ABSTRACT
In plants, pathogen resistance is brought about by the binding of certain transcription factor (TF) proteins to the cis-elements of certain target genes. These cis-elements are present upstream in the motif of the promoters of each gene. This ensures the binding of a specific TF to a specific promoter, therefore regulating the expression of that gene. Therefore, the study of each promoter sequence of all the rice genes would help identify the target genes of a specific TF. Rice 1 kb upstream promoter sequences of 55,986 annotated genes were analyzed using the Perl program algorithm to detect WRKY13 binding motifs (bm). The resulting genes were grouped using Gene Ontology and gene set enrichment analysis. A gene with more than 4 TF bm in their promoter was selected. Ten genes reported to have a role in rice disease resistance were selected for further analysis. Cis-acting regulatory element analysis was carried out to find the cis-elements and confirm the presence of the corresponding motifs in the promoter sequences of these genes. The 3D structure of WRKY13 TF and the corresponding ten genes were built, and the interacting residues were determined. The binding capacity of WRKY13 to the promoter of these selected genes was analyzed using docking studies. WRKY13 was considered for docking analysis based on the prior reports of autoregulation. Molecular dynamic simulations provided more details regarding the interactions. Expression data revealed the expression of the genes that helped provide the mechanism of interaction. Further co-expression network helped to characterize the interaction of these selected disease resistance-related genes with the WRKY13 TF protein. This study suggests downstream target genes that are regulated by the WRKY13 TF. The molecular mechanism involving the gene network regulated by WRKY13 TF in disease resistance against rice fungal pathogens is explored.
Subject(s)
Oryza , Transcription Factors , Transcription Factors/genetics , Transcription Factors/metabolism , Oryza/metabolism , Disease Resistance/genetics , Promoter Regions, Genetic , Gene Regulatory NetworksABSTRACT
The risk for community acquired pneumonia (CAP) is partially driven by genetics. To identify the CAP-associated genetic risk loci, we performed a meta-analysis of clinically diagnosed CAP (3,310 individuals) with 2,655 healthy controls. The findings revealed CYP1A1 variants (rs2606345, rs4646903, rs1048943) associated with pneumonia. We observed rs2606345 [G vs T; OR=1.49(1.29-1.69); p=0.0001; I2= 15.5%], and rs1048943 [T vs G; OR= 1.31(0.90-1.71); p=0.002; I2=19.3%] as risk markers and rs4646903 [T vs C; OR= 0.79(0.62-0.96); p=0.03; I2=0%] as a protective marker for susceptibility to CAP, when compared with healthy controls. Our meta-analysis showed the presence of CYP1A1 SNP alleles contributing significant risk toward pneumonia susceptibility. Interestingly, we observed a striking difference of allele frequency for rs2606345 (CYP1A1) among Europeans, Africans and Asians which may provide a possible link for observed variations in death due to coronavirus disease 2019 (COVID-19), a viral pneumonia. We report, for the first time, a significant positive correlation for the risk allele (T or A) of rs2606345, with a higher COVID-19 mortality rate worldwide and within a genetically heterogeneous nation like India. Mechanistically, the risk allele A (rs2606345) is associated with lower expression of CYP1A1 and presumably leads to reduced capacity for xenobiotic detoxification. We note that ambient air pollution, a powerful inducer of CYP1A1 gene expression, is globally associated with lower, not higher mortality, as would normally be predicted. In conclusion, we find that CYP1A1 alleles are associated with CAP mortality, presumably via altered xenobiotic metabolism. We speculate that gene-environment interactions governing CYP1A1 expression may influence COVID-19 mortality.
