Differences In Allele Distribution Research Articles

Different Allelic Distribution of a Single SNP Between Sexes in Humans

We searched for a difference in allele distribution between males and females of a single nucleotide polymorphism located in the human beta T-cell receptor, in 500 subjects (200 males and 300 females). Genotype analysis gave the following results: among the males, 114 (57%) were heterozygous for the T/C polymorphism, 52 (26%) were homozygous (T/T), and 34 (17%) were homozygous (C/C). Among the females, 142 (47.3%) were heterozygous, 73 (24.3%) were homozygous (T/T), and 85 (28.3%) were homozygous (C/C). The allele frequency was significantly different between sexes (chi2 = 8.799, P = 0.012).

Identification of a novel CHEK2variant and assessment of its contribution to the risk of breast cancer in French Canadian women

BackgroundBRCA1 and BRCA2 account for the majority of the known familial breast cancer risk, however, the impact of other cancer susceptibility genes largely remains to be elucidated. Checkpoint Kinase 2 (CHEK2) is an important signal transducer of cellular responses to DNA damage, whose defects have been associated with an increase in breast cancer risk. Previous studies have identified low penetrance CHEK2 alleles such as 1100delC and I157T, as well as variants such as S428F in the Ashkenazi Jewish population and IVS2 + 1G>A in the Polish population. No founder allele has been specifically identified in the French Canadian population.MethodsThe 14 coding exons of CHEK2 were fully sequenced for variant alleles in a panel of 25 affected French Canadian women and 25 healthy controls. Two variants were identified of which one novel variant was further screened for in an additional panel of 667 breast cancer patients and 6548 healthy controls. Additional genotyping was conducted using allele specific PCR and a restriction digest assay. Significance of amino acid substitutions were deduced by employing comparative analysis techniques.ResultsTwo variants were identified: the previously reported silent substitution 252A>G (E84E) and the novel missense variant, 1217G>A (R406H). No significant difference in allele distribution between French Canadian women with breast cancer and healthy controls was observed (3/692, 0.43% vs. 22/6573, 0.33%, respectively, P = 0.73).ConclusionThe novel CHEK2 missense variant identified in this study, R406H, is unlikely to contribute to breast cancer risk in French Canadian women.

Comparison of different methods to construct a core germplasm collection in woody perennial species with simple sequence repeat markers. A case study in cherimoya (Annona cherimola, Annonaceae), an underutilised subtropical fruit tree species

AbstractAlthough molecular markers are becoming the tool of choice to develop core collections in plants, the examples of their use in woody perennial species are very scarce. In this work, we used simple sequence repeat (SSR) marker data to develop a core collection in an underutilised subtropical fruit tree species, cherimoya (Annona cherimola, Annonaceae), from an initial collection of 279 genotypes from different countries. We compared six alternative allocation methods to construct the core collection, four not based upon the similarity dendrogram [random sampling, maximisation strategy (M strategy) and simulated annealing algorithm maximising both genetic diversity and number of SSR alleles] and two based on dendrogram data (logarithmic strategy and stepwise clustering). The diversity maintained in each subset was compared with that present in the entire collection. The results obtained indicate that the use of SSRs together with the M strategy is the most efficient method to develop a core collection in cherimoya. In the best subset, with 40 accessions, all the SSR alleles present in the whole collection were recovered and no significant differences in frequency distribution of alleles for any of the loci studied or in variability parameters (HO, HE) were recorded between the core and the whole collection.

