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Genetic association studies have linked a number of single nucleotide polymorphisms (SNPs) with unconjugated hyperbilirubinemia. The present study was undertaken to validate the association of SNPs with development of hyperbilirubinemia in Indian neonates. Genotyping of five SNPs in two candidate genes was performed in 126 infants with hyperbilirubinemia and 181 controls by PCR-RFLP, Gene Scan analysis and direct DNA sequencing. Genetic polymorphisms of the UGT1A1 promoter, specifically the -3279 T➔G phenobarbital responsive enhancer module (rs4124874) and (TA)7 dinucleotide repeat (rs8175347) as well as the coding region variants (rs2306283 and rs4149056) of the OATP2 gene were significantly higher among the cases than the controls. The presence of the mutant haplotypes either in homozygous, heterozygous or compound heterozygous state had a significant effect on neonatal hyperbilirubinemia as well as on the requirement of phototherapy than those with the wild haplotype. Further, a significantly higher number of hyperbilirubinemic cases had ≥3 variants than the controls (73.80% vs 40.36%, p<0.0001) and the mean total serum bilirubin levels and requirement of phototherapy also increased according to the number of variants co-expressed. This study demonstrates that UGT1A1 and OATP2 polymorphisms were associated with altered bilirubin metabolism and could be genetic risk factors for neonatal hyperbilirubinemia. [ABSTRACT FROM AUTHOR]

Abstract: Developmental Dyslexia (DD) is a heritable, complex genetic disorder characterized by specific impairment in reading and writing ability that is substantially below the expected reading ability given the person's chronological age, measured intelligence and age-appropriate education. More than ten susceptible genes have been identified for DD. A Single Nucleotide Polymorphism (SNP) of these genes was found to be associated with various phenotypes of DD. To identify the role of SNPs of four candidate genes namely, MRPL19/C2ORF3, ROBO1 and THEM2 in an Indian population, we genotyped eight SNPs of these genes in 157 children with DD and 212 normal readers using a MassARRAY technique with a MALDI-TOF MS analyzer. Power analysis of some of these SNPs showed >80% of power. Chi-square test, Odds Ratios (ORs), 95% Confidence Intervals (CIs) and Bonferroni's correction were applied to identify the significance of the genotyped SNPs and haplotypes. Our study failed to show any association of SNPs and haplotypes of these genes with DD in an Indian population. [Copyright &y& Elsevier]

Highlights: [•] First attempt from north India to dissect IL-17 axis in human tuberculosis (TB). [•] No association of IL17A and IL17F gene variants in pulmonary and extra-pulmonary TB [•] Correlated the serum cytokine levels and genotypes [•] IL17 variants might not be a major influencing gene for tuberculosis in north Indians. [ABSTRACT FROM AUTHOR]

Abstract: Chewing betel quid may release chemical carcinogens including xenobiotics resulting in oral malignancy cases preceded by potential malignant lesions and conditions — Oral Submucous Fibrosis (OSF) being one of them. The cytochrome P4501A1 (CYP1A1) enzyme is central to the metabolic activation of these xenobiotics, whereas CYP2E1 metabolizes the nitrosamines and tannins. The present study investigated the association of polymorphisms at CYP1A1m1 (T3801C), m2 (A2455G), and CYP2E1 PstI site (nucleotide 21259) with the risk of OSF. The study was conducted on 75 OSF patients and 150 controls from an eastern Indian population. The above polymorphisms were analyzed by PCR-RFLP method. Analyses of data show that polymorphisms in CYP1A1m2 [OR=8.25 (4.31–15.80)]; CYP1A1m1 [OR=2.88 (1.57–5.24)] and CYP2E1 PstI site [OR=3.16 (1.10–9.04)] revealed significant association with OSF. Our results suggest that polymorphism in CYP1A1 and CYP2E1 may confer an increased risk for Oral Submucous Fibrosis. [Copyright &y& Elsevier]