ABSTRACT
IntroductionSteroids have shown its usefulness in critically ill COVID19 patients. However time of starting steroid and dose tailored to severity remains a matter of inquiry due to still emerging evidences and wide-ranging concerns of benefits and harms. We did a retrospective record analysis in an apex teaching hospital ICU setting to explore optimal doses and duration of steroid therapy which can decrease mortality. Methodology114 adults with COVID19-ARDS admitted to ICU between 20thMarch-15thAugust2020 were included in chart review. We did preliminary exploratory analysis(rooted in steroid therapy matrix categorized by dose and duration) to understand the effect of several covariates on survival. This was followed by univariate and multivariate Cox proportion hazard regression analysis and model diagnostics. ResultsExploratory analysis and visualization indicated age, optimal steroid, severity (measured in P/F) of disease and infection status as potential covariates for survival. Univariate cox regression analysis showed significant positive association of age>60 years{2.6 (1.5-4.7)} and protective effect of optimum steroid{0.38(0.2-0.72)} on death (hazard) in critically ill patients. Multivariate cox regression analysis after adjusting effect of age showed protective effect of optimum steroid on hazard defined as death {0.46(0.23-0.87),LR=17.04,(p=2e- 04)}.The concordance was 0.70 and model diagnostics fulfilled the assumption criteria for proportional hazard model. ConclusionOptimal dose steroid as per defined optimum (<24 hours and doses tailored to P/F at presentation) criteria can offer protective effect from mortality which persists after adjusting for age. This protective effect was not found to be negatively influenced by the risk of infection. No funding was taken for this paper.
ABSTRACT
This a response to the commentary article entitled "The association between Interleukin-1ß gene rs1143634 polymorphism and the risk of breast cancer" by Bei Wang, Fenlai Yuan. We completely agree with Wang and Yuan that there is significant deviation of HWE in control subjects for IL-1beta exon 5 +3954 polymorphism. Therefore, the apparent genetic association in IL-1beta exon 5 +3954 polymorphism must be used cautiously for further interpretation.
Subject(s)
Breast Neoplasms , Interleukin-10/genetics , Female , Genetic Predisposition to Disease , Humans , Interleukin-1beta/genetics , Interleukin-6/genetics , Polymorphism, Single Nucleotide , Risk FactorsABSTRACT
TGF-ß1 is a pleiotropic cytokine, which plays a dual role in tumor development. In the early stages, it inhibits the growth of tumor while in the late stages of carcinoma, it promotes tumor growth. The purpose of this study was to analyze the distribution of the TGFB1 gene polymorphisms between cases and controls so as to assess their correlation with bladder cancer risk. This study included 237 cases of urinary bladder cancer and 290 age matched controls from the same ethnic background. Three polymorphisms in the TGFB1 gene, c.29C>T (rs-1800470), c.74G>C (rs-1800471) and +140A>G (rs-13447341), were analyzed by direct DNA sequencing. Statistical analyses revealed no significant differences in the demographical data, except that the frequencies of smokers and non-vegetarians were higher in the cases. Eighty percent of the bladder cancer patients had superficial transitional cell carcinoma, and 53.16% and 26.31% of the patients were in grade I and grade II, respectively. We found that c.29C>T substitution increased the risk of bladder cancer significantly and recessive model of analysis was the best fitted model (p=0.004; OR=1.72 95% CI 1.18-2.50). A significantly higher risk in the recessive form was also suggested by co-dominant analysis showing that the homozygous form (TT) was a significant risk factor in comparison to CC and CT genotypes. The other two polymorphisms, c.74G>C (p=0.18, OR=0.67 95% CI 0.37-1.21) and +140A>G (p=0.416, OR=0.77 95% CI 0.41-1.45) did not affect the risk of urinary bladder cancer. In conclusion, we found that the TGFB1 c.29C>T substitution increases the risk of bladder cancer significantly while c.74G>C and +140A>G polymorphisms do not affect the risk.
Subject(s)
Genetic Predisposition to Disease , Transforming Growth Factor beta1/genetics , Urinary Bladder Neoplasms/genetics , Apoptosis/genetics , Base Sequence , Carcinoma, Transitional Cell/complications , Carcinoma, Transitional Cell/genetics , Case-Control Studies , Cell Proliferation/genetics , Female , Gene Frequency , Genetic Association Studies , Genotype , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Risk , Sequence Analysis, DNA , Urinary Bladder Neoplasms/epidemiologyABSTRACT
RAD51 is a homolog of bacterial RecA protein, which plays an important role in preserving stability of the genome. RAD51 interacts with BRCA1 and BRCA2 for homologous recombination repair. A functional polymorphism (135G > C) in the RAD51 gene has been a subject of great interest, which is evidenced by at least 28 case-control studies and eight meta-analyses undertaken on this polymorphism till now. We undertook a meta-analysis on RAD51 135G > C data for 21,236 cases and 19,407 controls pooled from 28 studies on breast cancer in women. Pooled data analysis suggested a significant association of the substitution with breast cancer in the recessive model (GG + GC versus CC) and in the co-dominant models comparing GG versus CC and GC versus CC. Analysis of the results suggested that 'CC' genotype is a significant breast cancer risk factor in comparison to 'GG' and 'GC' genotypes. We also undertook pooled analyses on different ethnic groups and found that 'CC' was a strong risk factor in Caucasians, but not in East-Asians and populations of mixed ethnicity. In conclusion, the RAD51 135G > C substitution in the homozygous form (CC) increases the risk of breast cancer in an ethnic-specific manner.