한국재래닭 1번 염색체내 초위성체 유전표지를 이용한 경제형질 연관 지역 탐색

본 연구는 한국재래닭의 1번 염색체내 존재하는 17개의 MS(microsatellite) marker를 이용하여 경제형질과 관련하여 유의적인 연관성을 가진 지역을 탐색하기 위하여 실시하였다. 1번 염색체내 경제형질과의 유의적인 연관성을 가진 지역을 탐색하기 위하여 분석된 17개의 MS marker를 대상으로 각 marker별 대립 유전자의 최다 출현 빈도를 지닌 두 개의 대립 유전자를 선발하였다. 선발된 각각의 대립 유전자는 각 경제형질별 성적을 바탕으로 고능력 집단과 저능력 집단으로 나누었으며, 두 집단간의 Chi-squire 검정을 통해 경제형질과의 연관성을 확인하였다. 분석된 결과에 따르면 난중의 경우 94 cM에 위치한 MCW0106, 1개의 지역에서 유의적인 연관성이 탐색되었다. 시산일령의 경우, 3개의 지역(ADL0234, UMA 1.125, ADL0101)에서 유의적인 연관성이 탐색되었고, 체중의 경우 6개의 지역(UMA1.117, ADL0020, UMA1.019, LAMP1, ADL0101, ADL0238)에서 유의적인 연관성이 탐색되었으며, 마지막으로 산란수의 경우 2개의 지역(ADL0101, ADL0238)에서 유의적인 연관성을 확인하였다. ADL0101는 시산일령, 체중 그리고 산란수에서의 유의적인 연관성이 확인되었으며, 산란수에서는 두개의 대립 유전자(174, 178) 모두에서 유의적인 연관성이 탐색되었음을 확인하였다. A total of 17 polymorphic microsatellite markers on chromosome 1 were used for allelic association tests with phenotypic traits in Korean native chicken. Chi-square tests were performed to compare the frequencies of individual alleles between the high and the low trait groups. The frequency of allele 123 of MCW0160 showed a significant difference between the high and the low groups in the trait of egg weight (EW). Three markers, namely ADL0234, UMA1.125 and ADL0101, were found to show significant differences in allelic distribution for the trait of the first lay day (FLD). UMA1.117, ADL0020, UMA 1.019, LMA1 and ADL0238 were found to show significant differences in allelic distribution for the trait of body weight (BW). ADL0101 and ADL0238 were found to show significant differences in allelic distribution for the trait of number of egg production(EP). In this study, we identified the QTL for economic traits at around 94 (MCW0160), 151 (ADL0234), 170 (UMA1.125), 225 (UMA1.117), 285 (ADL0020), 387 (UMA1.019), 418 (LMA1), 500 (ADL0101) and 520 (ADL0238) cM on chromosome 1 in Korean native chicken. The results provided a useful guideline for identification of positional candidate gene and marker-assisted selection for economic traits in Korean native chicken.

Association analysis of monoamine oxidase A gene and bipolar affective disorder in Han Chinese

BackgroundMonoamine oxidase A (MAOA) is a mitochondrial enzyme involved in degrading several different biological amines, including serotonin. Although several pieces of evidence suggested that MAOA is important in the etiology of bipolar affective disorder (BPD), associations for markers of the MAOA gene with BPD were not conclusive and the association has not been investigated in Taiwanese population. This study was designed to illustrate the role of MAOA in the etiology of BPD in Han Chinese.MethodsTwo markers, a dinucleotide polymorphism in exon 2 and a functional uVNTR on the promoter of the MAOA gene, were used to study the genetic association in 108 unrelated patients with BPD and 103 healthy controls. Allelic distributions of two polymorphisms were analyzed and, caused the MAOA located at X chromosome, haplotype association was performed using haplotype unambiguously assigned in male participants.ResultsWhile no difference in allelic distributions of two MAOA polymorphisms was found, the risk haplotype 114S was associated with BPD in male patients (P = 0.03). The significance, however, was not found in female patients with 114S haplotype.ConclusionResults from this study suggest that MAOA may have a gender-specific and small effect on the etiology of BPD in Taiwan. Due to the limited sample size, results from this study need to be confirmed in replicates.

