An Investigation of Genome-Wide Studies Reported Susceptibility Loci for Ulcerative Colitis Shows Limited Replication in North Indians

Genome-Wide Association studies (GWAS) of both Crohn's Disease (CD) and Ulcerative Colitis (UC) have unearthed over 40 risk conferring variants. Recently, a meta-analysis on UC revealed several loci, most of which were either previously associated with UC or CD susceptibility in populations of European origin. In this study, we attempted to replicate these findings in an ethnically distinct north Indian UC cohort. 648 UC cases and 850 controls were genotyped using Infinium Human 660W-quad. Out of 59 meta-analysis index SNPs, six were not in the SNP array used in the study. Of the remaining 53 SNPs, four were found monomorphic. Association (p<0.05) at 25 SNPs was observed, of which 15 were CD specific. Only five SNPs namely rs2395185 (HLA-DRA), rs3024505 (IL10), rs6426833 (RNF186), rs3763313 (BTNL2) and rs2066843 (NOD2) retained significance after Bonferroni correction. These results (i) reveal limited replication of Caucasian based meta-analysis results; (ii) reiterate overlapping molecular mechanism(s) in UC and CD; (iii) indicate differences in genetic architecture between populations; and (iv) suggest that resources such as HapMap need to be extended to cover diverse ethnic populations. They also suggest a systematic GWAS in this terrain may be insightful for identifying population specific IBD risk conferring loci and thus enable cross-ethnicity fine mapping of disease loci

Genetic assessment of some phenotypic variants of rice (Oryza spp.) for some quantative characters under the Gangatic plains of West Bengal

Twenty two (22) recombinant inbreed lines (RIL’s) derived from interspecific cross derivative of Oryza sativa and Oryza rufipogon along with two local check varieties MTU 7029 and Ranjit were evaluated in randomized block design (RBD) with two replications at two different environments (1st at Regional Research Station, New Alluvial Zone (NAZ), Bidhan Chandra Krishi Viswavidyalaya, Sub-Centre, Chakdah, Nadia, West Bengal during Kharif season 2009 and 2nd at Instructional Farm, Bidhan Chandra Krishi Viswavidyalaya, Jaguli, Nadia, during Kharif season 2010), to study the polygenic variations in yield for yield and its attributing characters and their cause and effect relationship. The analysis of variances revealed the significant differences among the 24 genotypes against all the characters except panicle weight, grain length, grain breadth and grain L/B ratio. The magnitude of phenotypic coefficients of variation (PCV) was higher than genotypic coefficients of variation (GCV) for all the characters suggesting the influences of the environmental forces on the expression of these characters. High PCV and GCV values were observed in grain yield per plant, 1000 grain weight, L/B ratio, grain breadth and panicle weight. High heritability coupled with moderate to high genetic advance as percent of mean for plant height, panicle weight, grain length, grain L/B ratio, 1000 grain weight and yield per plant while low heritability estimates along with low genetic advance were observed for fertility percentage and florets number per panicle. In general, genotypic correlation coefficients were higher than their corresponding phenotypic correlation coefficients. Path coefficient analysis revealed that number of characters chosen was very much appropriate as evident from low value of residual effect. Maximum positive direct effect was imparted by number of gains per panicle followed by grain L/B ratio, days to 50% flowering and panicle length respectively. Florets number per panicle imparted the maximum negative direct effect followed by grain breadth, fertility percentage and panicle number per plant. Per se performance revealed that two lines viz; KS-7 and KS-13 were promising in respect of grain yield and some other yield related traits. Number of grains per panicle and floret number per panicle give significant positive correlation with yield. Key words: Correlation, genotypic coefficients of variation, genetic advance, heritability, phenotypic coefficients of variation, rice, recombinant inbreed lines

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Molecular interactions of the physiological anti-hypertensive peptide catestatin with the neuronal nicotinic acetylcholine receptor

