Forensic effectiveness and genetic distribution of 23 autosomal STRs included in Verifiler PlusTM multiplex in a population sample from Madhya Pradesh, India.

We report here the first ever global study on genetic polymorphism using a Verifiler PlusTM autosomal STR multiplex system. The study evaluated genetic characteristics of 23 autosomal STRs in 200 unrelated residents of Guna district of Madhya Pradesh, India. Allele frequencies and forensic parameters are reported. Population comparison analysis was also performed using NJ tree and PCA plot. Penta E marker showed highest power of discrimination (0.938) among all 23 studied markers. The study also presents the first ever global forensic assessment in Indian population on D6S1043 marker (PD 0.937). The results demonstrated that all the 23 markers were highly polymorphic and the Verifiler PlusTM kit is suitable for forensic purposes in Indian population.

Comparison of Bond Strength of Metal and Ceramic Brackets with or without Primer.

Background: Bonding is an integral part of orthodontic treatment. Orthodontic bonding could be accomplished without the use of primer, it might be possible to reduce the risk of occupational exposure to primer and will save time. So it is very important to know whether primer is required or not. Aim: The aim of this study is to evaluate and compare the shear bond strength (SBS) of metallic and ceramic brackets bonded with and without primer application and to check for residual adhesive post debonding. Material and Method: A total of 100 extracted human premolar teeth were divided into 2 main groups A and B which were further subdivided into: Group A1 - metallic brackets bonded with primer; Group A2 - ceramic brackets bonded with primer; Group B1 - metallic brackets bonded without primer; group B2 - ceramic brackets bonded without primer. The SBS of these brackets was measured. Result: The SBS of group A2 was significantly higher than the other groups, group A1 was the second highest, group B3 was the third highest and group B4 was the least significant. The adhesive remnant index was lowest on failure of ceramic brackets bonded with primer. Conclusion: SBS of ceramic brackets bonded without primer is superior to SBS of metallic bracket bonded without primer and metallic brackets bonded with primer was superior than metallic bonded without primer.

Association of kallikrein gene polymorphisms with intracranial aneurysms.

BACKGROUND AND PURPOSE: Genomewide DNA linkage analysis identified a susceptibility locus for intracranial aneurysm (IA) on chromosome 19q13 in the Finnish population, a region including the kallikrein gene cluster. We investigated the association of single nucleotide polymorphisms (SNPs) in the kallikrein gene cluster with IA in the Finnish population. METHODS: We genotyped 18 haplotype-tagging SNPs spanning a 244 kbp region in the kallikrein gene cluster for 266 Finnish IA cases and 290 Finnish control subjects. In a second phase, we genotyped 2 SNPs (rs1722561 and rs1701946) in an additional set of 102 Finnish IA cases and 102 Finnish control subjects; and in a third phase, we genotyped these 2 SNPs in 156 Russian IA cases and 186 Russian control subjects. Both single-marker and haplotype-based tests of association were performed. RESULTS: In phase I, SNPs rs1722561 and rs1701946 were significantly associated with IA in the Finnish population for single locus models (rs1722561: P=0.0395; rs1701946: P=0.0253). A 2-SNP haplotype block (rs1722561-rs1701946) identified in phase I was also associated with IA in the expanded Finnish (phase II) data set (asymptotic P=0.012; empirical P=0.019). In the Finnish and Russian combined data set (phase III) with 524 cases and 578 control subjects, the same 2 SNPs (OR: 1.35, 95% CI: 1.14, 1.60; P=0.0005 for rs1722561 and OR: 1.32, 95% CI: 1.12, 1.57; P=0.0011 for rs1701946) were significantly associated with IA. These SNPs are located in the intronic region of KLK8, although linkage disequilibrium could extend from rs268912-rs2250066, a approximately 76-kbp region that includes KLK5-KLK10. CONCLUSIONS: Polymorphisms within the kallikrein gene cluster are associated with IA suggesting that the kallikreins are important candidate genes for IA.

Local false discovery rate and minimum total error rate approaches to identifying interesting chromosomal regions.

The simultaneous testing of a large number of hypotheses in a genome scan, using individual thresholds for significance, inherently leads to inflated genome-wide false positive rates. There exist various approaches to approximating the correct genomewide p-values under various assumptions, either by way of asymptotics or simulations. We explore a philosophically different criterion, recently proposed in the literature, which controls the false discovery rate. The test statistics are assumed to arise from a mixture of distributions under the null and non-null hypotheses. We fit the mixture distribution using both a nonparametric approach and commingling analysis, and then apply the local false discovery rate to select cut-off points for regions to be declared interesting. Another criterion, the minimum total error, is also explored. Both criteria seem to be sensible alternatives to controlling the classical type I and type II error rates.

Linkage analysis of alcohol dependence using both affected and discordant sib pairs.

The basic idea of affected-sib-pair (ASP) linkage analysis is to test whether the inheritance pattern of a marker deviates from Mendelian expectation in a sample of ASPs. The test depends on an assumed Mendelian control distribution of the number of marker alleles shared identical by descent (IBD), i.e., 1/4, 1/2, and 1/4 for 2, 1, and 0 allele(s) IBD, respectively. However, Mendelian transmission may not always hold, for example because of inbreeding or meiotic drive at the marker or a nearby locus. A more robust and valid approach is to incorporate discordant-sib-pairs (DSPs) as controls to avoid possible false-positive results. To be robust to deviation from Mendelian transmission, here we analyzed Collaborative Study on the Genetics of Alcoholism data by modifying the ASP LOD score method to contrast the estimated distribution of the number of allele(s) shared IBD by ASPs with that by DSPs, instead of with the expected distribution under the Mendelian assumption. This strategy assesses the difference in IBD sharing between ASPs and the IBD sharing between DSPs. Further, it works better than the conventional LOD score ASP linkage method in these data in the sense of avoiding false-positive linkage evidence.