Leukotrienes are potent inflammatory and lipid mediators that participate in atherosclerosis. We analyzed the association of Leukotriene gene (ALOX5, ALOX5AP, LTA4H, and LTC4S) polymorphisms and plasma Leukotriene B4 (LTB4) levels with coronary artery disease (CAD) in a representative cohort of Asian Indians. In all, 136 functional single nucleotide polymorphisms (SNPs) were selected using in silico tools. Forty-five polymorphic SNPs were ranked for predicted functional effect using FastSNP. Finally, 14 functional SNPs along with 10 SNPs identified from the literature were genotyped in 340 CAD patients and 340 controls. Plasma LTB4 levels were measured in 150 cases and 150 controls. None of the 24 SNPs showed significant association with CAD. Plasma LTB4 levels were higher in cases than in controls (76.42 ± 4.46pg/mL versus 60.89 ± 2.61 pg/mL) (P = 0.003), with greater risk being associated with the top quartile as compared to the bottom quartile after adjusting for potential confounders (OR 8.94, 95% CI 2.56-31.95; P = 0.001). Four SNPs in the LTA4H gene showed significant association with LTB4 levels (P < 0.05)of which rs1978331 (P = 0.035) remained significant after correction for multiple testing. LTB4 showed strong correlation with lipids (r = 0.24-34) only in cases. Our pilot study suggests that the association between Leukotrienes gene polymorphisms and CAD risk may be modulated through plasma LTB4 levels. [ABSTRACT FROM AUTHOR]

Psoriasis is a common, chronic, recurrent, inflammatory, hyper proliferative disorder of the skin, which has a relatively high prevalence in the general population (0.6-4.8%). Linkage and association analyses in various populations have revealed a major locus for psoriasis susceptibility, PSORS1, at 6p21.3. Association of the disease with human leukocyte antigen (HLA) Cw6, corneodesmosin (CDSN) and the coiled-coil alpha-helical rod protein-1 (CCHCR1) has also been reported. Though the PSORS1 locus accounts for 30-50% of familial psoriasis in various global population groups, yet no studies have been published from the North Indian population. Some of the SNPs in HLA-C and CCHCR1 genes have been reported as markers for disease susceptibility. Therefore in the present study, DNA samples from psoriasis patients from North India were genotyped for polymorphisms in CCHCR1 and HLA-C genes. The allele frequencies were calculated for patients and controls, and were compared for odds ratio and confidence interval values. SNPn.7*22222 (rs12208888), SNPn.7*22333 (rs12216025), SNPn.9*24118 (rs10456057), CCHCR1_386 (rs130065), CCHCR1_404 (rs130076) and CCHCR1_1364 (rs130071) were found to be significant in psoriasis patients. Linkage disequilibrium analysis revealed two haplotypes (rs12208888, rs2844608, rs12216025, rs10456057, rs130065, rs130066, rs130068, rs130269, and rs12208888, rs2844608, rs12216025, rs130076, rs130066, rs130068, rs130269, rs130071) as highly susceptible haplotypes for psoriasis in the cohort studied. Preliminary analysis of the data also suggests the possibilities of ethnic group specific disease related polymorphisms, pending validation in future studies. [ABSTRACT FROM AUTHOR]

Background: Asthma is the most prevalent disease in India according to the national survey conducted by NFHS 2 in 1998-399. Prostaglandin D2 (PGD2) is a bronchoconstriction inducing metabolite of arachidonic acid in the mast cells, which is produced on exposure to allergens and acts as a ligand for the Prostaglandin D2 Receptor (PTGDR). Polymorphisms in the PTGDR gene have been suggested to be involved in the mechanism of asthma. Objective: This is the first study conducted in India, investigating the role of PTGDR -441C/T} promoter polymorphism in asthma pathogenesis. Methods: A case-control study was performed with a total of 992 subjects, including 410 adult asthmatics and 582 healthy controls from regions of North India. The PTGDR -441C/T polymorphism was genotyped by Tetra-Primer Amplification Refractory Mutation System Polymerase Chain Reaction (Tetra-Primer ARMS PCR). Results: Statistical analysis of the results between asthma cases and controls for the PTGDR -441C/T polymorphism showed Chi^{2} (χ ^{2})=0.29, OR=0.95, 95% CI (0.70-1.15) and p=0.599. Neither the genotypic nor the allelic frequencies observed for the PTGDR -441C/T polymorphism, were significantly associated with asthma or asthma phenotypes. Conclusions: The PTGDR -441C/T polymorphism is not associated with asthma or its phenotypes in the studied North Indian population. [ABSTRACT FROM AUTHOR]

