APOE distribution in World populations with new data from the Indian and the British populations P.P.Singh 1, M. Singh 1, S.S.Mastana 2 1. Department of Human Biology, Punjabi University, Patiala, India. 2. Human Genetics Lab., Department of Human Sciences, Loughborough University, Loughborough, UK. Introduction Apolipoprotein E (APOE) is a 299- amino acid plasma glycoprotein associated with very-low density lipoprotein (VLDL) and high-density lipoprotein (HDL). It plays a major role in lipoprotein metabolism as a ligand for receptors of the low density lipoprotein (LDL) receptor super family. The human APOE gene is on chromosome 19. The structural gene is polymorphic with three common alleles *E2, *E3, and *E4. These isoforms differ in amino acid sequence at positions 112 and 158. APOE*E3 contains cysteine at 112 and arginine at 158. APOE*E2 has cysteine at both positions, and *E4 has arginine at both sites. Several studies have revealed that genetic polymorphism of APOE gene affects the ApoE concentrations, total cholesterol, LDL cholesterol and APO B levels. Compared to the wild type allele APO*E3, the APO*E2 is associated with decrease while the APO*E4 allele tends to increase the TC, LDL-C and APO B levels. Human populations show extensive allelic variation at this locus and the gene has been associated with a variety of diseases. APOE*E4 allele is associated with increased risk for cardiovascular disease, Alzheimer disease, head trauma, cognitive decline and several other disorders and traits including successful ageing. The main purpose of this study is to a) assess genetic variation at the APOE locus in Indian and British samples and b) assess the extent and phylogeographic patterns of APOE variation in world populations. Samples and Methods Blood samples, with appropriate consent, were collected from 17 Indian caste and tribal populations and 8 populations from Britain as part of our ongoing genetic studies. In all more than 2100 samples were analysed. North India (Punjab) (Castes)- Ramdasias, Ramgarhias, Banias, Brahmins,Jatsikhs, Khatris, Scheduled castes, Lobana, Rajput, Punjabi Hindus and Punjabi Sikhs West India (Castes) Patels, Brahmins and Marathas Central India (Tribes) -Baiga, Maria Gond and Koch. Britain-NE England, NW Derbyshire, NE Derbyshire,South Derbyshire, Leicestershire, Nottinghamshire, East Midlands and West Midlands Polymorphism Analysis Genotype/Phenotypes scored by IEF or PCR based methods. Statistical Analysis Allele Frequencies: gene counting method Hardy-Weinberg equilibrium: chi-square method Correspondence analysis to assess genetic affinities. Longitude and latitudes was used for regression analysis. Allele frequency database on 272 World population/studies was compiled and used for comparative analyses. Genetic distance, correspondence and regression analyses were computed at major geographical and ethnic group levels. Spatial autocorrelation analyses. Results All populations analysed were polymorphic. Tribal populations of India showed either low frequency of APOE*E4 allele or its absence. Overall APOE*E4 frequency is low in India, though cardiovascular diseases are very common in these populations. All populations were in Hardy Weinberg equilibrium. Heterozygosity levels were higher for British populations. Conclusive heterogeneity was observed within the British and Indian populations. World population databases show extreme ranges of allele frequencies. APOE*E3 is highest in Indian and Asian populations while APOE*E2 and APOE*E4 are prominent in different regional populations of Africa. Europe is the most extensively studied region with 118 studies and shows a significant Latitudinal Cline of increasing APOE*E4 and decreasing APOE*E3. This increasing cline was not observed in Indian and Overall world populations. APOE*E2 revealed a statistically significant decreasing cline towards North in Asia ( r = , y= x , df 55, p<.05), which is not compatible with the coronary heart disease statistics in this continent. Spatial autocorrelation analysis depicts that the variation at this locus is influenced by ‘isolation by distance’ with a strong positive correlation for lower distances up to 1313 (distance class 2) kilometres. Correspondence analysis plot assigns most populations according to major ethnic groupings. In this plot African populations are most isolated and on periphery and European populations occupy a central position. Indians are in between European and Asian populations. Conclusions Appreciable APOE genetic variation observed in Indian, British and world populations. Low frequency of APOE*E4 among Indian populations warrants further analyses and its association with common diseases. Geographical cline of APOE*E4 is only significant in Europe. Natural Selection? Barriers? APOE is a good anthropogenetic marker and can be used to assess genetic relationships and disease risk analyses. Correspondence analysis plot of APOE allele frequencies Fig.4. Worldwide distribution of APOE*E4 allele Worldwide distribution of APOE*E4 allele Latitudinal Variation in World populations (Key to populations: Filled Pentagon-African, Green Triangle-South American, Red Triangle-North American, Light Blue Diamonds-Asian, Blue Diamonds-European, Circle-Indian, and Purple Square-Australian) For Details, Dr P. P. Singh/Dr M. Singh or Dr Sarabjit Mastana APOE allele frequencies