Subject(s)
Breast Neoplasms/genetics , Genetic Predisposition to Disease/genetics , Polymorphism, Single Nucleotide , Rad51 Recombinase/genetics , Asian People/genetics , Breast Neoplasms/ethnology , Female , Gene Frequency , Genetic Predisposition to Disease/ethnology , Genotype , Humans , Linkage Disequilibrium , Odds Ratio , Risk Factors , White People/geneticsABSTRACT
BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) acts at an important metabolic point in the regulation of cellular methylation reaction. It assists in the conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. The latter aids in remethylation of homocysteine to de novo methionine that is required for DNA synthesis. The objective of this study was to examine the effect of MTHFR 677 C>T polymorphism on the risk of breast cancer in the Indian sub-continent. METHODS AND RESULTS: We genotyped 677 C>T locus in 1096 individuals that were classified into cases (N=588) and controls (N=508). Genotype data were analyzed using chi-square test. No significant difference was observed in the distribution of genotypes between cases and controls in north Indian (P = 0.932), south Indian (P = 0.865), and pooled data (P = 0.680). To develop a consensus regarding the impact of 677C>T polymorphism on breast cancer risk, we also conducted a meta-analysis on 28031 cases and 31880 controls that were pooled from sixty one studies. The overall summary estimate upon meta-analysis suggested no significant correlation between the 677C>T substitution and breast cancer in the dominant model (Fixed effect model: OR = 0.97, P=0.072, Random effects model: OR = 0.96, P = 0.084) or the recessive model (Fixed effect model: OR = 1.05, P = 0.089; Random effects model: OR= 1.08, P= 0.067). CONCLUSION: 677 C>T substitution does not affect breast cancer risk in the Indo-European and Dravidian populations of India. Analysis on pooled data further ruled out association between the 677 C>T polymorphism and breast cancer. Therefore, 677 C>T substitution does not appear to influence the risk of breast cancer.
Subject(s)
Breast Neoplasms/genetics , Breast/pathology , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Polymorphism, Single Nucleotide , Adult , Aged , Aged, 80 and over , Asian People/genetics , Breast/metabolism , Breast Neoplasms/diagnosis , Breast Neoplasms/epidemiology , Female , Humans , India/epidemiology , Middle Aged , Risk , Young AdultABSTRACT
The promoter regions (1 kb upstream sequences) of 45,836 annotated genes of rice were analyzed for the presence of OsMYB4 binding sites using a Perl program algorithm. Based on the homotypic clustering concept, 113 promoters were found to have more than 4 binding site motifs. Among the downstream genes of these promoters, five genes which are known to have a role in disease resistance were selected and the binding capacity of OsMYB4 protein in the promoter regions was analyzed by docking studies. Expression level of these genes was analyzed by RT-PCR in Rhizoctonia solani infected rice seedlings. Upon pathogen challenge, higher expression of aminotransferase, ankyrin and WRKY 12 genes was observed corresponding to higher expression of Osmyb4. Over-expression of Osmyb4 cDNA in rice leaf tissues by agro-infection failed to result in similar over-expression of aminotransferase, ankyrin and WRKY 12 as expected. Although the role of OsMYB4 in sheath blight resistance was found to be definitive based on our initial results, artificial over-expression of this TF was observed to be insufficient in regulating the disease resistance related genes.
