Abstract: The aim of the present study was to investigate the association between Collagen 1 alpha 1 (COL1A1) polymorphism and osteoporosis in DEXA verified 349 (145 osteoporotic, 87 osteopenic and 117 normal) postmenopausal women of India, who were not taking hormone replacement therapy. Two single-nucleotide polymorphisms (SNPs), that is, -1997G/T (rs1107946) and +1245G/T (rs1800012, Sp1) of the COL1A1 gene, were analyzed. Minor allele frequencies of rs1107946 and rs1800012 were 0.15 and 0.20 in osteoporotic women, 0.18 and 0.18 in osteopenic and 0.20 and 0.17 in women having normal bone mass. An allele dose effect with BMD of lumbar spine has been exhibited by major allele G of rs1107946 (GG: 0.86Â g/cm(2), GT: 0.91Â g/cm(2) and TT: 0.93Â g/cm(2)) and minor allele T of rs1800012 (GG: 0.91Â g/cm(2), GT: 0.87Â g/cm(2) and TT: 0.81Â g/cm(2)). Disease association analysis revealed a haplotype GT that confers approximately threefold higher risk of osteoporosis in the carriers (OR 3.12, 95% CI 1.24-8.88, PÂ =Â 0.008) after adjusting the confounding effect of age, BMI and years since menopause. These results suggest that GT haplotype of COL1A1 gene is associated with a higher risk of postmenopausal osteoporosis in Northwest Indian women.
Abstract: C-reactive protein (CRP) is a blood marker of inflammation and a hallmark of the acute-phase response. Its elevation bears negative prognostic implications for many conditions and it has also been shown to be a nonspecific predictor of long-term risk of cerebrovascular disease (CVD) in several populations, while elevations of CRP associated with the major acute-phase response following ischemic or hemorrhagic stroke are associated with death and vascular complications. High-sensitivity assays that accurately measure levels of CRP have been proposed for use in risk assessment for CVD and as a prognostic marker after an acute event, although the pathogenic and clinical significance of these associations is controversial. In this article, we critically review the literature in narrative format and describe major epidemiological studies, novel experiments and possible future developments that may inform the debate. In our discussion, we will distinguish the different pathophysiological roles of high circulating CRP concentrations in individuals with acute stroke from the modestly and persistently increased levels of CRP concentration in generally healthy subjects. However, before any clinical application is possible, a critical appraisal of the strengths and deficiencies of the accumulated evidence is required, both to consider the current state of knowledge and to inform the design of future research.
Abstract: BACKGROUND: The association of apolipoprotein E (APOE) genotypes with bone mineral density (BMD) and risk of osteoporosis have remained unclear. The influence of APOE gene polymorphisms on BMD as genetic mediators of osteoporosis risk needs to be explored in Indian postmenopausal females where this disease is rising rampantly. METHODS AND RESULTS: The present study investigated the role and relevance of four pertinent APOE single nucleotide polymorphisms: 5'UTR G/C (rs440446), Int2 G/A (rs769450), Exon4 T/C (rs429358), Exon4C/T (rs7412) in DEXA verified 133 osteoporotic, 57 osteopenic and 83 normal postmenopausal females of India, who were not taking hormone replacement therapy. Minor allele frequencies of rs440446 and rs429358 were higher in osteoporotic females (0.31, 0.18) than osteopenic (0.29, 0.15) and females having normal bone mass (0.16, 0.07). Disease association analysis revealed a susceptibility haplotype CGTC (in order of rs440446, rs769450, rs429358, rs7412) and the carriers of this haplotype has higher risk of osteopenia (OR 3.53, 95% CI 1.21-11.0, P=0.017) and osteoporosis (OR 3.61, 95% CI 1.53-9.48, P=0.002) after adjusting the confounding effect of age, BMI and years since menopause. Females who possess either one copy or two copies of the haplotype have lesser BMD values of lumbar spine (0.88 and 0.85g/cm(2)) and femoral neck (0.84 and 0.82g/cm(2)) than those females who possess zero copy (0.9 and 0.87g/cm(2), respectively). CONCLUSIONS: The present study exposed a susceptibility haplotype CGTC, within APOE gene, which was found to be associated with BMD and risk of osteopenia and osteoporosis in postmenopausal females of India.