Interleukin-1 receptor antagonist gene polymorphisms are associated with disease severity in Black South Africans with rheumatoid arthritis

Objective To test for genetic associations between polymorphisms of the interleukin-1 (IL-1) gene cluster and disease susceptibility and severity in Black South Africans with rheumatoid arthritis (RA). Methods Allele and genotype frequencies of IL1B (−511) and (+3954) and IL1RN variable number of tandem repeat (VNTR) and (+2018) were compared between 141 RA patients and 101 healthy controls. Results No significant differences in allelic distribution at the four loci were observed between RA patients and controls. Within the RA group, the IL1RN*2 (two repeats of an 86 bp tandem repeat) at the IL1RN VNTR locus was independently associated with higher Larsen radiologic damage scores (LDS), corrected for disease duration ( p = 0.04). Moreover, the inferred haplotype, consisting of IL1RN*2 and (+2018) ‘C’ allele, was associated with significantly higher LDS, on average 15 points higher, compared to the base haplotype of IL1RN*long (three or more repeats) and (+2018) ‘T’ allele ( p = 0.009). The common IL1B (−511) ‘T’ allele was associated with a poorer modified health assessment questionnaire disability index ( p = 0.02). Conclusion Our findings provide further evidence of a possible role of polymorphisms of the IL-1 gene cluster in disease severity in RA, and particularly IL1RN*2 as a marker of erosive joint damage in Black South Africans with RA.

Single nucleotide polymorphisms in cell cycle regulator p21 and p27 genes are associated with susceptibility to epithelial ovarian cancer

To investigate the association of single nucleotide polymorphisms (SNP) in p21 and p27 genes with the risk of epithelial ovarian cancer (EOC). Genotypes were analyzed by polymerase chain reaction-restrictive fragment length polymorphism (PCR-RFLP) method in 234 patients with EOC and 284 control women in China. (1) The frequencies of the p21 in healthy controls were 34.2%, 49.6% and 16.2%, while the distribution of the C and T allele was 59.0% and 41.0%, respectively. The p21 C/C (28.2%), C/T (53.0%), T/T (18.8%) distribution in ovarian cancer patients was not significantly different from that in healthy controls (P > 0.05). There was no statistic difference in allele distribution between ovarian cancer patients and healthy controls (P > 0.05) either. The stratification analysis by tumor histological type did show that the genotype distribution in four types of ovarian cancer patients was significantly different from that in healthy controls (P = 0.02) . The C/C genotype was likely to reduce the risk of epithelial endometrial cancer, and the adjusted odds ratio was 0.56 (95% CI:0.32-0.98). (2) The genotype frequencies of the p27 in healthy controls were 88.4%, 10.9% and 0.7%, while the distribution of the V and G allele was 93.8% and 6.2%, respectively. The V/V (93.6%), V/G (5.1%) and G/G (1.3%) distribution in ovarian cancer patients was significantly different from that in healthy controls (P = 0. 04). There was no statistic difference in allele distribution between ovarian cancer patients and healthy controls (P > 0.05). Compared with the V/G and G/G genotypes, the V/V genotype increased the risk of EOC, the adjusted odds ratio was 1.92 (95% CI: 1.02-3.63). The C/C genotype of p21 may reduce the risk of epithelial endometrial cancer, and the genotype of p27 V/V may be a potential risk factor for susceptibility to EOC.

