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Genetic Variation Studies in Candidate Genes Related to Type 2 Diabetes in Mizo Population, Mizoram

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Genetic Variation Studies in Candidate Genes Related to Type 2 Diabetes in Mizo Population, Mizoram Genetic variation studies in candidate genes related to Type 2 Diabetes in Mizo population, Mizoram By FREDA LALROHLUI Department of Biotechnology Submitted In partial fulfillment of the requirement of the Degree of Doctor of Philosophy in Biotechnology of Mizoram University, Aizawl Department of Biotechnology School of Life Sciences MIZORAM UNIVERSITY (A Central University Accredited with “A Grade” by NAAC) Aizawl - 796 004, Mizoram, India Dr. N. Senthil Kumar Ph.D Professor Mobile: +91-9436352574 Email: [email protected] -------------------------------------------------------------------------------------------------------------------------------------- CERTIFICATE This is to certify that the thesis entitled “Genetic variation studies in candidate genes related to Type 2 Diabetes in Mizo population, Mizoram” to Mizoram University for the award of the degree of Doctor of Philosophy Biotechnology by Freda Lalrohlui Registration No. MZU/Ph.D/ 841 of 22.04.2016, Ph.D scholar in the Department of Biotechnology, under my guidance and supervision and has not been previously submitted for the award of any degree in any Indian or foreign University. She has fulfilled all criteria prescribed by the UGC (Minimum Standard and Procedure governing Ph.D. Regulations). She has fulfilled the mandatory publication (Publication enclosed) and completed Ph.D. course work. This also certifies that the scholar has been admitted in the Department through an entrance test, followed by an interview as per clause 9(i) and (ii) of the UGC Regulation 2009. Place:MZU Date:3rd October (Prof. N. Senthil Kumar) Supervisor i Declaration of the Candidate I, Freda Lalrohlui, hereby declare that the subject matter of this thesis entitled “Genetic variation studies in candidate genes related to Type 2 Diabetes in Mizo population, Mizoram” is a record of work done by me, that the contents of this thesis did not form basis of the award of any previous degree to me or to the best of my knowledge to anybody else, and that the thesis had not been submitted by me for any research degree in any other University/Institute. This is being submitted to Mizoram University for the award of the degree of Doctor of Philosophy in Biotechnology. Date: (Freda Lalrohlui) Candidate (Dr. Th. Robert Singh) (Prof. N. Senthil Kumar) Head Supervisor ii Acknowledgements • First and foremost, I would like to thank GOD for giving me strength, health and endurance to complete this work. • I would like to acknowledge my indebtedness and render my deepest gratitude to my supervisor Prof. N. Senthil Kumar, Biotechnology, Mizoram University for his guidance and support and for being a great mentor throughout my research. • I am also thankful to Dr.Th. Robert Singh, Head, Department of Biotechnology and all the faculties and non- teaching staff for their help, support and kind cooperation. • I would also like to express my deepest gratitude to all the participants who volunteered for this study. • I would also like to thank Advanced Level State Biotech Hub (BT/04/NE/2009) facility and Bio-informatics Infrastructure Facility (No.BT/BI/12/060/2012(NER-BIF-MUA), sponsored by Department of Biotechnology (DBT), New Delhi, Govt. of India for infrastructure support to carry out this work successfully . • I am thankful to Department of Science and Technology, New Delhi for providing DST-INSPIRE fellowship (DST/INSPIRE/03/2015/001832). • I owe my gratitude to Dr. John Zohmingthanga, Deputy Medical Superintendent, Civil Hospital, Aizawl and Genesis Laboratory, Dawrpui, Aizawl. • To all my lab mates and research scholars at Department of Biotechnology for their support. • Last but not the least, I would like to thank my family for their constant support and prayers and I would like to dedicate my work to my grandparents, Rev Tlanglawma (L) and Thansiami (L). Dated: Place: Aizawl, Mizoram Freda Lalrohlui iii Abbreviations and Symbols ~ Approximately °C Degree celcius ≥ Greater than or equal to ≤ Less than or equal to % percentage ± Plus or Minus A Adenine ANOVA Analysis Of Variance BAM Binary Alignment Map BLAST Basic Local Alignment Search Tool BMI Body Mass Index bp Base Pair C Cytosine CI Confidence Interval DNA Deoxyribonucleic Acid dNTPs deoxyribonucleotide triphosphate e.g. Exempli gratia : For example et al. et alii: and others etc. et cetera: and other things G Guanine GOD-POD Glucose Oxidase-peroxidase HGNC HUGO Gene Nomenclature Committee mg/dl Milli gram per deciliter ml milli litre mM Milli Molar MODY Maturity Onset Diabetes of the Young mtDNA Mitochondrial Deoxyribonucleic acid iv n Number NCBI National Center of Biotechnology Information ng/μl nanogram per microlitre nm Nanometre OMIM Online Mendelian Inheritance in Man OR Odds Ratio PCR Polymerase Chain Reaction pH Negative Ion Of Hydrogen Ion Concentration pmol Pico-Mol rCRS revised Cambridge Reference Sequence RNA Ribonucleic Acid ROC Receiver operating characteristic curve SAM Sequence Alignment Map SD Standard Deviation SNP Single Nucleotide Polymorphism SPSS Statistical Package for the Social Sciences T Thymine T2DM Type 2 diabetes Mellitus TE Tris Acetate EDTA v TABLE OF CONTENTS Contents Page No. Certificate…………………………………………………..