Abstract: The epistatic effects of ApoE (HhaI) and ApoA-I (PstI) genes as the genetic modulators of lipid levels were investigated in 165 angiographically verified CHD patients and 120 controls of Punjab, a northwest province of India. It has been revealed that of all the genotypic combinations of ApoE and ApoA-I, E4 allele carriers (E4+) with P1P2 genotype (ApoA-I/PstI) had higher risk of CHD (OR 2.99, CI 1.31-6.8, P<0.01) which exacerbated (OR 3.44, CI 1.45-8.15, P<0.01) after adjustment with the confounders. Individually, neither ApoA-I nor ApoE was found to be associated with TG levels however, pairwise epistasis (additive x additive model) explored their significant synergistic contributions with raised TG levels (P<0.01).
Abstract: Genomic consequences of factor VIII gene haplotypes for the indirect genetic analysis of haemophilia A has not been done in India hitherto. Consequently, BclI/intron18, HindIII/intron 19, and XbaI/intron 22 restriction sites were investigated in 159 individuals from 42 families with hemophilia A. The frequencies of haplotype II, IV, VI, that is, BclI (+)-HindIII (-)- XbaI (+), BclI (+)HindIII (+)-XbaI (-), and BclI (-)-HindIII (-)-XbaI (+) were 0.312, 0.198, and 0.164 respectively. The high heterogeneity of haplotype II highlighted its potential for indirect genetic diagnosis of factor VIII. Analysis revealed strong but incomplete linkage disequilibrium (D' = 0.76, 0.68, and 0.51) between BclI/HindIII, HindIII/XbaI, and BclI/XbaI, respectively. The overall cumulative polymorphism information content (PIC) of these three markers increased from 0.36 to 0.80. Escalation of PIC up to 80% in the present study suggests that haplotyping of factor VIII gene determines better prognosis in the direction of indirect genetic analysis of hemophilia A.
Abstract: ABSTRACT Apolipoprotein C3 plays an important role in the receptor mediated hydrolysis of
triglyceride rich lipoproteins (TRLs) by inhibition of lipoprotein lipase (LPL), delayed clearance of
which causes hypertriglyceridemia (HTG). Indians are considered to be more vulnerable to the adverse
effects of hypertriglyceridemia and consequently its probable sequel of cardiovascular disorders.
Several studies have revealed the association of rare allele (S2) of APOC3 (SstI) polymorphism with
dyslipidemias and coronary artery diseases. In order to investigate the role and relevance of this
polymorphism in Northwest India, the present study aimed to investigate the genetic variation of 3’
untranslated region of APOC3 (SstI) in 312 individuals belonging to four endogamous groups (Banias,
Brahmins, Jatsikhs and Khatris) of Punjab. Uncommon *S2 allele frequency was 22.6%, 22.5%, 22.7%
and 26.2% in Banias, Brahmins, Jatsikhs and Khatris respectively. Higher heterozygosity of 0.39 in
Khatris reflected their greater variation at this locus than the other populations. Chi-square analysis
did not reveal any significant differences between these populations and other studies from North
India (P > 0.05). Comparative analysis of 66 other populations across the world revealed large
heterogeneity at this locus whereby, Mongoloid populations have the highest frequencies of *S2
allele (0.19 to 0.48) followed by Indians (0.18 to 0.29), Africans (0.04 to 0.27) and Caucasian populations
(0.01 to 0.12). Genetic distance and multivariate analyses showed that Indian population is quite
distinct from other Caucasian and Oriental populations. Clinal heterogeneity of predisposing *S2
allele in Asia showed an increasing cline (y = 0.0043x + 0.1209, R2 = 0.1162) towards North. As this allele
is associated with HTG and other cardiovascular complications, differential variation in different
populations may have insightful implications for association and medical genetic studies.