Subject(s)
Disease Resistance , Oryza/genetics , Oryza/immunology , Plant Diseases/genetics , Plant Proteins/genetics , Plant Proteins/metabolism , Algorithms , Binding Sites , Computational Biology , Gene Expression Regulation, Plant , Molecular Docking Simulation , Plant Diseases/immunology , Plant Diseases/microbiology , Plant Proteins/chemistry , Plants, Genetically Modified , Promoter Regions, Genetic , Rhizoctonia/physiologyABSTRACT
Androgens in breast cancer have been studied alone and in correlation with estrogens as estrogen to testosterone ratio. 5-α-reductase is one of the important enzymes participating in androgen metabolism, which affects androgen activity by affecting conversion of testosterone to dihydrotestosterone. We hypothesized that polymorphisms in the SRD5A2 gene (encoding 5-α-reductase) may affect breast cancer risk by affecting total androgen activity. Complete coding region of the SRD5A2 gene was sequenced in a group of 628 patients and 244 control samples from three southern states (Tamil Nadu, Andhra Pradesh, and Karnataka) of India. We observed three common polymorphisms in this gene; namely, A49T, V89L, and (TA)n repeats. A49T locus was monomorphic in the study population, but V89L showed a strong correlation with breast cancer (P = 0.03, OR = 1.40, CI = 1.02-1.91). (TA)0/(TA)9 and (TA)9/(TA)9 genotypes were at a lower risk of breast cancer (P = 0.01, OR = 0.64, CI = 0.46-0.90). We conclude that SRD5A2 genotypes significantly affect breast cancer risk in the South Indian populations.
Subject(s)
3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics , Breast Neoplasms/genetics , Membrane Proteins/genetics , Polymorphism, Genetic , Adolescent , Adult , Aged , Aged, 80 and over , Female , Genetic Predisposition to Disease , Humans , India , Lymphatic Metastasis , Middle Aged , Polymerase Chain Reaction , Risk Factors , Young AdultABSTRACT
Essential oils of different species of the genus Ocimum are natural flavouring materials of commercial importance. The data given in current literature are pertaining to the chemical composition of essential oils of different Ocimum species viz., Ocimum basilicum Linn. (alt. Ocimum basilicum var. minimum, Ocimum basilicum var. purpurience), Ocimum campechianum Mill., Ocimum canum Sims. (Ocimum americanum), Ocimum citriodorum, Ocimum gratissimum Linn., Ocimum kilimandscharicum Linn., Ocimum micranthum Willd., Ocimum sanctum Linn., (alt. Ocimum tenuiflorum Linn.), Ocimum selloi Benth., Ocimum trichodon, Ocimum utricifolium from different geographical regions. A considerable difference in chemical composition of a particular species is found, which may be due to their occurrence in different eco-climatic zones and changes in edaphic factors. Attention is also focused on the biological properties of Ocimum oils which are related to their various interesting applications as antimicrobial, antioxidant, repellent, insecticidal, larvicidal, nematicidal and therapeutic (anti-inflammatory, antinociceptive, antipyretic, antiulcer, analgesic, anthelmintic, anticarcinogenic, skin permeation enhancer, immunomodulatory, cardio-protective, antilipidemic) agents.
ABSTRACT
INTRODUCTION: TGF-ß1 is a multi-functional cytokine that plays an important role in breast carcinogenesis. Critical role of TGF-ß1 signaling in breast cancer progression is well documented. Some TGF-ß1 polymorphisms influence its expression; however, their impact on breast cancer risk is not clear. METHODS: We analyzed 1222 samples in a candidate gene-based genetic association study on two distantly located and ethnically divergent case-control groups of Indian women, followed by a population-based genetic epidemiology study analyzing these polymorphisms in other Indian populations. The c.29C>T (Pro10Leu, rs1982073 or rs1800470) and c.74G>C (Arg25Pro, rs1800471) polymorphisms in the TGF-ß1 gene were analyzed using direct DNA sequencing, and peripheral level of TGF-ß1 were measured by ELISA. RESULTS: c.29C>T substitution increased breast cancer risk, irrespective of ethnicity and menopausal status. On the other hand, c.74G>C substitution reduced breast cancer risk significantly in the north Indian group (pâ=â0.0005) and only in the pre-menopausal women. The protective effect of c.74G>C polymorphism may be ethnicity-specific, as no association was seen in south Indian group. The polymorphic status of c.29C>T was comparable among Indo-Europeans, Dravidians, and Tibeto-Burmans. Interestingly, we found that Tibeto-Burmans lack polymorphism at c.74G>C locus as true for the Chinese populations. However, the Brahmins of Nepal (Indo-Europeans) showed polymorphism in 2.08% of alleles. Mean TGF-ß1 was significantly elevated in patients in comparison to controls (p<0.001). CONCLUSION: c.29C>T and c.74G>C polymorphisms in the TGF-ß1 gene significantly affect breast cancer risk, which correlates with elevated TGF-ß1 level in the patients. The c.29C>T locus is polymorphic across ethnically different populations, but c.74G>C locus is monomorphic in Tibeto-Burmans and polymorphic in other Indian populations.