… i Declaration………………………………………………….... ii Acknowledgements……………………………………….…. iii Abbreviations and symbols……………………………….… iv-v Table of Contents………………………………………….… vi List of Figures……………………………………………….. vii-viii List of Tables……………………………………………….… ix-x Chapter I: Introduction………………………………………. 1-10 Chapter II: Review of Literature………………………….… 11-24 Chapter III: Aim and Objectives……………………………. 25-26 Chapter IV: Materials and Methods………………………... 27-44 Chapter V: Results………………………………………....... 45-78 Chapter VI: Discussion………………………………….….. 79-90 Chapter VII : Summary and Conclusion………………...…. 91-95 References………………………………………………....… 96-107 Appendices: Appendix I…………………………………..…. 108-110 Appendix II…………………………………… 111-112 Appendix III……………….………………..… 113-114 vi List of Figures Figure 2.1 Common risk factors for type 2 diabetes development Figure 2.2 Schematic representation of type 2 diabetes development Figure 2.3 Schematic representation of genetic factors in relation with type 2 diabetes Figure 5.1 Estimated ROC curve for the significant demographic factors in multivariate analysis Figure 5.2 Scatter plot showing comparison of different clinical factors (after performing t-test) between male and female diabetic patients Figure 5.3 Graphical representation of type 2 diabetes mellitus and control groups with respect to salivary protein levels (mean± standard levels) Figure 5.4 Graphical representation of type 2 diabetes mellitus and control groups with respect to serum protein levels (mean± standard levels) Figure 5.5 Graphical representation of type 2 diabetes mellitus and control groups with respect to microalbumin levels (mean± standard levels) Figure 5.6 Representative Image of Genomic DNA Isolated from Blood samples Figure 5.7 Amplified products of A: KCNJII, B: HNF1A, C: PPARG, D: HNF4A genes vii Figure 5.8 G>C polymorphism on chromosome 12:121430908 of HNF1A gene Figure 5.9 3-D structure of mutations in samples: A=KRT18, B=CYP4A11, C=SLC4A3, D= KCNS1 genes Figure 5.10 3-D structure of mutations in samples: A=YTHDC2, B=KCNQ1, C=ACP7, D= ACP7 genes Figure 5.11 Circos plot and heat map representing Common variants of Cases and Control Figure 5.12 Circos plot and heat map representing Case specific variants viii List of Tables Table 4.1 Candidate gene primers and their associated exons Table 4.2 Ensembl, HGNC, Entrez, Uniprot and OMIM ID’s of the candidate genes from public database Table 4.3 Candidate genes selected for the study and their functional role Table 5.1 Univariate analysis of dietary and lifestyle factors Table 5.2 Multivariate analysis of dietary and lifestyle factors Table 5.3 Comparison of type 2 diabetes mellitus and control groups in relation to salivary protein (mg/dl) by ANOVA Table 5.4 Comparison of type 2 diabetes mellitus and control groups in relation to serum protein (mg/dl) by ANOVA Table 5.5 Comparison of type 2 diabetes mellitus and control groups in relation to microalbumin (mg/dl) by Paired t-test Table 5.6 Allelic frequency distribution and risk associated with UCP3 variation in Mizo population Table 5.7 Allelic frequency distribution and risk associated with MACF1 variation in Mizo population Table 5.8 Plink data showing associated genes Red denotes associated; Yellow denotes less likely associated; Black denotes not associated Table 5.9 Non synonymous variants observed in all the diabetic samples Table 5.10 Missense variants previously reported in the databases Table 5.11 Novel variants not reported in the databases ix Table 5.12 Pathways and phenotype of the genes having variants which were not reported for diabetes Table 5.13 Reported pathogenic variants based on GWAS panel Table 5.14 Unreported pathogenic variants based on GWAS panel with HOPE prediction Table 5.15 Pathways and phenotype of the genes having variants which were reported Table 5.16 InDel’s observed in the exonic region and not reported for any disease so far. Table 5.17 InDel’s observed in the intonic region and not reported for any disease so far. Table 5.18 List of genes from our study previously reported as possible prognostic or diagnostic markers. Table 5.19 Common variants of cases and controls with Mitomaster scores Table 5.20 Sample specific variants with Mitomaster scores Table 5.21 Potential impact of non-synonymous case specific as well as common variants as predicted by Pmut. Table 5.22 Common variants of cases and control in D-loop Table 5.23 Sample specific variants in D-Loop x Introduction Chapter I Introduction 1 Introduction 1. Introduction Diabetes refers to a group of polygenic metabolic diseases which may be portrayed by hyperglycemia leading to the alterations in carbohydrate, protein as well as fat metabolism, which in turn leads to the defects in the action of insulin (ADA, 2012). Once the food is ingested, it gets digested in to smaller components like carbohydrates and starch which can be converted to maltose by the action of amylase enzyme, which may be further broken down in to monosaccharide such as glucose.
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