Analysis of 61 SNPs from the CAD specific genomic loci reveals unique set of SNPs as significant markers in the Southern Indian population of Hyderabad.

BACKGROUND: The present study is a part of the major project on coronary artery disease (CAD) carried out at Indian Statistical Institute, Hyderabad to investigate the pattern of association of SNPs selected from the CAD specific genomic loci. The study is expected to portray the genetic susceptibility profile of CAD specifically in the Southern Indian population of Hyderabad. METHODS: The study was conducted in a cohort of 830 subjects comprising 350 CAD cases and 480 controls from Hyderabad. A prioritized set of 61 SNPs selected from the NHGRI GWAS catalogue were genotyped using FluidigmNanofluidic SNP Genotyping System and appropriate statistical analyses were used in interpreting the results. RESULTS: After data pruning, out of 45 SNPs qualified for the association analysis, four SNPs were found to be highly significantly associated with increased risk for CAD even after Bonferroni correction for multiple testing (p < 0.001). These results were also replicated in the random subsets of the pooled cohort (70, 50 and 30%) suggesting internal consistency. The ROC analysis of the risk scores of the significant SNPs suggested highly significant area under curve (AUC = 0.749; p < 0.0001) implying predictive utility of these risk variants. CONCLUSIONS: The rs10455872 of LP(A) gene in particular showed profound risk for CAD (OR 35.9; CI 16.7-77.2) in this regional Indian population. The other significant SNP associations observed with respect to the pooled CAD cohort and in different anatomical and phenotypic severity categories reflected on the role of genetic heterogeneity in the clinical heterogeneity of CAD. The SNP rs7582720 of WDR12 gene, albeit not individually associated with CAD, was found to be conferring significant risk through epistatic interaction with two SNPs (rs6589566, rs1263163 in ZPR1, APOA5-APOA4 genes) of the 11q23.3 region.

Association of vitamin D receptor gene polymorphisms with polycystic ovary syndrome among Indian women.

BACKGROUND & OBJECTIVES: The Vitamin-D receptor (VDR) regulates vitamin D levels and calcium metabolism in the body and these are known to be associated with endocrine dysfunctions, insulin resistance and type-2 diabetes in polycystic ovarian syndrome (PCOS). Studies on VDR polymorphisms among PCOS women are sparse. We undertook this study to investigate the association pattern of VDR polymorphisms (Cdx2, Fok1, Apa1 and Taq1) with PCOS among Indian women. METHODS: For the present study, 250 women with PCOS and 250 normal healthy control women were selected from Hyderabad city, Telangana, India. The four VDR polymorphisms were genotyped and analysed using ASM-PCR (allele specific multiple PCR) and PCR-RFLP (restriction fragment length polymorphism). RESULTS: The genotype and allele frequency distributions of only Cdx2 showed significant difference between the PCOS cases and control women, indicating protective role of this SNP against PCOS phenotype. However, significant association was observed between VDR genotypes and some of the PCOS specific clinical/biochemical traits. For example, Fok1 showed a significant genotypic difference for the presence of infertility and Cdx2 genotpes showed association with testosterone levels. Further, the two haplotypes, ACCA and ACTA, were found to be significantly associated with PCOS indicating haplotype specific risk. INTERPRETATION & CONCLUSIONS: Although VDR polymorphisms have not shown significant association with PCOS, in view of functional significance of the SNPs considered, one cannot yet rule out the possibility of their association with PCOS. Further, specifically designed studies on large cohorts are required to conclusively establish the role of VDR polymorphisms in PCOS, particularly including data on vitamin D levels.

Methylation status of CEBPA gene promoter in chronic myeloid leukemia.

CCAAT/enhancer binding protein alpha is one of the crucial transcription factors for myeloid cell development that has been found to be involved in hematopoietic differentiation and leukemiogenesis. Recently, epigenetic regulation of CEBPA expression through DNA methylation has been demonstrated in leukemia. The aim of this study was to investigate the methylation status of CEBPA gene in chronic myeloid leukemia (CML) patients. The methylation status of CEBPA promoter was studied in 100 patients with CML and 98 normal healthy individuals from Hyderabad, India, using methylation-specific polymerase chain reaction. The aberrant methylation of CEBPA gene promoter was found in 32 of the 100 CML cases. A highly significant association was found between the frequency of CEBPA gene promoter hypermethylation and the CML stages (P = 0.017), but association with respect to age and gender of the patient was not found. The results suggest that aberrant methylation in the CpG island of the promoter region of this gene might be a common event in CML, and systemic expression studies will be needed to unfold the role of CEBPA promoter methylation in the development, progression, and prognosis of CML.

Incidence of internal tandem duplications and D835 mutations of FLT3 gene in chronic myeloid leukemia patients from Southern India.

OBJECTIVE: To screen two important FLT3 mutations (internal tandem duplication (ITD) and D835 point mutations) in chronic myeloid leukemia (CML) patients from Southern India and report their incidence. METHODS: Screened 350 CML patients and 350 controls for the two FLT3/mutations through polymerase chain reaction and restriction fragment length polymorphism methods. RESULTS: ITDs were detected in 12 of the 350 CML patients (3.4%) and D835 mutations in only four cases (1.14%), relatively low in frequency as compared to those reported earlier from non-Indian populations. None of the cases showed simultaneous occurence of both ITD and D835 mutations. DISCUSSION: These FLT3 mutations seem to be very rare in CML, and it is possible that these could be found only in a subset of patients who are in the progressive stage and/or with varied drug response. Prospective studies are needed to confirm the role of FLT3 mutations in CML pathogenesis, which may help devising therapeutic interventions.

Association of XRCC1 gene polymorphisms with chronic myeloid leukemia in the population of Andhra Pradesh, India.

Chronic myeloid leukemia (CML), a clonal myeloproliferative disorder, is characterized primarily by the presence of chimeric BCR-ABL oncogene, and its progression from chronic to blast phase is associated with the accumulation of additional molecular and chromosomal abnormalities. The molecular mechanisms underlying this genetic instability are poorly understood. The activity of BCR-ABL is known to be associated with the increased production of intracellular reactive oxygen species and spontaneous DNA damage, which when effected by impaired/inaccurate DNA repair systems result in increased susceptibility to CML progression. Using case-control study design, we explored possible association of the repair gene, XRCC1, particularly the codons 399, 280, and 194 polymorphisms screened through PCR-RFLP, with the CML in the sample of 350 cases (206 male and 144 female) and 350 controls from Hyderabad, the capital city of state of the Andhra Pradesh, India. The patient group constituted 301 early chronic phase cases followed by 28 accelerated and 21 blast phase cases. The median age of the patients was 42 years (range, 9-70 years). The genotype distribution revealed significant association of codons 399 (χ(2) = 11.904, degree of freedom (d.f.) = 2; P = 0.002) and 194 (χ(2) = 8.091, d.f. = 2, P = 0.017) with CML, not 280 (P = 0.29). Although these polymorphisms are known to affect the function of XRCC1, the nature and extent of their genetic association with CML does not indicate their direct role in its development. The results seem to suggest that XRCC1 gene might have an important role in CML progression but not in its causation.