WITHDRAWN: Association of uncoupling protein 2 and 3 gene polymorphisms with type 2 diabetes in Asian Indians.

Ahead of Print article withdrawn by publisher.

Kalyani cohort - the first platform in Eastern India for longitudinal studies on health and disease parameters in peri-urban setting.

The Kalyani cohort created in 2010 by the National Institute of Biomedical Genomics, West Bengal, India, is designed to serve as a platform for conducting prospective basic and translational studies on epidemiology and genomics of health and disease-related parameters, particularly of non-communicable diseases (NCDs). The overall goal is to assess behavioural, biological, genetic, social and environmental factors and obtain necessary evidence for effective health improvement. Collected baseline data comprise 15727 individuals, >14 years of age from seven municipal wards in the Kalyani and Gayeshpur regions. Data are being collected on demographics, current health status, medical history and health-related behaviours. Blood samples were also collected from a subset of individuals (n = 5132) and analysed for estimation of known markers of NCDs. DNA has been extracted from blood samples and stored for future use. Important baseline findings include a high prevalence of diabetes, dyslipidemias and hypothyroidism. Prevalence estimates for these disorders obtained from self-reported data are significantly lower, indicating that participants are unaware of their health problems. The identification of 'at risk' individuals will allow formation of sub-cohorts for further investigations of epidemiological and genetic risk factors for NCDs. Access to the resource, including data and blood samples, created by this study will be provided to other researchers.

Remarkable variation in the informativeness of RFLP markers linked to hemophilia B locus in Indian population groups: implication in the strategy for carrier detection.

Hemophilia B, an X-linked recessive bleeding disorder, is caused by heterogeneous mutations in the factor IX (F9) gene. Hence, carriers of the disease are usually detected by F9 gene linked RFLP analysis. We aimed to test a set of RFLP markers (DdeI, XmnI, MnlI, TaqI & HhaI), used worldwide for carrier detection, to estimate its heterozygosity in different population groups of India, and identify additional single nucleotide polymorphisms (SNPs) if necessary. A total of 8 population groups encompassing different regions of India, consisting of 107 unrelated normal females without any history of hemophilia B in the family and 13 unrelated obligate carriers were recruited in the study. Regions of F9 gene were amplified by PCR from genomic DNA of the donors followed by restriction enzyme digestion and/or sequencing as appropriate. Combined informativeness for the markers varied between 52-86% among normal females belonging to different geographical locations of India. Haplotype analysis revealed that the most prevalent haplotype lacked the restriction sites for all five RFLP markers. Screening regions of F9 gene that harbor 10 SNPs reported in dbSNP yielded only two SNPs, which increased the overall informativeness in each population group and heterozygosity in the obligate carriers for the disease from 38% to 69%. Our data show that heterozygosity of commonly used RFLP markers is remarkably variable across different regions of India. Thus prudent selection of the markers based on specific population groups including usage of additional markers is recommended for efficient carrier detection.

Absence of the HIV-1 protective Delta ccr5 allele in most ethnic populations of India.

Recent epidemiological data and projections indicate that HIV infection will spread rapidly in India. An allele Delta ccr5 of the beta-chemokine receptor gene CCR5 has been found to confer protection against HIV-1. We find that this protective allele is absent in most ethnic populations of India, except some populations of the northern and western regions where this allele may have been introduced by Caucasian gene flow. The implications of this finding are discussed in the light of increasing HIV prevalence in India.

Human-specific insertion/deletion polymorphisms in Indian populations and their possible evolutionary implications.

DNA samples from 396 unrelated individuals belonging to 14 ethnic populations of India, inhabiting various geographical locations and occupying various positions in the socio-cultural hierarchy, were analysed in respect of 8 human-specific polymorphic insertion/deletion loci. All loci, except Alu CD4, were found to be highly polymorphic in all populations. The levels of average heterozygosities were found to be very high in all populations and, in most populations, also higher than those predicted by the island model of population structure. The coefficient of gene differentiation among Indian populations was found to be higher than populations in most other global regions, except Africa. These results are discussed in the light of two possible scenarios of evolution of Indian populations in the broader context of human evolution.