Subject(s)
Breast Neoplasms/epidemiology , Breast Neoplasms/genetics , Carcinoma/epidemiology , Carcinoma/genetics , Polymorphism, Single Nucleotide , Transforming Growth Factor beta1/genetics , Adult , Aged , Aged, 80 and over , Alleles , Asian People , Breast Neoplasms/ethnology , Carcinoma/ethnology , Case-Control Studies , Female , Genetic Predisposition to Disease , Humans , India/epidemiology , Menopause , Middle Aged , Premenopause , Risk Factors , White PeopleABSTRACT
The m.10398G>A polymorphism in the MT-ND3 gene has been linked to the manifestation of several neurodegenerative disorders and cancers. Several research groups have analyzed the association between m.10398G>A polymorphism and breast cancer; however, the results do not follow a consensus. We have studied this polymorphism in three Dravidian populations from South India. Analysis on 716 cases and 724 controls found no association between m.10398G>A polymorphism and breast cancer [OR = 0.916 (0.743-1.128); P = 0.409]. Menopausal stratification also revealed no significant association in either pre-menopausal or post-menopausal breast cancer groups. In addition, we undertook a meta-analysis on 16 study groups, comprising a total of 7202 cases and 7490 controls. The pooled odds ratio suggested no significant association of m.10398G>A substitution with breast cancer [OR = 1.016 (0.85-1.22); P = 0.86]. In conclusion, there is no evidence of association between m.10398G>A polymorphism and breast cancer risk among South Indian women. Meta-analysis suggested no overall correlation between this polymorphism and breast cancer risk.
Subject(s)
Breast Neoplasms/genetics , DNA, Mitochondrial/genetics , Ethnicity/genetics , Female , Humans , IndiaABSTRACT
BACKGROUND: Cytokines are known as important regulators of the entire gamut of cancer from initiation, invasion and metastasis. This fact and plethora of gene polymorphism data prompted us to investigate cytokine gene polymorphisms in breast cancer (BC) patients. METHODS: Selected polymorphisms in the IL-1ß [-511 T>C (rs16944) and +3954 C>T (rs1143634)]; IL-6 [-174 G>C (rs1800795)]; IL-10 [-1082 A>G (rs1800896), -819 T>C (rs1800871) and -592 A>C (rs1800872)] genes were genotyped in 200 BC patients and 200 healthy volunteers in a case-control study using PCR-RFLP and direct DNA sequencing techniques. Peripheral cytokine levels were measured using ELISA. Allele and genotype data were analyzed for significance of differences between cases and controls using Chi-Square [χ(2)] test. Two sided P-values of less than 0.05 were considered to be statistically significant. RESULTS: Peripheral level of all three cytokines did not show any significant difference between cases and controls. Allele and genotype frequency of IL-1ß [-511 T>C (rs16944)] did not show any difference between cases and controls. On the other hand mutant allele and genotype at IL-1ß [+3954 C>T (rs1143634)] associated with increased risk of BC. This was also true for pre-menopausal cases and for mutant genotype in post-menopausal cases. Mutant allele and genotypes at IL-6 [-174 G>C (rs1800795)] appeared to be protective in nature such that controls had a higher frequency of both mutant alleles and genotypes. None of the three SNPs in IL-10 gene associated with risk of BC, except significant association of mutant allele and genotypes of -1082 A>G (rs1800896) polymorphism with postmenopausal BC. CONCLUSIONS: Mutant allele and genotype at IL-1ß [+3954 C>T (rs1143634)] site associated with increased BC risk, while mutant allele and genotypes at IL-6 [-174 G>C (rs1800795)] polymorphism appeared to be protective. Also, there was significant association of mutant allele and genotypes of IL-10 [-1082 A>G (rs1800896)] with postmenopausal BC. None of the other polymorphisms investigated appear to affect BC risk.