Catestatin (CST), a chromogranin-A-derived peptide, is a potent endogenous inhibitor of the neuronal nicotinic acetylcholine receptor (nAChR). It exerts an anti-hypertensive effect by acting as a 'physiological brake' on transmitter release into the circulation. However, the mechanism of interaction of CST with nAChR is only partially understood. To unravel molecular interactions of the wild-type human CST (CST-WT) as well as its naturally occurring variants (CST-364S and CST-370L, which have Gly -> Ser and Pro -> Leu substitutions, respectively) with the human alpha 3 beta 4 nAChR, we generated a homology-modeled human alpha 3 beta 4 nAChR structure and solution structures of CST peptides. Docking and molecular dynamics simulations showed that similar to 90% of interacting residues were within 15 N-terminal residues of CST peptides. The rank order of binding affinity of these peptides with nAChR was: CST-370L > CST-WT > CST-364S; the extent of occlusion of the receptor pore by these peptides was also in the same order. In corroboration with computational predictions, circular dichroism analysis revealed significant differences in global structures of CST peptides (e. g. the order of alpha-helical content was: CST-370L > CST-WT > CST-364S). Consistently, CST peptides blocked various stages of nAChR signal transduction, such as nicotine-or acetylcholine-evoked inward current, rise in intracellular Ca2+ and catecholamine secretion in or from neuron-differentiated PC12 cells, in the same rank order. Taken together, this study shows molecular interactions between human CST peptides and human alpha 3 beta 4 nAChR, and demonstrates that alterations in the CST secondary structure lead to the gain of potency for CST-370L and loss of potency for CST-364S. These findings have implications for understanding the nicotinic cholinergic signaling in humans

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Functional Genetic Variants of the Catecholamine-Release-Inhibitory Peptide Catestatin in an Indian Population ALLELE-SPECIFIC EFFECTS ON METABOLIC TRAITS

Catestatin (CST), a chromogranin A (CHGA)-derived peptide, is a potent inhibitor of catecholamine release from adrenal chromaffin cells and postganglionic sympathetic axons. We re-sequenced the CST region of CHGA in an Indian population (n = 1010) and detected two amino acid substitution variants: G364S and G367V. Synthesized CST variant peptides (viz. CST-Ser-364 and CST-Val-367) were significantly less potent than the wild type peptide (CST-WT) to inhibit nicotine-stimulated catecholamine secretion from PC12 cells. Consistently, the rank-order of blockade of nicotinic acetylcholine receptor (nAChR)-stimulated inward current and intracellular Ca2+ rise by these peptides in PC12 cells was: CST-WT > CST-Ser-364 > CST-Val-367. Structural analysis by CD spectroscopy coupled with molecular dynamics simulations revealed the following order of alpha-helical content: CST-WT > CST-Ser-364 > CST-Val-367; docking of CST peptides onto a major human nAChR subtype and molecular dynamics simulations also predicted the above rank order for their binding affinity with nAChR and the extent of occlusion of the receptor pore, providing a mechanistic basis for differential potencies. The G364S polymorphism was in strong linkage disequilibrium with several common CHGA genetic variations. Interestingly, the Ser-364 allele (detected in similar to 15% subjects) was strongly associated with profound reduction (up to similar to 2.1-fold) in plasma norepinephrine/epinephrine levels consistent with the diminished nAChR desensitization-blocking effect of CST-Ser-364 as compared with CST-WT. Additionally, the Ser-364 allele showed strong associations with elevated levels of plasma triglyceride and glucose levels. In conclusion, a common CHGA variant in an Indian population influences several biochemical parameters relevant to cardiovascular/metabolic disorders

List of significant (p<0.05) SNPs in and around IL23R gene.

<p>List of significant (p<0.05) SNPs in and around IL23R gene.</p

Association status of 59 GWAS reported UC/CD specific susceptibility loci in a north Indian UC cohort.

<p> <b>^a</b><b>Mc Govern, et al., Genome-wide association identifies multiple ulcerative colitis susceptibility loci (2010) Nat Genet.; 42(4):332–7.</b></p><p> <b>^b</b><b>Monomorphic.</b></p><p> <b>^c</b><b>SNPs not in the Illumina Human600W-Quad used in this study.</b></p><p>*<b>p<0.05.</b></p><p>**<b>Significant after Bonferroni correction.</b></p