Analysis of CAG and CCG repeats in Huntingtin gene among HD patients and normal populations of India.

We have analysed the distribution of CAG and adjacent polymorphic CCG repeats in the Huntingtin gene in 28 clinically diagnosed unrelated Huntington's disease (HD) patients and in normal individuals belonging to different ethnic groups of India. The range of expanded CAG repeats in HD patients varied from 41 to 56 repeats, whereas in normal individuals this number varied between 11 and 31 repeats. We identified six CCG alleles from a total of 380 normal chromosomes that were pooled across different ethnic populations of India. There were two predominant alleles: (CCG)7 (72.6%) and (CCG)10 (20%). We report here for the first time one four-repeat CCG allele which has not been found in any population so far. We found 30 haplotypes (two loci CAG-CCG) for 380 normal chromosomes. In the present study, no statistically significant preponderance of expanded HD alleles was found on either (CCG)7 or (CCG)10 backgrounds. Our studies suggest that the overall prevalence of HD in Indian populations may not be as high as in Western populations. Further studies are necessary to identify the origin of HD mutation in these populations.

Association analysis of CAG repeats at the KCNN3 locus in Indian patients with bipolar disorder and schizophrenia.

Bipolar affective disorder and schizophrenia are severe behavioral disorders with a lifetime risk of approximately 1% in the population worldwide. There is evidence that these diseases may manifest the phenomenon of anticipation similar to that seen in diseases caused by trinucleotide repeat expansions. A recent report has implicated a potassium channel-coding gene, KCNN3, which contains a polymorphic CAG repeat in its coding region, in schizophrenia and bipolar disorder. We have tried to confirm these findings in Indian patients suffering from bipolar disorder and schizophrenia. No statistically significant evidence for the presence of an excess of longer alleles in the patient population, as compared to ethnically matched controls, was found. However, an analysis of the difference of allele sizes revealed a significantly greater number of patients with schizophrenia having differences of allele sizes > or = 5 when compared to normal controls. This finding may be of functional significance as the KCNN3 protein is thought to act as a tetramer, and a large difference in allele sizes would result in an asymmetric molecule with a different number of glutamine residues in each monomer. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:744-748, 2000.

Pattern of familial aggregation of vitiligo.

BACKGROUND AND DESIGN: Vitiligo is a disorder whose cause is not well understood. This study was undertaken to clarify whether genetic factors are involved in the pathogenesis of vitiligo. Data on 160 white kindreds living in the United States have been collected. Each family was ascertained through a proband afflicted with vitiligo. The nature and extent of familial aggregation and other relevant epidemiologic features have been determined. RESULTS: The mean age at onset of vitiligo is about 19 years in male and about 24 years in female individuals. The percentage of probands reporting one or more first-degree relatives also afflicted with vitiligo is 20%. Children of probands are found to be afflicted about 1.7 times more commonly than other first-degree relatives. The relative risk (RR) for vitiligo is about 7 for parents, about 12 for siblings, and about 36 for children. For second-degree relatives, the RR varies between 1 and 16. Relative risks for all first- and second-degree relatives, except uncles and grandsons, are significant at the 5% level. In families in which one or more relatives of the proband are afflicted with vitiligo, the intrafamilial correlation of ages at onset of vitiligo is moderate (0.6). No statistically significant effect (at the 5% level) of parental age at first childbirth was seen on the proportion of offspring afflicted with vitiligo. No significant association of some commonly related diseases (eg, thyroid disorder or alopecia areata) was observed with vitiligo or with a family history of vitiligo. CONCLUSIONS: The extent of familial aggregation of vitiligo is statistically significant. The pattern of relationship between RR and degree of kinship indicates involvement of genetic factors, although it is not consistent with single-locus mendelian transmission.

