haplotypes were constructed for 445C>T (His149Tyr), 507C>T, 600G>C and 638G>A (Arg213His) using GENECOUNTING software. After adjustment for age, cigarette smoking and betel quid chewing, we found that haplotype c containing 445C>T (His149Tyr), 507C>T or 600G>C but not 638G>A (Arg213His) variant was significantly associated with increased risk of OSCC (odds ratio, 3.24; 95% confidence interval, 1.57-6.68) when compared with the haplotype a (wild-type). We analyzed the activity in sulfonation of 2-naphthol and 1'-hydroxysafrole of recombinant His149Tyr (445C>T) variant, which led to 51 and 33% reduced activity, respectively; Arg213His (638G>A) variant led to 72 and 54% reduced activity, respectively, when compared with the wild-type. Taken together, haplotype analysis provides a novel evaluation of the SULT1A1 gene as a risk modifier on environmental carcinogen in OSCC and the association of SULT1A1 haplotypes with the risk of OSCC might be modified by betel quid chewing.

Familial combined hyperlipidemia (FCHL) has been associated with abnormalities in fatty acid metabolism. The adipose triglyceride lipase (PNPLA2) plays a pivotal role in the turnover of fatty acids in adipose tissue and liver. This study was designed to evaluate whether selected PNPLA2 variants may influence the susceptibility to FCHL or its lipid-related traits.

Familial combined hyperlipidemia (FCHL) has been associated with abnormalities in fatty acid metabolism. The adipose triglyceride lipase (PNPLA2) plays a pivotal role in the turnover of fatty acids in adipose tissue and liver. This study was designed to evaluate whether selected PNPLA2 variants may influence the susceptibility to FCHL or its lipid-related traits.

Familial combined hyperlipidemia (FCHL) has been associated with abnormalities in fatty acid metabolism. The adipose triglyceride lipase (PNPLA2) plays a pivotal role in the turnover of fatty acids in adipose tissue and liver. This study was designed to evaluate whether selected PNPLA2 variants may influence the susceptibility to FCHL or its lipid-related traits.

Familial combined hyperlipidemia (FCHL) has been associated with abnormalities in fatty acid metabolism. The adipose triglyceride lipase (PNPLA2) plays a pivotal role in the turnover of fatty acids in adipose tissue and liver. This study was designed to evaluate whether selected PNPLA2 variants may influence the susceptibility to FCHL or its lipid-related traits.

Familial combined hyperlipidemia (FCHL) has been associated with abnormalities in fatty acid metabolism. The adipose triglyceride lipase (PNPLA2) plays a pivotal role in the turnover of fatty acids in adipose tissue and liver. This study was designed to evaluate whether selected PNPLA2 variants may influence the susceptibility to FCHL or its lipid-related traits.

Familial combined hyperlipidemia (FCHL) has been associated with abnormalities in fatty acid metabolism. The adipose triglyceride lipase (PNPLA2) plays a pivotal role in the turnover of fatty acids in adipose tissue and liver. This study was designed to evaluate whether selected PNPLA2 variants may influence the susceptibility to FCHL or its lipid-related traits.

Familial combined hyperlipidemia (FCHL) has been associated with abnormalities in fatty acid metabolism. The adipose triglyceride lipase (PNPLA2) plays a pivotal role in the turnover of fatty acids in adipose tissue and liver. This study was designed to evaluate whether selected PNPLA2 variants may influence the susceptibility to FCHL or its lipid-related traits.

Familial combined hyperlipidemia (FCHL) has been associated with abnormalities in fatty acid metabolism. The adipose triglyceride lipase (PNPLA2) plays a pivotal role in the turnover of fatty acids in adipose tissue and liver. This study was designed to evaluate whether selected PNPLA2 variants may influence the susceptibility to FCHL or its lipid-related traits.

Familial combined hyperlipidemia (FCHL) has been associated with abnormalities in fatty acid metabolism. The adipose triglyceride lipase (PNPLA2) plays a pivotal role in the turnover of fatty acids in adipose tissue and liver. This study was designed to evaluate whether selected PNPLA2 variants may influence the susceptibility to FCHL or its lipid-related traits.

Familial combined hyperlipidemia (FCHL) has been associated with abnormalities in fatty acid metabolism. The adipose triglyceride lipase (PNPLA2) plays a pivotal role in the turnover of fatty acids in adipose tissue and liver. This study was designed to evaluate whether selected PNPLA2 variants may influence the susceptibility to FCHL or its lipid-related traits.

Familial combined hyperlipidemia (FCHL) has been associated with abnormalities in fatty acid metabolism. The adipose triglyceride lipase (PNPLA2) plays a pivotal role in the turnover of fatty acids in adipose tissue and liver. This study was designed to evaluate whether selected PNPLA2 variants may influence the susceptibility to FCHL or its lipid-related traits.