Variants in genes involved in pancreatic β-cell development and function are known to cause monogenic forms of type 2 diabetes and are also associated with complex form. In this study, we studied the genetic association of polymorphisms in such important genes with type 2 diabetes in the high-risk Indians. We genotyped 91 polymorphisms in 19 genes (ABCC8, HNF1A, HNF1B, HNF4A, INS, INSM1, ISL1, KCNJ11, MAFA, MNX1, NEUROD1, NEUROG3, NKX2.2, NKX6.1, PAX4, PAX6, PDX1, USF1 and WFS1) in 2025 unrelated North Indians of Indo-European ethnicity comprising of 1019 diabetic and 1006 non-diabetic subjects. HNF4A promoter P2 polymorphisms rs1884613 and rs2144908, which are in high linkage disequilibrium, showed significant association with type 2 diabetes (odds ratio (OR)=1.37 (95% confidence interval (CI) 1.19-1.57), P=9.4 × 10−6 for rs1884613 and OR=1.37 (95%CI 1.20-1.57), P=6.0 × 10−6 for rs2144908), as previously shown in other populations. We observed body mass index-dependent association of these variants with type 2 diabetes in normal-weight/lean subjects. Variants in USF1, ABCC8, ISL1 and KCNJ11 showed nominal association, while haplotypes in these genes were significantly associated. rs3812704 upstream of NEUROG3 significantly increased risk for type 2 diabetes in normal-weight/lean subjects (OR=1.68 (95%CI 1.25-2.24), P=4.9 × 10−4). Thus, pancreatic β-cell development and function genes contribute to susceptibility to type 2 diabetes in North Indians. [ABSTRACT FROM AUTHOR]

Objectives: Obesity is associated with high levels proinflammatory cytokines like tumour necrosis factor alpha (TNF-α), which may play an important role in the genesis of insulin resistance. We evaluated the relationship of -308G/A polymorphism of TNF-α gene with obesity and insulin resistance in Asian Indians in north India. Methods: This cross-sectional study included 151 apparently healthy individuals (79 males, 72 females) 18-50 yrs of age from New Delhi, India. Body composition by dual-energy x-ray absorptiometry (DEXA) and abdominal fat by magnetic resonance imaging (MRI) were measured. Biochemical measurements included OGTT, lipids, fasting insulin, hs-CRP and TNF-α levels. We analysed -308G/A polymorphism of TNF-α gene and studied its association with obesity and biochemical parameters. Results: At comparable BMI, abdominal obesity was more prevalent in females (50%) as compared to males (20%). The wild genotype (GG) was present in 78.8%, GA in 17.9%, and AA in 3.3% subjects. Measures of body composition, abdominal fat distribution, lipids, insulin, hs-CRP and TNF-α levels were not influenced by the presence of -308G/A polymorphism. Serum TNF-α levels correlated significantly with fasting insulin in both genders. Conclusion: TNF-α levels correlate with fasting insulin but not with indicators of body composition in Asian Indians. The -308G/A polymorphism of TNF-α gene is not associated with differences in the serum levels of TNF-α in Asian Indians. [ABSTRACT FROM AUTHOR]

Background: Obstructive sleep apnea (OSA) is prevalent in 7.5% in urban Asian Indians. Peroxisome proliferator activated receptor gamma2 (PPARγ2) has been implicated in adipocyte differentiation. Neuropeptide Y (NPY) is also considered as a candidate gene for excess body fat accumulation. The association of PPARγ2 (Pro12Ala)} and NPY (Leu7Pro) gene polymorphisms with OSA has not been studied in Asian Indians. Objective: To study the distribution of PPARγ2 (Pro12Ala) and NPY (Leu7Pro) polymorphism in Asian Indians with and without OSA. Methods and results: This study was carried out in 252 obese subjects [(body mass index (BMI > 25 kg/m^{2})]; 142 with OSA and 110 without OSA. Measurements included anthropometric and biochemical parameters (fasting blood glucose, lipid profile, various circumferences and skin-fold thicknesses). PPARγ2 (Pro12Ala) and NPY (Leu7Pro) gene} polymorphisms were studied in all subjects. The frequency of the variant allele (Ala12) of PPARγ2 gene was significantly higher in subjects with OSA (14.4%) when compared with subjects without OSA (5.5%; χ^{2}= 9.7; p = 0.001). The distribution of the variant allele (Pro7) of NPY gene was comparable in subjects with OSA (3.5%) and without OSA (3.6%; χ ^{2} = 0.001, p = 0.94). Conclusion: This study reveals a significantly higher frequency of PPARγ2 (Ala12) allele in obese Asian Indians with OSA when compared to obese Asian Indians without OSA. [ABSTRACT FROM AUTHOR]