Ethnic populations of India as seen from an evolutionary perspective.

It is now widely accepted that (i) modern humans, Homo sapiens sapiens, evolved in Africa, (ii) migrated out of Africa and replaced archaic humans in other parts of the world, and (iii) one of the first waves of out-of-Africa migration came into India. India, therefore, served as a major corridor for dispersal of modern humans. By studying variation at DNA level in contemporary human populations of India, we have provided evidence that mitochondrial DNA haplotypes based on RFLPs are strikingly similar across ethnic groups of India, consistent with the hypothesis that a small number of females entered India during the initial process of the peopling of India. We have also provided evidence that there may have been dispersal of humans from India to southeast Asia. In conjunction with haplotype data, nucleotide sequence data of a hypervariable segment (HVS-1) of the mitochondrial genome indicate that the ancestors of the present austro-asiatic tribal populations may have been the most ancient inhabitants of India. Based on Y-chromosomal RFLP and STRP data, we have also been able to trace footprints of human movements from west and central Asia into India.

Recent investigations on vitiligo vulgaris.

Vitiligo is a depigmenting disorder of the skin caused by destruction of melanocytes. The depigmented skin has several abnormal functions, including some autonomic nervous functions. The inflammatory response in the depigmented skin is muted. Recent genetic and epidemiologic studies indicate that vitiligo affects men and women equally. The prevalence in the population is about one in 200. Vitiligo seems to be transmitted as a polygenic trait. New data suggest that it is not associated with autoimmune endocrine disorders, but more comprehensive studies are required.

Genetic & cultural determinants of high-density lipoprotein cholesterol & serum triglycerides among Marwaris of Calcutta.

A genetic epidemiological study of serum lipid and lipoprotein levels was conducted among families of Marwaris residents in Calcutta. A total of 210 families, comprising over 100 individuals, were studied. Analyses were performed to estimate the genetic and environmental effects on the determination of high density lipoprotein cholesterol (HDL-C) and serum triglycerides (TG). Familial correlations for HDL-C and TG were estimated: parent-child and sib-sib correlations were found to be significant. Spouse correlations were not significant. Correlations between environments of siblings were significant. Genetic analysis of data on HDL-C and TG performed under a path model, taking genetic transmission and possible environmental associations among family members into account, indicated that lipid and lipoprotein levels adjusted and standardized for age, gender, education, occupation and disease status are primarily determined by genetic factors. The effects of environmental factors were also significant, although in comparison with genetic factors these effects were much smaller. The estimated genetic heritability for HDL-C was approximately 80 per cent, while that for TG was approximately 55 per cent. The genetic effects and environmental effects were not significantly different between adults and children.

Projection of HIV infection in Calcutta.

Starting with the base year of 1991, the HIV infection projection for 1992-99 for the total, as well as various high-risk sub-populations of Calcutta, the first of its kind is provided. These projections are based on statistical methodology developed in this paper. Our methodology for spread of HIV infection takes into account various social interactions and practices and also uses available data. Rates of these interactions and practices and estimates of demographic parameters used in making projections were obtained primarily from surveys and census data. Since one of these estimated rates, that of HIV transmission rate through heterosexual encounters between an infected and an uninfected had a large range, we have provided two sets of projections based on the largest of these rates (worst-case scenario) and another that is consistent with the available data. The total projection of the number of HIV infected cases in Calcutta for 1999 is between 49,000 and 1,26,000. Separate projections are also provided for high-risk sub-groups. Among these, the sex workers expectedly will continue to manifest the highest numbers of newly infected cases. The temporal rate of increase in prevalence is projected to be alarmingly higher in the general population than even among sex workers, although the actual prevalence will continue to be the lowest in the general population compared to all other sub-groups of the population.