Abstract: In developing countries, especially in those with limited facilities and low budget resources, a reliable approach to carrier detection and prenatal diagnosis of haemophilia B might be based on indirect diagnostic strategies. As, the cost-effectiveness of indirect genetic analysis of haemophilia B has been little investigated so far, we here report our experience in India. Polymerase chain reaction analysis of DdeI/intron1, XmnI/intron 3 and HhaI/3' flanking region of the gene for factor IX (F9) was investigated in 68 individuals (23 haemophilia patients, 18 obligate carriers, 27 probable carriers) from 23 families of haemophilia B. Linkage disequilibrium analysis was done and haplotypes were generated employing the expectation-maximization algorithm. DdeI (+) and (-) allele frequencies were found to be 0.522 and 0.478, respectively, with the highest observed heterozygosity of 46.6% as compared to XmnI (24.4%) and HhaI (42.2%). The frequencies of haplotype III and VI, that is DdeI (+)-XmnI (-)-HhaI (-) and DdeI (-)-XmnI (-)-HhaI (-) were observed to be 0.363 and 0.257, respectively. Haplotype III was found to be the most heterogeneous that suggests its efficacy in the indirect genetic analysis of F9 gene. Linkage disequilibrium analysis revealed no association between DdeI/HhaI (D' = 0.092); however, significant but incomplete linkage disequilibrium was observed in XmnI/HhaI and DdeI/XmnI (D' = 0709, 0.515, respectively). The overall cumulative polymorphism information content of these three markers increased from about 0.33 to 0.72, which suggested the efficiency of haplotyping of these markers over individual gene analysis in the direction of carrier assessment of haemophilia B in India.
Abstract: BACKGROUND : The present investigation is aimed at examining the Apolipoprotein E (APOE) genotypic influence on coronary heart disease (CHD) risk in northwest India (Punjab), where this disease is emerging as a major threat to public-health care system. MATERIALS AND METHODS: The present study comprised of angiographically diagnosed coronary heart disease patients (n = 193) and controls (n = 150) of Punjab. Genetic polymorphism of APOE gene was investigated by polymerase chain reaction (PCR), and its association with lipid levels was evaluated. RESULTS : The allele frequencies of epsilon2, epsilon3, and epsilon4 were 0.054, 0.795, 0.151; and 0.077, 0.856, 0.067 in patients and controls respectively. The bearers of E3/E4 genotype had threefold higher propensity of developing CHD in this population (OR, 3.04; CI, 1.55-6.25; P < 0.001), which exacerbated (OR, 4.18; CI, 2.03-9.27; P < 0.001) after correcting for age, sex, BMI, and lipid-lowering drugs. Lower HDL-C levels and higher LDL-C levels were found to be correlated with E3/E4 genotype (P < 0.01). Other concomitants like body mass index (BMI), total cholesterol (TC), and triglyceride (TG) levels did not show up as genetic determinants in this part of the region. CONCLUSIONS : A significant association (P = 0.016) of epsilon4 allele, especially E3/E4 genotype, with CHD was observed, along with HDL-C and LDL-C concentrations, in the population of northwest India.
Abstract: The present study investigated the genetic variation of 3' flanking region of ApoA-I (PstI), 3' untranslated region of ApoC-III (SstI) and intron 2 of ApoA-IV (XbaI) in 193 angiographically diagnosed CHD patients and 150 CHD negative controls of Punjab, Northwest India. Haplotype analysis reveals that P2-S2-X1 is a susceptibility haplotype that confers the risk of CHD (OR 2.33, CI 1.08-4.38, P<0.05), which exacerbates (OR 2.61, CI 1.23-5.92, P<0.01) after adjustment with the confounders. This exacerbating effect of P2-S2-X1 may umpire significant higher levels of TG, LDL/HDL ratio and lower levels of HDL in CHD patients.
Abstract: OBJECTIVE: Post transfusion manifestations and its affiliated factors are vital to understand in a disease like hemophilia where multi-transfusions are given to the patients. METHODS: To investigate the implications of factor replacement therapy on plasma proteins, 52 hemophiliacs and 68 carrier females were examined for 12 plasma proteins using various electrophoretic techniques. RESULTS: Severe hemophiliacs showed raised levels ( p< 0.05) of a2 M, IgG and Albumins where values were found to be 4.78 +/- 0.865 g/l, 21.48 +/- 3.38 g/l, 66.26 +/- 11.92 g/l respectively at 95% confidence intervals however, controls and carriers showed trivial variations. CONCLUSION: Juxtaposing the dissimilarities of 12 plasma proteins in carriers, controls and hemophiliacs, it has been gleaned that factor replacement therapy do play role when seen in severe hemophiliacs with raised levels.