Biodiversity in Mediterranean buffalo using two microsatellite multiplexes

The present study was carried out to investigate genetic diversity in Nile-Delta and Southern-Egypt buffalo populations in comparison with the Italian buffalo utilizing two microsatellite multiplexes. A total of 104 animals classified into three groups were used, 28, 38 and 38 representing the Nile-Delta, Southern-Egypt and Italian buffalo, respectively. The 15 studied microsatellites were CSSM38, CSSM70, CYP21, CSSM42, CSSM60, MAF65, BM0922, CSSM19, INRA006, ETH02, BM1706, BMC1013, CSSM47, INRA026 and CA004. All studied microsatellites showed allelic polymorphism. Number of polymorphic alleles ranged between 4 alleles (CSSM38, CSSM70 and CYP21) and 11 alleles (CA004). Pairwise Chi-square test for Nile Delta and Southern Egypt showed significant differences in allelic distribution at five loci, CSSM70, CSSM38, BM0922, ETH02 and BM1706. Italian buffalo showed the lowest percentage of observed heterozygotes (65%), while the Southern Egypt showed the highest (71%). Both the Italian and the Delta populations deviated significantly ( P < 0.05) from HW equilibrium. Italian buffalo is relatively the most inbred population while the Southern-Egypt buffalo is the only outbred population. High level of genetic differentiation ( F ST estimates) between the Italian group and each of the Delta and Southern-Egypt group (0.083 and 0.076, respectively) was observed while Southern-Egypt group showed a lower level of genetic differentiation with the Delta group (0.014). Italian buffalo had the greatest genetic distance values with the two Egyptian groups (0.25 and 0.23) while much lower values between the Southern-Egypt and the Delta groups (0.06) was observed. Genetic variation between the Italian buffalo and the Egyptian buffalo was detected in 14 (out of 15) microsatellite loci. While a lower level (than that between Egyptian and Italian) of genetic variation between Southern-Egypt and Delta buffalo populations was expressed by 5 loci. It was concluded that the Southern-Egypt buffalo could be considered as distinct population from the Delta buffalo. In addition, Southern-Egypt group, being the only group with non-significant global deviation from HW equilibrium, the most heterozygous, and the only outbred population as well, is expected to respond more favorably to selection.

Five X-chromosome short tandem repeats in a Western Mexican population

X-linked microsatellites represent an efficient complement of autosomal and Y-chromosomal markers in forensic and kinship analysis. DXS337 (n=208), DXS101 (n=208), HPRTB (n=206), DXS8377 (n=220), and DXS7423 (n=213) were genotyped in male and female samples from a Western Mexican Mestizo population using singleplex systems and polyacrylamide gel electrophoresis. Genotype distributions did not deviate from Hardy-Weinberg expectations, and pairwise allele combination analysis was consistent with independent segregation for every marker (p>0.05). Allele frequencies were not different by gender. Differences in allele distribution with respect to Caucasian population data (DXS101, HPRTB, DXS8377, DXS7423) seem attributable to the native Mexican component. For the set of five markers, the combined power of discrimination and the probability of exclusion in paternity tests in trios were greater than 0.999. The present data reveal that the panel of five X-short tandem repeats analyzed is highly informative in forensic identity and parentage studies in Western Mexico.

The allelic distribution of a single nucleotide polymorphism in the PDCD5 gene locus of Japanese non-small cell lung cancer patients

It has been reported that the rs1862214 single nucleotide polymorphism (SNP) in the programmed cell death 5 gene (PDCD5) is associated with smoking-related lung cancer risk and prognosis in a European population with a history of smoking. The aim of this study was to investigate the status and impact of SNPs in the PDCD5 locus of a Japanese population. We developed an assay based on real-time PCR with melting curve analysis for determining the rs1862214 SNP, and examined this SNP in 165 lung cancer patients and 180 healthy volunteers. Of the 165 lung cancer patients (107 smokers), 25 (17), 72 (47) and 68 (43) had the CC, CG and GG genotypes of rs1862214, respectively. Of the 180 volunteers (117 smokers), 31 (24), 81 (52) and 68 (41) had the CC, CG and GG genotypes of rs1862214, respectively. No significant difference in allelic distribution was found between Japanese patients and healthy controls, even among smokers. Based on the published data, the distribution of this SNP appears to be significantly different in Japanese and European populations. No significant difference in prognosis according to the SNP was observed, either in patients with a history of smoking or in the total number of patients. This too differs from the results from a European population. In conclusion, we developed a convenient real-time PCR-based assay for the genotyping of rs1862214 in the PDCD5 locus. The distribution of the rs1862214 SNP in our Japanese population differs from its distribution in a European population, and is not related to the risk of cancer or to poor prognosis in lung cancer. This suggests the presence of an ethnicity-related difference in the role of PDCD5 in the pathogenesis of lung cancer.