Density-based clustering in haplotype analysis for association mapping.

Clustering of related haplotypes in haplotype-based association mapping has the potential to improve power by reducing the degrees of freedom without sacrificing important information about the underlying genetic structure. We have modified a generalized linear model approach for association analysis by incorporating a density-based clustering algorithm to reduce the number of coefficients in the model. Using the GAW 15 Problem 3 simulated data, we show that our novel method can substantially enhance power to detect association with the binary rheumatoid arthritis (RA) phenotype at the HLA-DRB1 locus on chromosome 6. In contrast, clustering did not appreciably improve performance at locus D, perhaps a consequence of a rare susceptibility allele and of the overwhelming effect of HLA-DRB1/locus C, 5 cM distal. Optimization of parameters governing the clustering algorithm identified a set of parameters that delivered nearly ideal performance in a variety of situations. The cluster-based score test was valid over a wide range of haplotype diversity, and was robust to severe departures from Hardy-Weinberg equilibrium encountered near HLA-DRB1 in RA case-control samples.

Prediction of empirical p values from asymptotic p values for conditional logistic affected relative pair linkage analysis.

OBJECTIVE: p Values are inaccurate for model-free linkage analysis using the conditional logistic model if we assume that the LOD score is asymptotically distributed as a simple mixture of chi-square distributions. When analyzing affected relative pairs alone, permuting the allele sharing of relative pairs does not lead to a useful permutation distribution. As an alternative, we have developed regression prediction models that provide more accurate p values. METHODS: Let E(alpha) be the empirical p value, which is the proportion of statistical tests whose LOD score under the null hypothesis exceeds a threshold determined by alpha, the nominal single test significance value. We used simulated data to obtain values of E(alpha) and compared them with alpha. We also developed a regression model, based on sample size, number of covariates in the model, alpha and marker density, to derive predicted p values for both single-point and multipoint analyses. To evaluate our predictions we used another set of simulated data, comparing the Ealpha for these data with those obtained by using the prediction model, referred to as predicted p values (P(alpha)). RESULTS: Under almost all circumstances the values of P(alpha) were closer to the E(alpha) than were the values of alpha. CONCLUSION: The regression models suggested by our analysis provide more accurate alternative p values for model-free linkage analysis when using the conditional logistic model.

Genetic analysis of polymorphisms in biologically relevant candidate genes in patients with abdominal aortic aneurysms.

BACKGROUND: Abdominal aortic aneurysms (AAAs) are characterized by histologic signs of chronic inflammation, destructive remodeling of extracellular matrix, and depletion of vascular smooth muscle cells. We investigated the process of extracellular matrix remodeling by performing a genetic association study with polymorphisms in the genes for matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and structural extracellular matrix molecules in AAA. Our hypothesis was that genetic variations in one or more of these genes contribute to greater or lesser activity of these gene products, and thereby contribute to susceptibility for developing AAAs. METHODS: DNA samples from 812 unrelated white subject (AAA, n = 387; controls, n = 425) were genotyped for 14 polymorphisms in 13 different candidate genes: MMP1(nt-1607), MMP2(nt-955), MMP3(nt-1612), MMP9(nt-1562), MMP10(nt+180), MMP12(nt-82), MMP13(nt-77), TIMP1(nt+434), TIMP1(rs2070584), TIMP2(rs2009196), TIMP3(nt-1296), TGFB1(nt-509), ELN(nt+422), and COL3A1(nt+581). Odds ratios and P values adjusted for gender and country of origin using logistic regression and stratified by family history of AAA were calculated to test for association between genotype and disease status. Haplotype analysis was carried out for the two TIMP1 polymorphisms in male subjects. RESULTS: Analyses with one polymorphism per test without interactions showed an association with the two TIMP1 gene polymorphisms (nt+434, P = .0047; rs2070584, P = .015) in male subjects without a family history of AAA. The association remained significant when analyzing TIMP1 haplotypes (chi 2 P = .014 and empirical P = .009). In addition, we found a significant interaction between the polymorphism and gender for MMP10 ( P = .037) in cases without a family history of AAA, as well as between the polymorphism and country of origin for ELN ( P = .0169) and TIMP3 ( P = .0023) in cases with a family history of AAA. CONCLUSIONS: These findings suggest that genetic variations in TIMP1, TIMP3, MMP10, and ELN genes may contribute to the pathogenesis of AAAs. Further work is needed to confirm the findings in an independent set of samples and to study the functional role of these variants in AAA. It is noteworthy that contrary to a previous study, we did not find an association between the MMP9 (nt-1562) polymorphism and AAA, suggesting genetic heterogeneity of the disease. CLINICAL RELEVANCE: Abdominal aortic aneurysms (AAAs) are an important cardiovascular disease, but the genetic and environmental risk factors, which contribute to individual's risk to develop an aneurysm, are poorly understood. Histologically, AAAs are characterized by signs of chronic inflammation, destructive remodeling of the extracellular matrix, and depletion of vascular smooth muscle cells. We hypothesized that genes involved in these events could harbor changes that make individuals more susceptible to developing aneurysms. This study identified significant genetic associations between DNA sequence changes in tissue inhibitor of metalloproteinase 1 (TIMP1), TIMP3, matrix metalloproteinase 10 (MMP10) and elastin (ELN) genes, and AAA. The results will require confirmation using an independent set of samples. After replication it is possible that these sequence changes in combination with other risk factors could be used in the future to identify individuals who are at increased risk for developing an AAA.