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Angira Dasgupta,1– 3 Rahul Chakraborty,1,2 Bodhisattwa Saha,1 Himanshi Suri,1 Praveen Singh,1,2 Anurag Raj,1,2 Bhupesh Taneja,1,2 Debasis Dash,1,2 Shantanu Sengupta,1,2 Anurag Agrawal1,2 1Institute of Genomics and Integrative Biology, New Delhi, India; 2Academy of Scientific and Innovative Research, CSIR-HRDG, Ghaziabad, Uttar Pradesh, 201002, India; 3B R Singh Hospital and Centre for Medical Education and Research, Kolkata, West Bengal, IndiaCorrespondence: Angira DasguptaB R Singh Hospital and Centre for Medical Education and Research, Sealdah, Kolkata, West Bengal, IndiaTel +91 9831517266Email angiradasgupta@gmail.comBackground: Chronic mucous hypersecretion (CMH or chronic bronchitis) per se or when associated with chronic inflammatory airway diseases such as asthma or chronic obstructive pulmonary disease (COPD) has several adverse clinical consequences. The sputum fluid phase has several candidate proteins including mucins which have the potential of being therapeutic targets, but has not yet been explored in-depth. This study aimed at exploring the profile of sputum proteins in various airway diseases.Methods: Sputum from thirty-one patients with various airway diseases was collected and the fluid phase analyzed by LC-MS/MS and subsequently by sequential window acquisition of all theoretical fragments ion spectra (SWATH) (n = 15) for protein quantitation. Hierarchical clustering and functional grouping were performed.Results: A total of 185 proteins were quantitated by SWATH of which 21 proteins were identified which could distinguish between the clinical phenotypes by hierarchical clustering. Functional protein clustering revealed 4 groups: those that are inflammation related, oxidative stress related, mucin related and a cytoskeletal and calcium related group. The levels of eight proteins (Azurocidin1, Neutrophil defensin 3, Lactotransferrin, Calmodulin 3, Coronin1A, Mucin 5B, Mucin 5AC and BPI fold containing family B1) were significantly altered (relative to mean) in exacerbator prone subjects compared to nonexacerbators. Another simple but useful metric which emerged from this study was total protein concentration in sputum which was significantly higher in frequent exacerbators.Conclusion: Sputum proteins can detect the various airway disease clinical phenotypes. Total protein concentration and eight other proteins are biomarkers for frequent exacerbators. The clinical and therapeutic implications of the functional groups of proteins need further evaluation.Keywords: proteomics, chronic bronchitis, asthma, COPD, mucin, phenotyping

Coronary artery disease (CAD) has been increasing alarmingly in India. We had earlier shown that vitamin B12 deficiency is associated with CAD in Indian population. However, only about a quarter of the total vitamin B12 is internalised in the cells by the proteins transcobalamin II. Vitamin B12-bound transcobalamin II (holotranscobalamin, holoTC) is thus referred to as biologically active B12. In this study, we ascertained the levels of holoTC in 501 CAD cases and 1253 healthy controls and for the first time show that holoTC levels are significantly lower (p = 2.57E-4) in CAD (26.81 pmol/l) cases as compared to controls (29.97 pmol/l).

Transcobalamin (TCII) is a key enzyme involved in intracellular transport of vitamin B12. We had earlier shown that vitamin B12 levels are associated with Coronary Artery Disease (CAD). Herein, we evaluated the association of four nonsynonymous single nucleotide polymorphisms (SNPs) of TCII gene with CAD in 1398 individuals (589 CAD cases and 809 controls). Using logistic regression, we found that three SNPs (G1196A, C776G and C1043T) were significantly associated with CAD and one (G1196A) with vitamin B12 levels even after controlling for confounding factors. Thus, polymorphisms in TCII gene may play an important role in the etiology of CAD.

Cystathionine beta-synthase (CBS) is a key enzyme that plays a critical role in homocysteine metabolism and intracellular redox balance. We have analysed the association of the CBS 844Ins68 polymorphism alone and in combination with methylenetetrahydrofolate reductase (MTHFR C677T) and choline dehydrogenase (CHDH A119C) polymorphisms (the two polymorphisms recently shown to be associated with levels of homocysteine) with homocysteine, cysteine, folate and vitamin B(12) in 817 individuals (397 patients with coronary artery disease and 420 controls). The CBS 844Ins68 polymorphism alone or in combination with MTHFR C677T and CHDH A119C polymorphisms was not significantly associated with any of the biochemical variables studied.

Human papillomavirus is considered to be a major aetiological factor but is not sufficient for the development of cervical cancer. Other host factors, including altered homocysteine levels, a functional marker of folate inadequacy, might contribute to the carcinogenic process. Herein we investigated the potential association of homocysteine levels and MTHFR polymorphisms with cervical cancer in 203 histologically confirmed cases including 39 precancer cases and 231 healthy controls with normal cervical cytology. Both patients and controls were screened for human papillomavirus infection. We found that homocysteine and consequently cysteine levels were significantly higher in cases, both cancer and precancer (p < 0.001) than controls. However, polymorphisms in the MTHFR gene (677C/T and 1298A/C) that are reported to modulate homocysteine levels were not associated with disease. Thus, our study establishes an association of total homocysteine levels with the risk of developing carcinoma of the uterine cervix.