Vitamin D Receptor (VDR) Polymorphisms in Chronic Lymphocytic Leukaemia (CLL) Patients.

Chronic Lymphocytic Leukaemia (CLL) is a lymphoproliferative disorder in which leukaemic B cells are arrested in the G0/G1 phase of the cell cycle, resulting in their prolonged lifespan. The clinical course of CLL is highly variable with survival ranging from a few months to decades. Thus, a good prognostic tool is needed to help predict the course of the disease. The pathogenesis of CLL is unknown but it has been associated with the “escape” of B cells from apoptosis, possibly due to overexpression of anti-apoptotic genes and downregulation of pro-apoptotic genes. The expression of these genes is influenced by alterations in chromatin structure through a change in DNA methylation (chromatin remodelling) mediated by multi-protein complexes. The Vitamin D receptor (VDR), which forms part of one such chromatin remodelling complex, has been shown to be linked to the susceptibility to and outcome of other malignancies (e.g. prostate cancer). We hypothesised that VDR polymorphisms (FokI, TaqI, BsmI and ApaI) may be linked to CLL pathogenesis and/or might be a marker of CLL progression, given the immunomodulatory actions of Vitamin D. The genotypes of 34 patients with CLL were determined by either allele-specific PCR (FokI) or PCR/restriction digestion analysis (TaqI, BsmI and ApaI). Clinical data including disease stage (Rai), other prognostic markers (e.g. lymphocyte doubling time) and therapy status were recorded. Statistical analysis including Wilcoxon, Chi-square and Spearman correlation tests were performed. Initial analysis-to-date has not shown significant difference in allelic distribution between CLL patients and a healthy control population. There was no statistically significant association between the 4 VDR polymorphisms and the clinical parameters of CLL (all p>0.05). A larger cohort of CLL patients is currently under study to determine any such potential correlation.

Genetic polymorphism of 15 STR loci in central western Colombia

Fifteen autosomal short tandem repeat (STR) loci were analyzed using the AmpFISTR Identifiler PCR Amplification Kit in 1944 samples of healthy unrelated individuals, born in the regions of Caldas, Quindio and Risaralda, Colombia. Allele frequencies and statistical parameters of forensic interest are presented for all markers (D8S1179, D21S11, D7S820, CSF1PO, D3S1358, THO1, D13S317, D16S539, D2S1338, D19S433, vWA, TPOX, D18S51, D5S818 and FGA). All loci of the pooled data were in agreement with Hardy–Weinberg equilibrium, after Bonferroni correction. Comparisons with neighboring Latin American populations and Andalucia (Spain) revealed significant differences in allele distributions. Genetic data presented in this study can be used for routine forensic applications in the region.

Analysis of IL-1A(-889) and TNFA(-308) gene polymorphism in Brazilian patients with generalized aggressive periodontitis.

Generalized aggressive periodontitis (GAP) comprises a group of periodontal diseases characterized by the rapid destruction of periodontal tissues which affect young individuals who generally present no systemic disorders. Polymorphisms in the interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) genes have been associated with an increased severity of chronic periodontitis. The objective of the present study was to evaluate the association between IL-1A (-889) and TNFA (-308) gene polymorphisms and GAP. One hundred nonsmoking subjects were selected, including 30 with GAP and 70 without periodontal disease. Gene polymorphisms were analyzed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. For IL-1 (-889), the frequency of genotype 1/1 was 54.3% in the control group and 56.7% in the study group. The frequency of genotype 1/2 was 37.1% in the control group and 40% in the study group. Genotype 2/2 was detected at a frequency of 8.6% and 3.3% in the control and study groups, respectively. For TNFA, genotype 1/1 was present in 68.6% of control subjects and in 80.0% of patients with GAP, while the frequency of genotype 1/2 was 27.1% in the control group and 20% in the study group. Genotype 2/2 was present in 4.3% of control subjects and was not detected in the study group. The frequencies of allele 1 and allele 2 of the IL-1A (-889) gene were 72.9% and 27.1%, respectively, in the control group and 76.7% and 23.3% in the GAP group. For the TNFA (-308) gene, the frequency of allele 1 was 82.15% in the control group and 90% in the study group, whereas the frequency of allele 2 was 17.85% in the control group and 10% in the study group. Statistical analysis revealed no significant difference in allele distribution for either gene between the two groups. No association was observed between GAP and IL-1A (-889) and TNFA (-308) gene polymorphisms in Brazilian patients.