Subject(s)
Breast Neoplasms/genetics , Genetic Predisposition to Disease/genetics , Interleukin-10/genetics , Interleukin-1beta/genetics , Interleukin-6/genetics , Polymorphism, Single Nucleotide , Adult , Aged , Aged, 80 and over , Alleles , Breast Neoplasms/blood , Case-Control Studies , Chi-Square Distribution , Cohort Studies , Enzyme-Linked Immunosorbent Assay , Gene Frequency , Genotype , Humans , Interleukin-10/blood , Interleukin-1beta/blood , Interleukin-6/blood , Middle Aged , Polymerase Chain Reaction , Polymorphism, Restriction Fragment Length , Risk Factors , Young AdultABSTRACT
End-organ resistance to androgens, called androgen insensitivity syndrome (AIS), is a rare disorder. The most common cause of AIS is mutations(s) in the androgen receptor (AR) gene; however, a significant number of these mutations have not been functionally analyzed. In the present study, we analyzed a case of complete AIS for mutations in the AR gene. Sequencing of the entire coding region of the AR gene revealed a 2650G>A mutation (mRNA sequence reference) in exon 4 of the gene, resulting in replacement of glycine with glutamate at codon 708 in the ligand-binding domain of the AR protein. The mutation was absent in 200 normal male individuals analyzed to look at its occurrence in general population. In vitro androgen-binding and transactivation assays showed that the mutation resulted in approximately 65% loss of ligand binding and almost complete loss of transactivation function. Complete AIS in this individual was due to a G708E substitution in the AR protein.
Subject(s)
Androgen-Insensitivity Syndrome/genetics , Receptors, Androgen/genetics , Amino Acid Sequence , Amino Acid Substitution , Animals , COS Cells , Chlorocebus aethiops , Humans , Male , Molecular Sequence Data , Sequence AlignmentABSTRACT
TNF-α and -ß, the multi-functional pro-inflammatory cytokines, are known to play important roles in both tumor progression and destruction based on their concentrations. Growth factors and various stimuli such as cytokines regulate proliferation of the breast epithelial cells. Therefore, the polymorphisms in the genes encoding these signaling molecules could affect the risk of breast cancer. We have investigated selected genetic polymorphisms in TNF-α promoter (rs1800629, -308 G>A and rs361525, -238 G>A) and TNF-ß intron 1 (rs909253, +252 A>G) in ethnically two different case-control groups from India. The study included 200 cases and 200 controls from an Indo-European (North Indian) group, and 265 cases and 237 controls from a Dravidian (South Indian) group. Genotyping of a total of 902 individuals was done by direct DNA sequencing. None of the polymorphisms showed significant association with breast cancer in the Indo-European group; however, all the three polymorphisms showed strong association with breast cancer in the Dravidian group. Further, sub-group analysis in the Indo-European group showed no significant difference between pre-menopausal cases and controls or between post-menopausal cases and controls at any of the loci analyzed. However, all the polymorphisms in the Dravidian group were significantly associated with pre-menopausal but not with post-menopausal breast cancer. In conclusion, TNF-α and -ß polymorphisms are strongly associated with breast cancer in the Dravidian but not in the Indo-European group.