Abstract: The present study investigated genetic variation in the 3' flanking region of ApoA-I (PstI), the 3' untranslated region of ApoC-III (SstI) and intron 2 of ApoA-IV (XbaI) in 435 type 2 diabetes mellitus patients, divided according to the presence or absence of coronary heart disease (CHD). Uncommon allele frequencies (P2, S2, X2) were 17.5%, 32.5%, 16.2% and 29.5%, 17.9%, 13.8% in patients with and without CHD, respectively. Linkage disequilibrium (D' = 0.31-0.73, p<0.01) was observed in all diallelic pairs except XbaI/PstI and XbaI/SstI in patients having CHD. Haplotype analysis revealed that P1-S2-X1 is a susceptibility haplotype that increases the risk of CHD in diabetes (OR 2.85, CI 1.51-5.61), exacerbating risk (OR 3.57, CI 1.81-7.45) even after adjustment for confounders. The findings in the present study suggest that each unit of P1-S2-X1 in diabetes increases the risk of CHD by a factor of 1.37+/-0.307 (beta + SE), which is manifest in its multiplicative mode.
Abstract: Familial and epidemiological studies have shown that genetic factors play a role in the development and progression of type 2 diabetes mellitus (T2DM). Asian Indians have shown an increasing prevalence of T2DM. Apolipoprotein E (APOE) and Angiotensin-1 converting enzyme (ACE) I/D polymorphisms have been associated with T2DM. This study examined the association of APOE and ACE genes with T2DM patients of Punjab, India. APOE (HhaI) and ACE (I/D) genotypes analysed by polymerase chain reaction were available from 90 patients and 97 random healthy controls. All loci and populations are in Hardy-Weinberg equilibrium. There is no significant association of APOE vis-Ã -vis T2DM, however APOE*4 allele frequency is low in diabetics (3.9% and 8.8%). DD genotype and *D allele of ACE are associated with T2DM (OR=1.90, p<0.05, and OR=1.58, p<0.05, respectively). Recessive and multiplicative mode of inheritance for *D allele provided the strongest support for the association. Height, weight and BMI did not reveal any significant association with APO or ACE. DD-33 and ID-23 combinations (ACE-APOE) showed higher odds of 2.01 and 2.14, respectively. ACE but not APOE polymorphism is positively associated with T2DM in Indian population, however, the synergistic effects of DD-33 and ID-23 are also evident.
Abstract: BACKGROUND: The APOE gene and its protein product is associated with a number of plasma proteins like very-low density lipoprotein (VLDL), high density lipoprotein (HDL) chylomicrons, chylomicron remnants, and plays a crucial role in lipid metabolism. The APOE gene is polymorphic and common alleles (*E2, *E3 and *E4) have been associated with a number of common and complex diseases in different populations. Due to their crucial role in metabolism and clinical significance, it is imperative that allelic variation in different populations is analysed to evaluate the usage of APOE in an evolutionary and clinical context. AIM: We report allelic variation at the APOE locus in three European and four Indian populations and evaluate global patterns of genetic variation at this locus. The large, intricate and unexpected heterogeneity of this locus in its global perspective may have insightful consequences, which we have explored in this paper. SUBJECT AND METHODS: Apolipoprotein E genotypes were determined in four population groups (Punjabi Sikhs, Punjabi Hindus, Maria Gonds and Koch, total individuals = 497) of India and three regionally sub-divided British populations (Nottinghamshire, East Midlands and West Midlands, total individuals = 621). The extent and distribution of APOE allele frequencies were compared with 292 populations of the world using a variety of multivariate methods. RESULTS: Three alleles, APOE*E2, APOE*E3 and APOE*E4, were observed with contrasting variation, although *E4 was absent in the tribal population of Koch. Higher heterozygosities (>43%) in British populations reflected their greater genetic diversity at this locus. The overall pattern of allelic diversity among these populations is comparable to many European and Indian populations.At a global level, higher frequencies of the *E2 allele were observed in Africa and Oceania (0.099 +/- 0.083 and 0.111 +/- 0.052, respectively). Similarly, *E4 allele averages were higher in Oceania (0.221 +/- 0.149) and Africa (0.209 +/- 0.090), while Indian and Asian populations showed the highest frequencies of *E3 allele. The coefficient of gene differentiation was found to be highest in South America (9.6%), although the highest genetic diversity was observed in Oceania (48.7%) and Africa (46.3%). APOE*E2 revealed a statistically significant decreasing cline towards the north in Asia (r = -0.407, d.f. = 70, p < 0.05), which is not compatible with the coronary heart disease statistics in this continent. APOE*E4 showed a significant increasing cline in North European populations. Spatial autocorrelation analysis shows that the variation at this locus is influenced by 'isolation by distance' with a strong positive correlation for lower distances up to 1313 km. CONCLUSION: Overall APOE allelic variation in UK and Indian populations is comparable to previous studies but in tribal populations *E4 allele frequency was very low or absent. At a global level allelic variation shows that geography, isolation by distance, genetic drift and possibly pre-historical selection are responsible for shaping the spectrum of genetic variation at the APOE gene. Overall, APOE is a good anthropogenetic and clinical diagnostic marker.
