An Indian database has been created by profiling the population on the basis of changes in genes with disease linkages. THE first results from the project of the Indian Genome Variation Consortium (IGVC) have clearly demonstrated (Frontline, June 6) that even as the Indian population exhibits a genetic diversity unmatched anywhere in the world, there are within it pockets of homogeneous ethnic groups that have remained relatively genetically unadmixed. (The IGVC's multi-institutional project was set up to evolve a disease-linked genetic map of India.) The project has also shown that the Indian population includes groups that show genetic affinities to the populations of Central Europe (CE), China (CH) and Japan (JP) and are genetically well separated from the rest of the Indian groups. One of the findings of the International HapMap Project launched in 2002, which included the above population groups but significantly did not sample any Indian population groups, was that certain (functional) alleles, or variants of disease-associated genes, had distinct distribution frequencies across the groups studied, notwithstanding the fact that the sample sizes in HapMap were small. Following HapMap, but going much further, an Indian Genome Variation database (IGVdb) has been created by profiling the population on the basis of changes, or polymorphisms, in genes with established or suggested disease linkages. The database has revealed a significant differentiation of these polymorphisms across Indian population groups. At the end of the project's first phase, the IGVdb includes data on 75 genes and 405 associated polymorphisms. The data were obtained by genotyping the 1,871 samples drawn from the 54 distinct ethnic groups that represent the four major linguistic groups (Austro-Asiatic, Tibeto-Burman, Indo-European and Dravidian) and the six geographical areas of the country (north, south, east, west, central and north-east) and the one "outgroup' known to be of Negroid origin. The significance of this basal data lies in the fact that it has, for the first time, provided a proper basis for the identification of appropriate cohort groups for pooling samples in gene-disease association studies in the country. A countrywide random sampling would miss this stratification and could lead to false conclusions. Following the IGVC project, a population stratification on the basis of variants of established or candidate disease genes now exists in the Indian context, and the database could serve as the background template for a genetic map for disease risk. This article describes some studies on validated functional polymorphisms of certain disease-linked genes and the implications for the different population groups of the country of the data generated by the IGVdb. In fact, the IGVdb, particularly after its second phase, which is based on 1,000 genes and nearly 5,000 genetic markers, becomes a potential tool for population-specific, pre-emptive medical intervention in the country's public health programmes of the future. These initial association studies also indicate directions for future such investigations in India and elsewhere. "We first looked at things that we can do; disorders where the number of genes expressed is low, like the eye, muscles, diabetes and also genes which are well studied at the protein level, like the drug metabolism genes or the drug response genes where polymorphisms can lead to altered metabolism rates,' points out Samir K. Brahmachari, Director General of the Council of Scientific and Industrial Research (CSIR) and former Director of the Institute of Genomics and Integrative Biology (IGIB), the project's nodal institution. "For instance, dosage-dependent, long-acting neuropsychiatric drugs can lead to complications if the drugs are metabolised more. So the first step was to obtain data on such disorders and the associated set of gene polymorphisms on limited clinical samples,' says Brahmachari. In fact, many of the 405 gene polymorphisms used for the project were identified on the basis of several earlier clinical studies in India. "Now with the IGVdb, we can look at the frequencies of these polymorphisms across the country. One can then ask what do the data imply for countrywide population groups,' Brahmachari adds. In a significant 2001 study, Partha Majumder and Badal Dey of the Indian Statistical Institute (ISI), Kolkata, found that the bulk of the Indian population was susceptible to the human immunodeficiency virus (HIV). They studied 1,436 individuals, unrelated at least to the second cousin level and belonging to 40 ethnic groups, and found that a protective allele, a certain polymorphism of a gene called beta-chemokine receptor gene CCR5, was absent in most ethnic populations inhabiting the eastern, north-eastern, southern and central regions of the country. The highest frequency of this allele was found among Muslims of the north. This obviously has important implications for the epidemiology of HIV and for the strategy to control acquired immune deficiency syndrome (AIDS) in the country, especially when projections indicate that HIV infection will spread rapidly in India (notwithstanding the recent downward revision of infection rates). HIV gains entry into a susceptible cell through a certain family of receptors of chemokines (proteins secreted by cells), the most important of which is the CCR5 gene. But the polymorphism of the CCR5 gene (Fig.1) that confers protection against HIV-1, the dominant transmitting virus strain in India, is largely absent in Indian populations. This protective allele has a 32 base-pair deletion in the gene CCR5. Majumder and Dey also found that the individuals who were homozygous in this particular allele were the ones highly resistant to HIV-1 infection and not those who were heterozygous. Homozygotes are those who carry two copies of the allele in the paired chromosomes, at identical loci, and heterozygotes carry one copy of the allele and one copy of the unchanged gene. In some studies, heterozygotes too were found to have significantly lower viral loads. Interestingly, the ISI study found no homozygotes at all, even in populations where a few samples carried the allele. It was originally believed that non-European populations did not carry the protective allele. A more recent global survey, however, has found that the allele is present at frequencies of 2 to 5 per cent throughout Europe, West Asia and the Indian subcontinent. But the survey was limited, in the sense that it covered only the northern and western regions of the country, where the allele was found to be present at levels of 1.5 to 4.7 per cent. Majumder and Dey point out that the surveyed regions are known to have had a high admixture with Caucasians about 8,000 to 10,000 years ago, and the relatively higher frequencies in these regions may be due to the Caucasian gene flow. The ISI study, while consistent with the global survey, points to a situation of concern for the country as a whole, one that calls for appropriate disease-control strategies. The IGVdb data, whose sample size was somewhat larger than the ISI study, only seems to confirm the earlier findings. Malaria Variants of as many as 30 to 40 genes have been associated with susceptibility or resistance to Plasmodium falciparum malaria. It is also believed that malaria has been the selective pressure for several disorders of the red blood cells such as sickle cell anaemia and thalassaemia. Different population groups across the world have exhibited differential association of the disease with these genes. However, most polymorphism-disease association studies have been carried out in African and South-East Asian populations, and only limited studies exist in Indian populations. The incidence of and mortality rates from P. falciparum malaria in India are high. Several regions of the country are at "high risk' for P. falciparum, with the infection accounting for more than 80 per cent of all malaria cases in some areas (Fig. 2D). "Pathogenicity of the disease is quite different in several Indian population groups compared with African populations,' points out Saman Habib, a malaria expert at the Central Drug Research Institute (CDRI), Lucknow, and a lead scientist in the IGVC project. In a case-control study published in January, Saman Habib and associates looked at the correlation of the severity of the disease and susceptibility to severe malaria with polymorphisms in two genes known to play an important role in the pathogenesis of P. falciparum malaria. The study included 86 subjects from regions of endemicity