PIP: HIV/AIDS is spreading faster in Asia than anywhere else in the world. Findings are presented upon a statistical analysis of data on HIV seroprevalence in Calcutta. The study begins with the base year of 1991, and ends with the annual projected HIV-infected adult population of the city in 1999. A statistical methodology is developed in the paper which projects the spread of HIV infection while taking into account various social interactions and practices, and using available data. The rates of those interactions and practices and estimates of demographic parameters used in making the projections were obtained mainly from surveys and census data. The projections indicate that Calcutta could have 49,000-126,000 HIV-infected people in 1999. Separate projections are provided for the following high-risk subgroups: prostitutes, slum dwellers, and pavement dwellers. The highest number of new HIV cases is expected to be among prostitutes, but the temporal rate of increase in HIV prevalence is projected to be far higher in the general population than even among prostitutes. Actual HIV prevalence will, however, continue to be the lowest in the general population compared to all other population subgroups.

Absence of HTLV-I infection in some Indian populations.

A total of 946 adults belonging to ten population groups of Uttar Pradesh and West Bengal were screened for HTLV-I using a gelatin particle agglutination test. The percentage of seroreactive cases varied from 0 to 5.8 per cent. The overall prevalence of seroreactivity was 2 per cent. Of the 19 seroreactive cases, 15 were subjected to Western blot analysis, none could be confirmed. HTLV-I infection is, therefore, absent in these populations.

Familial resemblance for psychoactive substance use disorders: behavioral profile of high risk boys.

Familial transmission plays an etiologically important role in psychoactive substance use disorders (PSUD). The delineation of the risk status of families is central to implementation of the "high risk paradigm" in studying liability characteristics for PSUD. We have utilized a latent variable approach to characterizing familial resemblance for PSUD which incorporates elements of both the affected parent design, as well as a genetic epidemiologic indicator of familial aggregation of disease. Family resemblance scores were computed for 175 families in which fathers either met diagnostic criteria for PSUD or did not. We then compared the problem behavior profiles of 10-12 year-old boys grouped by familial resemblance for PSUD, and by paternal PSUD only. Boys grouped by paternal PSUD only had higher problem behavior scores than controls across all scales except for somatic complaints. Boys from families that have significant PSUD familial resemblance were characterized by higher scores on measures of externalizing conduct and socialization problems. Thus, the familial resemblance approach was more specific for the externalizing problem behaviors that have been described in longitudinal studies of childhood risk factors for later substance abuse.

Prepubertal sons of substance abusers: influences of parental and familial substance abuse on behavioral disposition, IQ, and school achievement.

In order to better understand the transgeneration liability for a substance abuse disorder, we investigated the impact of parental and familial substance abuse disorders on prepubertal boys. Specifically, the influence of each parent's substance abuse history and the effects of significant family aggregation of substance abuse disorders were tested as predictors of the child's behavioral disposition, IQ, and school achievement scores, while controlling for socioeconomic status (SES). Sons of substance abusing fathers were found to have higher externalizing and internalizing problem-behavior scores, lower IQ scores, and lower school achievement scores. Internalizing and externalizing problem-behavior scores were most strongly associated with bilineal parental substance abuse, whereas SES and paternal substance abuse were most strongly associated with IQ and school performance scores. The results are compatible with the hypothesis that although paternal substance abuse has an adverse impact on the son's functioning, bilineal parental substance abuse is associated with the greatest behavioral deviancy among prepubertal males and is associated with a greater liability for substance abuse.

High-resolution analysis of Y-chromosomal polymorphisms reveals signatures of population movements from Central Asia and West Asia into India.