Abstract: BACKGROUND: Short tandem repeats (STRs) and variable number of tandem repeats (VNTRs) have been used successfully in disease analysis and studies of human evolution and population genetic diversity. However DNA-based comprehensive population genetic studies of the East Midlands, England are limited. SUBJECTS AND METHODS: To enlarge our understanding of genetic variation in the East Midlands, a study was conducted on five regional populations: north-west Derbyshire,north-east Derbyshire, south Derbyshire, Nottinghamshire and Leicestershire. Blood samples were collected from donors whose ancestors had lived in the region for at least three generations. Seven VNTRs (MSI (DIS7), MS31 (D7S21), MS43A (D12SII) and YNH24 (D2S44), DIS0, APOB, YNZ22 (D17S5)), six STRs (HumTHOI, HumVWA31A, HumF13AOl1, HumFESFPS, HumCSFIPO, HumTPOX) and six Alu insertion/deletion polymorphisms (TPA25, ACE, PV92, F13B, APO, DI) were analysed in approximately 500 individuals. Allele or bin frequencies were calculated using gene counting and fixed bin methods. The chi-square method and exact tests were used to assess Hardy-Weinberg equilibrium. Genetic distances were calculated using Nei's DA method and correspondence analysis was used to assess population affinities. RESULTS: The overall pattern of allele frequencies was similar to many European and UK populations for a number of genetic systems. Overall heterogeneity was observed for five loci: MS43A, MS31, HumF13A0l, HumFESFPS and HumTHOI. Twenty-three of 190 pairwise population comparisons were also statistically significant at the 5% level. Average molecular genetic system heterozygosity was 1.5 times higher than observed with conventional blood group systems. GsT values for molecular systems were also higher than conventional systems (0.012 vs 0.005) and suggest a low to moderate level of differentiation. CONCLUSION: The allele frequency spectrum and inter-population comparisons show that there is significant genetic variation in the five contiguous regional populations of the East Midlands. Some of this variation may be due to local geographical barriers, genetic drift and possibly the settlement patterns of Continental European invaders.
Abstract: Apolipoprotein CII genotypes were determined in Brahmins, Banias, Jat Sikhs, Khatris, Ramgarhia, Ramdasia and Scheduled Castes of Punjab, North India (n = 930). The Apo CII exhibits three common polymorphic alleles CII*1, CII*2 and CII*3 with pooled frequencies 0.883, 0.114 and 0.003, respectively. CII*3 was absent in Brahmins. Distribution of Apo CII isoforms highlights a considerable variation among different ethnic groups across the world. The average heterozygosity of the Punjabi populations was 0.208. The gene diversity among these population groups was less than 0.1%.