Polymorphisms in Genes Involved in Innate Immunity Predispose Toward Mycetoma Susceptibility

Madurella mycetomatis is the main causative agent of mycetoma, a tumorous fungal infection characterized by the infiltration of large numbers of neutrophils at the site of infection. In endemic areas the majority of inhabitants have Abs to M. mycetomatis, although only a small proportion of individuals actually develop mycetomal disease. It therefore appears that neutrophils are unable to clear the infection in some individuals. To test this hypothesis, 11 single nucleotide polymorphisms involved in neutrophil function were studied in a population of Sudanese mycetoma patients vs geographically and ethnically matched controls. Significant differences in allele distribution for IL-8 (CXCL8), its receptor CXCR2, thrombospondin-4 (TSP-4), NO synthase 2 (NOS2), and complement receptor 1 (CR1) were found. Further, the NOS2(Lambaréné) polymorphism was clearly associated with lesion size. The genotypes obtained for CXCL8, its receptor CXCR2, and TSP-4 all predisposed to a higher CXCL8 expression in patients, which was supported by the detection of significantly elevated levels of CXCL8 in patient serum. The NOS2 genotype observed in healthy controls was correlated with an increase in NOS2 expression and higher concentrations of nitrate and nitrite in control serum. We present the first evidence of human genetic predisposition toward susceptibility to mycetoma, a neglected infection of the poor.

Incidence of abacavir hypersensitivity and its relationship with HLA-B*5701 in HIV-infected patients in Taiwan

To describe the incidence of hypersensitivity to abacavir and frequency of human leucocyte antigen (HLA)-B*5701 in HIV-infected Taiwanese persons. Medical records of 337 HIV-infected Taiwanese in whom abacavir-containing combination antiretroviral therapy (CART) was prescribed from 1 May 2001 to 31 December 2006 were reviewed, and HLA typing of the patients was performed in 320 patients (232 receiving abacavir and 88 not receiving abacavir) with available blood samples. HLA class I and II polymorphisms were determined by PCR with specific primers. HLA-B*5701 was further confirmed by sequence-based typing. Of the 337 patients, median CD4 count was 166.5 cells/mm3 (range, 1.0-1914.0) and 83 patients (24.6%) had AIDS-defining opportunistic infections. Thirty-eight patients (11.3%) discontinued abacavir within 6 weeks of starting abacavir-containing CART. Among them, 10 patients had successful abacavir re-challenge and another 11 patients had other specific reasons for abacavir discontinuation. Therefore, 14 patients (4.2%) were classified as cases in whom abacavir hypersensitivity could not be excluded, and 3 patients (0.9%) met the criteria of abacavir hypersensitivity. Of the 320 patients undergoing HLA typing, HLA-A02 was the most common allele and only one individual (0.3%) expressed HLA-B*5701. Along with some differences in allele distributions, there was a significant difference in the genetic frequency of HLA-B57 in our patients compared with those of previous studies in other Chinese populations. Abacavir hypersensitivity was less frequently encountered in HIV-infected Taiwanese initiating abacavir-containing CART than in Caucasians, which might be explained by the low frequency of the HLA-B*5701 allele.