Background: The APOA1-C3-A5 gene cluster plays an important role in the regulation of lipids. Asian Indians have an increased tendency for abnormal lipid levels and high risk of Coronary Artery Disease (CAD). Therefore, the present study aimed to elucidate the relationship of four single nucleotide polymorphisms (SNPs) in the Apo11q cluster, namely the -75G>A, +83C>T SNPs in the APOA1 gene, the Sac1 SNP in the APOC3 gene and the S19W variant in the APOA5 gene to plasma lipids and CAD in 190 affected sibling pairs (ASPs) belonging to Asian Indian families with a strong CAD history. Methods & results: Genotyping and lipid assays were carried out using standard protocols. Plasma lipids showed a strong heritability (h² 48% - 70%; P < 0.0001). A subset of 77 ASPs with positive sign of Logarithm of Odds (LOD) score showed significant linkage to CAD trait by multipoint analysis (LOD score 7.42, P < 0.001) and to Sac1 (LOD score 4.49) and -75G>A (LOD score 2.77) SNPs by single-point analysis (P < 0.001). There was significant proportion of mean allele sharing (pi) for the Sac1 (pi 0.59), -75G>A (pi 0.56) and +83C>T (pi 0.52) (P < 0.001) SNPs, respectively. QTL analysis showed suggestive evidence of linkage of the Sac1 SNP to Total Cholesterol (TC), High Density Lipoprotein-cholesterol (HDL-C) and Apolipoprotein B (ApoB) with LOD scores of 1.42, 1.72 and 1.19, respectively (P < 0.01). The Sac1 and -75G>A SNPs along with hypertension showed maximized correlations with TC, TG and Apo B by association analysis. Conclusion: The APOC3-Sac1 SNP is an important genetic variant that is associated with CAD through its interaction with plasma lipids and other standard risk factors among Asian Indians. [ABSTRACT FROM AUTHOR]

Background: Asian Indians display a high prevalence of diseases linked to changes in diet and environment that have arisen as their lifestyle has become more westernized. Using 1200 genome-wide polymorphisms in 432 individuals from 15 Indian language groups, we have recently shown that: (i) Indians constitute a distinct population-genetic cluster, and (ii) despite the geographic and linguistic diversity of the groups they exhibit a relatively low level of genetic heterogeneity. Results: We investigated the prevalence of common polymorphisms that have been associated with diseases, such as atherosclerosis (ALOX5), hypertension (CYP3A5, AGT, GNB3), diabetes (CAPN10, TCF7L2, PTPN22), prostate cancer (DG8S737, rs1447295), Hirschsprung disease (RET), and age-related macular degeneration (CFH, LOC387715). In addition, we examined polymorphisms associated with skin pigmentation (SLC24A5) and with the ability to taste phenylthiocarbamide (TAS2R38). All polymorphisms were studied in a cohort of 576 India-born Asian Indians sampled in the United States. This sample consisted of individuals whose mother tongue is one of 14 of the 22 "official" languages recognized in India as well as individuals whose mother tongue is Parsi, a cultural group that has resided in India for over 1000 years. Analysis of the data revealed that allele frequency differences between the different Indian language groups were small, and interestingly the variant alleles of ALOX5 g.8322G>A and g.50778G>A, and PTPN22 g.36677C>T were present only in a subset of the Indian language groups. Furthermore, a latitudinal cline was identified both for the allele frequencies of the SNPs associated with hypertension (CYP3A5, AGT, GNB3), as well as for those associated with the ability to taste phenylthiocarbamide (TAS2R38). Conclusion: Although caution is warranted due to the fact that this US-sampled Indian cohort may not represent a random sample from India, our results will hopefully assist in the design of future studies that investigate the genetic causes of these diseases in India. Our results also support the inclusion of the Indian population in disease-related genetic studies, as it exhibits unique genotype as well as phenotype characteristics that may yield new insights into the underlying causes of common diseases that are not available in other populations. [ABSTRACT FROM AUTHOR]