Familial combined hyperlipidemia (FCHL) has been associated with abnormalities in fatty acid metabolism. The adipose triglyceride lipase (PNPLA2) plays a pivotal role in the turnover of fatty acids in adipose tissue and liver. This study was designed to evaluate whether selected PNPLA2 variants may influence the susceptibility to FCHL or its lipid-related traits.

Dopamine D2 receptor signalling is strongly implicated in the aetiology of schizophrenia. We have recently characterized the function of three DRD2 SNPs: rs12364283 in the promoter affecting total D2 mRNA expression; rs2283265 and rs1076560, respectively in introns 5 and 6, shifting mRNA splicing to two functionally distinct isoforms, the short form of D2 (D2S) and the long form (D2L). These two isoforms differentially contribute to dopamine signalling in prefrontal cortex and in striatum. We performed a case-control study to determine association of these variants and of their main haplotypes with several schizophrenia-related phenotypes. We demonstrate that the minor allele in the intronic variants is associated with reduced expression of %D2S of total mRNA in post-mortem prefrontal cortex, and with impaired working memory behavioural performance, both in patients and controls. However, the fMRI results show opposite effects in patients compared with controls: enhanced engagement of prefronto-striatal pathways in controls and reduced activity in patients. Moreover, the promoter variant is also associated with working memory activity in prefrontal cortex and striatum of patients, and less robustly with negative symptoms scores. Main haplotypes formed by the three DRD2 variants showed significant associations with these phenotypes consistent with those of the individual SNPs. Our results indicate that the three functional DRD2 variants modulate schizophrenia phenotypes possibly by modifying D2S/D2L ratios in the context of different total D2 density.

Genetic diversity at the human β-globin locus has been implicated as a modifier of sickle cell anaemia (SCA) severity. However, haplotypes defined by restriction fragment length polymorphism sites across the β-globin locus have not been consistently associated with clinical phenotypes. To define the genetic structure at the β-globin locus more thoroughly, we performed high-density single nucleotide polymorphism (SNP) mapping in 820 children who were homozygous for the sickle cell mutation (HbSS). Genotyping results revealed very high linkage disequilibrium across a large region spanning the locus control region and the HBB (β-globin gene) cluster. We identified three predominant haplotypes accounting for 96% of the β(S) -carrying chromosomes in this population that could be distinguished using a minimal set of common SNPs. Consistent with previous studies, fetal haemoglobin level was significantly associated with β(S) -haplotypes. After controlling for covariates, an association was detected between haplotype and rate of hospitalization for acute chest syndrome (ACS) (incidence rate ratio 0·51, 95% confidence interval 0·29-0·89) but not incidence rate of vaso-occlusive pain or presence of silent cerebral infarct (SCI). Our results suggest that these SNP-defined β(S) -haplotypes may be associated with ACS, but not pain or SCI in a study population of children with SCA.

Huntington disease (HD) is an inherited neurodegenerative disease caused by an abnormal expansion of a CAG repeat in the huntingtin HTT (HD) gene. The primary genetic determinant of the age at onset (AO) is the length of the HTT CAG repeat; however, the remaining genetic contribution to the AO of HD has largely not been elucidated. Recent studies showed that impaired functioning of the peroxisome proliferator-activated receptor gamma coactivator 1a (PGC-1alpha) contributes to mitochondrial dysfunction and appears to play an important role in HD pathogenesis. Further genetic evidence for involvement of PGC-1alpha in HD pathogenesis was generated by the findings that sequence variations in the PPARGC1A gene encoding PGC-1alpha exert modifying effects on the AO in HD. In this study, we hypothesised that polymorphisms in PGC-1alpha downstream targets might also contribute to the variation in the AO.

Huntington disease (HD) is an inherited neurodegenerative disease caused by an abnormal expansion of a CAG repeat in the huntingtin HTT (HD) gene. The primary genetic determinant of the age at onset (AO) is the length of the HTT CAG repeat; however, the remaining genetic contribution to the AO of HD has largely not been elucidated. Recent studies showed that impaired functioning of the peroxisome proliferator-activated receptor gamma coactivator 1a (PGC-1alpha) contributes to mitochondrial dysfunction and appears to play an important role in HD pathogenesis. Further genetic evidence for involvement of PGC-1alpha in HD pathogenesis was generated by the findings that sequence variations in the PPARGC1A gene encoding PGC-1alpha exert modifying effects on the AO in HD. In this study, we hypothesised that polymorphisms in PGC-1alpha downstream targets might also contribute to the variation in the AO.

ALL is the most common pediatric cancer. The causes of the majority of pediatric acute leukemia are unknown and are likely to involve an interaction between genetic and environmental factors. Therefore, unfavourable gene-environmental interactions might be involved in the genesis of ALL. The aim of this work was to evaluate, in a case-control study, whether the common polymorphisms in 5, 10-methylenetetrahydrofolate reductase (MTHFR) namely (C677T and A1298C) and methionine synthase (MS) (A2756G) genes may play a role in altering susceptibility to pediatric ALL as individual genes and in combination.