Abstract: BACKGROUND: Human apolipoprotein H (beta(2)-glycoprotein I, apoH, protein; APOH, gene) is a single-chain glycoprotein that has been implicated in several metabolic pathways, including lipid metabolism, coagulation and production of antiphospholipid antibodies and many disease phenotypes. The structural, molecular and genetic bases of APOH have been studied in detail but population studies, especially from the Indian subcontinent, are limited. OBJECTIVE: This study seeks to enlarge our understanding of APOH genetic diversity in human populations from different regions and social groups of India. Also, we examine the level and extent of genetic variation at this locus in world populations and its utility as a population genetic marker. Subjects and methods: Blood samples from 1381 unrelated and randomly selected individuals were screened for APOH genetic polymorphism. Eleven populations from North India (Brahmins, Banias, Jat Sikhs, Khatris, Scheduled Castes, Lobanas and Rajputs), West India (Brahmin and Patels) and Central India (Brahmins and Baiga tribe) were studied for APOH polymorphism using isoelectric focusing. Allele frequencies were calculated by the gene counting method. The results were statistically evaluated using chi-square statistics for regional and ethnic variation. Genetic distances were computed on Indian populations to determine the population affinities. Correspondence analysis was used to assess ethnic variation in world populations. RESULTS: An interesting and wide genetic variation at this locus was observed in Indian populations. The frequency distribution of three observed alleles ranged from 0.034 to 0.091 for APOH*1, 0.852 to 0.917 for APOH*2 and 0.027 to 0.075 for APOH*3. The world's highest APOH*2 allele frequency was observed in the Patel (0.917) caste group from West India. CONCLUSIONS: Overall, the observed variation at this locus in Indian populations is comparable to many Caucasian populations. An analysis of world populations showed that APOH is a useful genetic marker for population and anthropological studies.
Abstract: BACKGROUND: Highly polymorphic genetic markers like short tandem repeats (STRs) have been used successfully in disease analysis and studies of human evolution and population genetic diversity. However, DNA-based population genetic studies of Indian populations are limited. SUBJECTS AND METHODS: To enlarge our understanding of genetic variation in Indian populations, a population genetic study was carried out on Jat Sikh (Punjab, North India) individuals (n = 150) using a battery of the STR loci. The STR loci analysed by means of PCR amplification followed by electrophoresis and silver staining included HUMCSF1PO, HUMTPOX, HUMTHO1, HUMLPL, HUMF13A01, HUMF13B, HUMFESFPS and HUMVWA loci. RESULTS: The overall pattern of allele frequencies was similar to many Caucasian and Indian populations and heterozygosity varied from 65% (HUMLPL) to 85% (HUMVWA). For all eight loci, no deviations from the Hardy-Weinberg equilibrium hypothesis were detected. Significant differences were observed between Jat Sikhs and African, Chinese and Indian tribes. The mean exclusion probability ranged from 35% to 70%, and the power of discrimination from 81% to 93%, indicating the potential of these loci for forensic and paternity investigations. CONCLUSION: The allele frequency spectrum, heterozygosity, probability of exclusion, match probability and discrimination probability estimates show interesting variation and suggest the usefulness of these loci for anthropogenetic, paternity and forensic investigations in Indian populations.
Abstract: Genetic variation at three apolipoprotein loci (APOA4, APOH, and APOE) has been examined in nine endogamous populations of Punjab, North India. The overall pattern of allele frequency variation at different loci is compatible with that of European populations, but observed microvariation differentiates the populations according to their position in the Indian caste structure. The most common allele at the APOA4 locus was APOA4*1 with a narrow frequency range (89%-92%). APOH*2 allele frequency was highest in these populations (0.852-0.914). APOE*E4 allele frequency was relatively low (6%-10%) in the North Indian populations compared to its frequency in many European populations. The anthropological usage of these polymorphisms was evaluated using multivariate analyses. Genetic distance analysis and principal correspondence analysis showed that the North Indian populations are closest to Europeans, followed by Chinese and African populations. Overall, this study highlights the usefulness of apolipoproteins as genetic markers for clinical, population, and anthropological studies.
Abstract: High resolution two dimensional gel electrophoresis with the combination of isoelectric focusing (IEF) and density gradient sodium dodecyl-polyacrylamide gel electrophoresis (DG-PAGE) have been employed to investigate the distribution of APOE in Ramgarhia (n = 80) and Ramdasia (n = 70) of Punjab, India. Three alleles APOE*E2, APOE*E3 and APOE*E4 were observed in Ramgarhia and Ramdasia with the frequencies of 0.031, 0.913, 0.056 and 0.043, 0.886 and 0.071, respectively. Higher heterozygosity (20.8%) in Ramdasia reflects greater variation at the APOE locus. The APOE*E3 allele is found to be the highest (0.913) in Ramgarhia in comparison to forty-one populations of the world. A decreasing cline from south to north was evident for *E2 and *E4 allele frequencies (y = -0.002x + 0.141, r = 0.78 and y = -0.004x + 0.229, r = 0.83, respectively, and an increasing cline for the *E3 allele towards north was observed (y = 0.006x + 0.629, r = 0.82) in Asia.