Linguistic evidence suggests that West Asia and Central Asia have been the two major geographical sources of genes in the contemporary Indian gene pool. To test the nature and extent of similarities in the gene pools of these regions we have collected DNA samples from four ethnic populations of northern India, and have screened these samples for a set of 18 Y-chromosome polymorphic markers (12 unique event polymorphisms and six short tandem repeats). These data from Indian populations have been analysed in conjunction with published data from several West Asian and Central Asian populations. Our analyses have revealed traces of population movement from Central Asia and West Asia into India. Two haplogrops, HG-3 and HG-9, which are known to have arisen in the Central Asian region, are found in reasonably high frequencies (41.7% and 14.3% respectively) in the study populations. The ages estimated for these two haplogroups are less in the Indian populations than those estimated from data on Middle Eastern populations. A neighbour-joining tree based on Y-haplogroup frequencies shows that the North Indians are genetically placed between the West Asian and Central Asian populations. This is consistent with gene flow from West Asia and Central Asia into India.

Working status and anxiety levels of urban educated women in Calcutta.

The primary objective of the present study was to assess the impact of out-of-home employment on anxiety levels of mothers. A study group of working mothers resident in Calcutta (India) was compared with a socioeconomically similar group of non-working mothers with respect to their anxiety level, measured by the Anxiety Scale Questionnaire, in terms of the total anxiety score and its various personality components. The possible relationships between anxiety score and age of these mothers as well as their children were studied. Non-working mothers showed higher anxiety levels than their working counterparts with respect to the total anxiety score as well as its components, although the differences were statistically non-significant. The anxiety scores of non-working mothers showed increasing values with increasing age of children. This trend was absent among the working mothers. The age of these mothers was not related to their anxiety level.

Portability of tag SNPs across isolated population groups: an example from India.

Isolated population groups are useful in conducting association studies of complex diseases to avoid various pitfalls, including those arising from population stratification. Since DNA resequencing is expensive, it is recommended that genotyping be carried out at tagSNP (tSNP) loci. For this, tSNPs identified in one isolated population need to be used in another. Unless tSNPs are highly portable across populations this strategy may result in loss of information in association studies. We examined the issue of tSNP portability by sampling individuals from 10 isolated ethnic groups from India. We generated DNA resequencing data pertaining to 3 genomic regions and identified tSNPs in each population. We defined an index of tSNP portability and showed that portability is low across isolated Indian ethnic groups. The extent of portability did not significantly correlate with genetic similarity among the populations studied here. We also analyzed our data with sequence data from individuals of African and European descent. Our results indicated that it may be necessary to carry out resequencing in a small number of individuals to discover SNPs and identify tSNPs in the specific isolated population in which a disease association study is to be conducted.

Rage gene promoter polymorphisms and diabetic retinopathy in a clinic-based population from South India.

PURPOSE: The main objective of this study was to evaluate if the -429T/C, -374T/A and 63 bp deletion polymorphisms in the RAGE gene are associated with diabetic retinopathy (DR) among Type 2 diabetic subjects in a clinic-based population from South India. METHODS: We screened 149 normal glucose tolerant subjects (NGT), 189 Type 2 diabetes subjects without retinopathy (DM) and 190 subjects with DR for these polymorphisms using the PCR-RFLP method. DR was diagnosed by grading color fundus photography. Logistic regression models were used to evaluate the association of individual polymorphisms with DR. Expectation-maximization algorithms were implemented in haplotype tests of association to examine the combined effects of -429T/C and -374T/A polymorphisms on DR. RESULTS: The allelic frequencies of -429T are 0.83 in NGT, 0.84 in DM and 0.85 in DR subjects, and that of -374T are 0.93 in NGT, 0.92 in DM and 0.88 in DR subjects. The -374 polymorphism was found to be associated with non-proliferative retinopathy when this subgroup was compared to the DM group (OR=1.814, 95% CI=1.005-3.273). However, this association was not obvious when both the subphenotypes of DR (the nonproliferative and proliferative DR groups) were studied jointly. We found no evidence for associations between the -429T/C polymorphism and the DR phenotype. Finally, extension to a 2-SNP haplotype did not reveal any significant statistical difference between the groups (P=0.668). CONCLUSION: In this study, we found a modest association with the -374T/A polymorphism in the nonproliferative DR subgroup.