Pharmacogenomic (PG) analysis of Japan-SWOG common arm study in advanced stage non-small cell lung cancer (NSCLC): A model for testing population-related pharmacogenomics

7500 Background: We have previously reported differences in outcomes (increased survival, neutropenia &amp; febrile neutropenia) in Japanese versus US patients (pts) treated with a paclitaxel-carboplatin “common arm” in a prospectively designed fashion in 3 phase III trials (FACS, LC03, S0003) in advanced NSCLC (Gandara, ASCO 05 &amp; Crowley, ASCO 06). We hypothesized that these findings were due in part to PG alterations in paclitaxel disposition. Methods: Genomic DNA was prospectively collected from pts in 2 of these phase III trials (LC03 [N=78, 37 on common arm] &amp; S0003 [N=78]) with identical eligibility, staging, treatment plan (paclitaxel 225 mg/m2 &amp; carboplatin AUC 6), response &amp; toxicity criteria. Analysis for genotypic variants of CYP3A4, CYP3A5, CYP2C8, NR1I2–206, ABCB1, ERCC2 was performed by pyrosequencing, and results assessed by Cox model for survival/PFS &amp; logistics regression for response/toxicity. Results: There was a significant difference between Japan &amp; US pts in genotypes: CYP3A4*1b (p=0.01), CYP3A5*3c (p=0.03), ERCC2 k751q (p &lt;0.001), and CYP2C8 r139k (p=.01). Genotypic correlations were observed between CYP3A4*1b for PFS (HR 2.75, 1.06–7.08, p=0.04) &amp; ERCC2 k751q for response (HR 0.33, 0.13–0.84, p=0.02). There were no other statistically significant associations, although for grade 4 neutropenia, the HR for ABCB1 3425c-&gt;T was 1.84 (0.77–4.48), p=0.19. The low number of events for febrile neutropenia within this data set precluded assessment of this parameter. Additional PG testing is ongoing &amp; will be presented. Conclusions: 1) Differences in allelic distribution for genes involved in paclitaxel disposition or DNA repair were observed between Japanese &amp; US pts. 2) Statistically significant genotype-associated correlations were present for PFS (CYP3A4*1b) &amp; response (ERCC2 k751q), but not for neutropenia (p=0.19). 3) The small sample size limits interpretation of these data. Further studies based on this common arm approach are warranted for the prospective study of population-related PGs where ethnic/racial differences in anti-neoplastic drug disposition are anticipated. [Table: see text]

Haplotype-Based Case-Control Study of the Association between the Guanylate Cyclase Activator 2B (GUCA2B, Uroguanylin) Gene and Essential Hypertension

Uroguanylin (gene name: guanylate cyclase activator 2B, GUCA2B) is a peptide regulator of intestinal salt and water transport. It has been reported that the uroguanylin knockout mouse exhibits elevated blood pressure. Therefore, the GUCA2B gene is thought to be a susceptibility gene for essential hypertension (EH). Despite extensive studies, however, the relationship between the GUCA2B gene and EH has not yet been defined. The aim of this study was to assess the association between the human GUCA2B gene and EH. Using four single nucleotide polymorphisms (SNPs), we conducted a genetic association study in 281 EH patients and 279 age-matched normotensive (NT1) individuals. To derive more reliable data, we performed a duplicate case-control study in which we recruited another normotensive group (NT2). There was no significant difference in the overall distribution of alleles for any of the SNPs between the EH and NT1 groups, or between the EH and NT2 groups. Therefore, these four SNPs cannot be the genetic markers for EH. The occurrences of the C-A haplotype (rs883062-rs1047047) and the C-A-G haplotype (rs883062-rs1047047-rs2297566) were significantly higher in the EH group than in the NT1 group (p<0.0001) or the NT2 group (p<0.0001). These results suggest that the C-A haplotype and the C-A-G haplotype of the GUCA2B gene are the genetic markers for EH, and that GUCA2B or a neighboring gene might be a susceptibility gene for EH.