The association between apolipoprotein E (apo E) polymorphism and stroke has been controversial. So far there are no studies reported on the polymorphism of apolipoprotein E in cerebrovascular diseases in the Asian Indians. A blinded case–control study was therefore undertaken and the apo E genotypes and lipid profile of a total of 120 subjects (63 stroke patients and 57 healthy controls) were done. The frequency distribution of apo E alleles and genotypes were assessed and their relation with the occurrence of stroke in Asian Indian subjects was determined. A significantly high frequency of apo ε4 allele (30%) was observed in the stroke patients than the controls (11%) (p < 0.005), and patients with ε4 allele had a fourfold higher odds to develop stroke OR (95%CI) 4.2 (1.8–10.1) (p < 0.005). On multivariate analysis, after adjusting for age, triglycerides and hypertension, the association of ε4 allele with stroke was found to be no longer statistically significant, OR (95%CI) 1.2 (0.4–4.5) (p = NS). On multiple logistic regression analysis age, OR (95%CI) 1.1 (1.1–1.2) (p < 0.001), and hypertension OR (95%CI) 15.1 (2.6–89.1) (p < 0.005) were found to be independent risk factors for development of stroke. This is the first report to have examined the association of apo E gene polymorphism with stroke in the Asian Indians. This study suggests that apo ε4 allele, triglycerides, age and hypertension are the predictors for stroke development. [ABSTRACT FROM AUTHOR]

Background: The role of glucokinase (GCK) in the pathogenesis of maturity-onset diabetes of the young is well established. However, its role in the common form of type 2 diabetes is far from convincing. We investigated the role of the G-to-A polymorphism in the hepatic GCK promoter on insulin sensitivity and beta cell function in 63 normotensive Asian Indians with normal glucose tolerance. As proposed by Matsuda and DeFronzo, hepatic insulin sensitivity (ISIH) and total body insulin sensitivity (ISIM) were estimated from the oral glucose tolerance test. Beta cell function was estimated using %B from the Homeostasis Model Assessment and insulingenic index (dI/dG). Result: We identified 38 GG, 24 GA, and one AA subjects. The AA subject was pooled with the GA subjects during the analysis. No difference was noted in the demographic features between the two genotypic groups (GG vs. GA/AA). Compared to the GG group, the GA/AA group had a lower ISIH (p=0.002), a lower ISIM (p=0.009), a higher %B (p=0.014), and a higher dI/dG (p=0.030). Multivariate analysis revealed that this polymorphism is an independent determinant for ISIH (p=0.019) and along with age, waist-hip ratio, gender, and diastolic blood pressure accounted for 51.5% of t he variation of ISIH. However, this polymorphism was a weak, but independent determinant for ISIM (p=0.089) and %B (p=0.083). Furthermore, it had no independent effect on dI/dG (p=0.135). Conclusions: These data suggest that the G-to-A polymorphism in the hepatic GCK promoter is associated with hepatic insulin resistance in Asian Indians. [ABSTRACT FROM AUTHOR]

We and others in a variety of ethnic groups have previously described associations of various SNPs of the uncoupling protein genes UCP2 and UCP3 (located within 17 kb of each other on chromosome 11q13) with both central fat disposition and BMI. The aim of this study was to do a replication study in South Indian subjects using a family based approach and selecting SNP's by' a priori hypothesis' defined by a previous association with obesity/waits in other studies and/or functional data. Five SNPs were studied; 1 by Ampliflour (UCP2-866 rs659366), 1 by SNAPSHOT (UCP3Y210Y rs2075577), 2 by TaqMan (UCP3-55 rs1800849, UCP2 A55V rs660339) and one by PCR-RFLP (UCP2 exon 8 INDEL) in 882 South Indian participants from 236 families ascertained from community based study of healthy families living in Chennai, India. Statistical analysis was performed using SOLAR and anthropometric variables were corrected for age and sex. The QTLD analysis showed the BMI was associated to the UCP3 rs1800849 (AA 23.9±0.29, AB 23.5±0.32, BB 23.0±0.5, p=0.027) and UCP3 rs2075577 (AA 24.6±0.37, AB 24.0±0.30, BB 23.4±0.39, p=0.022). Waist circumference to the UCP2 rs660339 (AA 84.3±0A8, AB 85.1±0.41, BB 85.9±0.65, p=0.028). Body fat percentage to UCP2 rs660339 (AA 22.9±0.31, AB 23.2±0.27, BB 23.5±0.42, p=0.048) and UCP2 rs659366 (AA 22.7±0.31, AB 22.9±0.26, BB 23.27±0.41, p=0.076). This detailed analysis confirms associations between anthropometric traits and the UCP2/UCP3 locus but that separate SNPs are associated with either BMI or fat distribution. [ABSTRACT FROM AUTHOR]