Parkinson's disease (PD) is a complex neurodegenerative disorder. Although the p.G2385R allele of leucine-rich repeat kinase 2 (LRRK2) has been recently reported as a common genetic variant that increases the risk for typical PD exclusively among Asian population, its genetic modifiers is yet to be studied. Brain-derived neurotrophic factor (BDNF) has been shown to play an important role in the survival of dopaminergic neurons and its genetic polymorphism was associated with an increased risk for PD at an older age onset. The current case-control study was performed to investigate the interaction between LRRK2 p.G2385R and BDNF p.V66M in a Chinese PD cohort. A total of 464 PD patients and 549 controls were involved in this study.LRRK2 p.G2385R variant (odds ratio [OR]=3.2; 95% confidence interval [CI]=1.96-5.15, p<0.0001), not BDNF p.V66M alone significantly increased the risk of PD. However, the simultaneous presence of bothLRRK2 and BDNF variants significantly enhanced the risk for PD (OR=4.033; 95% CI=2.188-7.435, p<0.0001), particularly in patients with an onset age of older than 60 (OR=6.439; 95% CI=3.096-13.389, p<0.0001). Our results further support that LRRK2 variants are an independent genetic risk factor for typical PD, but BDNF variants can greatly increase LRRK2-induced risk for patients with an onset age of older than 60 indicating an additive effect between the 2 genes, which might aid in studying the mechanism underlying LRRK2 parkinsonism and developing potential therapeutic strategies.

F508del-CFTR, the most frequent disease-causing mutation among Caucasian cystic fibrosis (CF) patients, has been characterised as a mutant defective in protein folding, processing and trafficking. We have investigated the two neighbouring cytokeratin genes KRT8 and KRT18 in a candidate gene approach to ask whether variants in KRT8 and/or KRT18 modify the impaired ion conductance known as the CF basic defect, and whether they are associated with correct trafficking of mutant CFTR and disease severity of CF.

The complications of sickle cell disease are probably determined by genes whose products modify the pathophysiology initiated by the sickle haemoglobin mutation. Priapism, one vaso-occlusive manifestation of sickle cell disease, affects more than 30% of males with the disease. We examined the possible association of single nucleotide polymorphisms (SNPs) in 44 candidate genes of different functional classes for an association with the occurrence of priapism. One hundred and forty-eight patients with sickle cell anaemia and incident or a confirmed history of priapism were studied, along with 529 controls that had not developed priapism. Polymorphisms in the KLOTHO gene (KL; 13q12) showed an association with priapism by genotypic [reference SNP cluster identifier number (rs)2249358; odds ratio (OR) = 2.6 (1.4-5.5); rs211239; OR = 1.7 (1.2-2.6)] and haplotype analyses [rs211234 and rs211239; OR = 2.3 (1.5-3.4)]. These findings may have broader implications in sickle cell disease, as KL encodes a membrane protein that regulates many vascular functions, including vascular endothelial growth factor expression and endothelial nitric oxide release.

Dilated cardiomyopathy (DCM) is a myocardial disease of unknown etiology with left ventricular dilatation and impaired myocardial contractility leading to heart failure. It is considered to be a multifactorial disorder with the interplay of both genetic and environmental factors. One of the possible genes implicated in DCM is endothelin 1 (EDN1). The genetic variants of EDN1 may be involved in the pathophysiology of DCM hence the entire EDN1 gene was screened to examine for the possible genotypic associations with DCM. A total of 115 DCM patients and 250 control subjects were included in the present study. PCR based SSCP analysis was carried out followed by commercial sequencing. Screening of EDN1 revealed two common and two rare polymorphisms. Allelic and genotypic frequencies were estimated in patient and control groups by appropriate statistical tests. The heterozygotes of insertion variation (+138A) were found to exhibit four-fold increase risk to DCM (OR=4.12, 95% CI 2.10-8.08; p=0.0001). The two rare variants (G>A transition (rs150035515) at c.90 and C>T transition (rs149399492) at c.119) observed in the present study were found to be unique in DCM. The secondary mRNA structures of these variations were found to have less free energy than wild type. The haplotype analysis revealed 4A-T to be risk haplotype for DCM (OR 5.90, 95% CI 2.29-15.25, p=0.0001). In conclusion, EDN1 polymorphisms (+138A, A30A, T40I) appear to play a significant role in the pathogenesis of DCM, as they influence the stability of protein. The increased EDN1 production may lead to constriction of coronary arteries, reducing coronary blood flow which may in turn increase the load on left ventricle, impairing contractility of the heart resulting in a DCM phenotype, an end stage of heart failure.