Linkage and RH mapping of 10 genes to a QTL region for fatness and muscling traits on pig chromosome X

Microsatellite alleles, their sizes and distribution in affected and control Boxer and WHWT animals are shown in Table 1. The microsatellites were informative, and the alleles were equally distributed among cases and controls in both breeds. No statistically significant difference in allele distribution was observed (data not shown). Plausible haplotypes were computed for the genotypes using PHASE version 2.1. Based on the observed microsatellite alleles, 19 and 14 possible haplotypes were generated in the PHASE analysis yet five and eight haplotypes were observed in Boxers and WHWTs, respectively. Statistical evaluations were performed by chi-square analyses and showed alleles in significant LD. The distribution of these marker alleles defined haplotype blocks at the KLK7 locus (Table 2). None of the observed haplotypes showed genetic association in either CAD-affected dogs or unaffected dogs.

Association screen for atopic dermatitis candidate gene regions using microsatellite markers in pooled DNA samples

Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting up to 16% of children in developed countries. A complex genetic background for AD has been suggested, with genetic as well as environmental factors influencing disease susceptibility. Among other factors, dysregulation in both the innate and the adaptive immune system has been proposed to play a role in AD pathophysiology. We present here an extended association screen for AD using microsatellite markers in 154 genes related to innate and adaptive immunity in pooled DNA samples from 150 German children with AD and 100 controls. After Bonferroni correction, no marker revealed a significant association with AD. Yet, markers representing the nuclear factor kappa B (NFKB)1 and chemokine receptor (CCR)4 genes showed differences in allelic distributions between cases and controls for both pooled DNA analysis and individual genotyping and were thus further investigated. Evaluation of additional single nucleotide polymorphisms (SNP) in the NFKB1 and CCR4 genes revealed no association of individual SNPs with AD. In contrast, haplotype analyses showed a significantly different haplotype distribution between patients and controls for CCR4 (P < 0.001). Furthermore, when SNP-SNP interaction effects were analysed for these two genes, we found significant evidence for epistatic interactions between SNPs within each of the two genes but no evidence for a gene-gene interaction, suggesting that variation in or near both the CCR4 and the NFKB1 genes might individually contribute to AD pathogenesis.

Nitric oxide synthase gene polymorphisms and nephropathy in Asians with Type 2 diabetes

Objective Recent studies on Caucasians have reported an association between diabetic microvascular complications and polymorphisms in the inducible nitric oxide synthase (iNOS) gene. In view of the differences in the pattern of diabetic complications in Asians, we studied these iNOS polymorphisms in Asians with Type 2 diabetes who do and those who do not have nephropathy. Methods Two hundred fifty-eight Asians who have had Type 2 diabetes for at least 10 years, with overt nephropathy or with normoalbuminuria, were genotyped for the (AAAT) n and (CCTTT) n polymorphisms in the promoter region of the iNOS gene. A subanalysis was made of the findings from the three ethnic groups (Chinese, Malays, and Indians). Results The (AAAT) 3 polymorphism, which is the most common allele in Caucasians, was completely absent in our entire cohort of 258 Asian diabetics. The (AAAT) 4 polymorphism was the commonest, with a frequency of 0.984 as compared with 0.2 in Caucasians. We also found previously unreported alleles: (AAAT) 5 in 6 patients and (AAAT) 6 in 1 patient. There was no statistically significant association with nephropathy, in view of the highly skewed distribution of the alleles. However, the higher repeats (AAAT) 5 and (AAAT) 6 were found in the patients with a very rapid onset of severe nephropathy. The (CCTTT) n polymorphism also showed significant differences in allele distribution between the Asian and the Caucasian and African populations ( P=.001). However, there was also no significant association with nephropathy and no significant difference in the ethnic distribution of alleles. Conclusions We have identified significant differences in the (AAAT) n and (CCTTT) n polymorphisms in Asian diabetics. We have shown that there are significant differences in the overall allele distribution between the Asian and the Caucasian and African populations. However, our study did not demonstrate an association between iNOS gene polymorphisms and diabetic nephropathy.