Subject(s)
Breast Neoplasms/ethnology , Breast Neoplasms/genetics , Genetic Variation , Lymphotoxin-alpha/genetics , Polymorphism, Genetic , Tumor Necrosis Factor-alpha/genetics , Adult , Aged , Aged, 80 and over , Breast/metabolism , Case-Control Studies , Ethnicity , Female , Genotype , Humans , India , Menopause , Middle Aged , RiskABSTRACT
We analyzed the length of the CAG repeats of the androgen receptor gene in Indian women with breast cancer, and compared the data with that of other populations across the world in an attempt to find a potential pattern of association. The study was undertaken on 1,408 individuals comprising 747 breast cancer patients and 661 control individuals recruited from three southern states of India: Andhra Pradesh, Tamil Nadu, and Karnataka. The comparison revealed no difference in mean length of the repeat between cases and controls in any of the three groups or in the analysis of pooled data. No significant difference between pre- and post-menopausal cases in any of the three groups or in the analysis of pooled data was observed. Most of the studies to date support either positive association (longer repeats--increased disease risk) or no association, and only 2 out of 20 studies reported negative association (inverse correlation between repeat length and disease risk). Comparison of these data with those from other populations revealed several interesting facts. Particularly notable is that repeat length shows association with breast cancer risk in a population-specific manner with most of the studies on American and Canadian women showing positive association, whereas those on Australian and Israeli women showing no association. Only one study had been conducted on other populations including Asians/South Asians; this restricted us from finding any patterns of association in these populations.
Subject(s)
Breast Neoplasms/genetics , Genetic Association Studies , Polymorphism, Genetic , Receptors, Androgen/genetics , Tandem Repeat Sequences , Adolescent , Adult , Aged , Aged, 80 and over , Androgens/genetics , Female , Genetic Predisposition to Disease , Humans , India , Middle Aged , Risk FactorsABSTRACT
BACKGROUND & OBJECTIVE: Hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome), is a genetically heterogeneous disorder that is believed to account for 2-10 per cent of all the colorectal cancer cases. The disease follows autosomal dominant inheritance pattern with high penetrance (85%) and younger age of onset when compared to patients with sporadic tumours. HNPCC is associated with germ-line mutations in the DNA mismatch repair (MMR) genes namely MLH1, MSH2, MSH6, and PMS2. The present study was aimed at analyzing mismatch repair gene(s) in an extended Indian family satisfying the Amsterdam criteria, and extending the analysis to general population to estimate frequency of the mutations/polymorphisms observed. METHODS: A total 12 members of the HNPCC family were studied for genetic investigation. Ethnically matched 250 normal individuals were also included as controls to study the observed mutations/polymorphisms at population level. RESULTS: The analysis resulted in identification of a 1975C>T mutation in exon 17, resulting in substitution of arginine residue with stop codon at codon 659. 655A>G substitution was also observed, resulting in replacement of isoleucine with valine at codon 219. Similar analysis on 250 ethnically matched control subjects revealed complete absence of R659X mutation, while I219V variant was found in 9.8 per cent of the controls. INTERPRETATION & CONCLUSION: R659X mutation correlates with disease phenotype, and 655A>G locus is highly polymorphic. Our study suggested that R659X substitution was prime cause for the disease phenotype in this family. I219V substitution is a polymorphism having no association with the disease onset or segregation. The family members harbouring this mutation were advised to be under regular medical surveillance.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Mutation , Nuclear Proteins/genetics , Aged , Base Pair Mismatch , Base Sequence , DNA Primers , DNA Repair/genetics , Exons , Female , Humans , India , Male , Middle Aged , MutL Protein Homolog 1 , PedigreeABSTRACT
Testosterone is converted to 5 alpha-dihydrotestosterone (DHT) by 5 alpha-reductase enzyme, which is encoded by the SRD5A2 gene. DHT is the main androgen responsible for prostate growth. We have analyzed the complete coding region of the SRD5A2 gene in 87 histologically confirmed prostate cancer (PC) patients, 40 benign prostatic hyperplasia (BPH) cases, and 96 control samples from southern parts of India. The study revealed the A49T site to be monomorphic, the V89L site to be highly polymorphic, and the (TA)(n) repeat site to be polymorphic with only 2 alleles in our populations. The distribution of V89L alleles between PC cases and controls was not significantly different; however, (TA)(9) alleles distributed differently between the 2 groups. BPH cases exhibited alleles similar to controls at all polymorphic sites. The sequencing of the whole coding region did not reveal any other known or novel polymorphism in this gene. Our study emphasizes that the (TA)(9) allele might confer certain PC risk but that A49T and V89L polymorphisms do not confer PC risk in South Indian men.