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Major Allele (major + allele)

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Medical Sciences	75%

Selected Abstracts

Hip geometry variation is associated with bone mineralization pathway gene variants: The framingham study

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2010
Ching-Lung Cheung
Abstract Mineralization of bone matrix is an important process in bone formation; thus defects in mineralization have been implicated in bone mineral density (BMD) and bone structure alterations. Three central regulators of phosphate balance, ALPL, ANKH, and ENPP1, are central in the matrix mineralization process; therefore, the genes encoding them are considered important candidates genes for BMD and bone geometry. To test for an association between these three candidate genes and BMD and bone geometry traits, 124 informative single-nucleotide polymorphisms (SNPs) were selected and genotyped in 1513 unrelated subjects from the Framingham offspring cohort. Initial results showed that SNP rs1974201 in the gene ENPP1 was a susceptibility variant associated with several hip geometric indices, with the strongest p value of 3.8,×,10,7 being observed for femoral neck width. A few modest associations were observed between SNPs in or near ALPL and several bone traits, but no association was observed with ANKH. The association signals observed for SNPs around rs1974201 were attenuated after conditional analysis on rs1974201. Transcription factor binding-site prediction revealed that the HOXA7 binding site was present in the reference sequence with the major allele, whereas this potential binding site is lost in the sequence with the minor allele of rs1974201. In conclusion, we found evidence for association of bone geometry variation with an SNP in ENPP1, a gene in the mineralization pathway. The alteration of a binding site of the deregulator of extracellular matrix HOXA7 warrants further investigation. © 2010 American Society for Bone and Mineral Research [source]

Influence of Genetic Variation in the C-Reactive Protein Gene on the Inflammatory Response During and After Acute Coronary Ischemia

ANNALS OF HUMAN GENETICS, Issue 6 2006
J. Suk Danik
Summary The aim of this research was to assess whether common genetic variants within the C-reactive protein gene (CRP) are related to the degree of acute rise in plasma C-reactive protein (CRP) levels following an acute coronary syndrome (ACS). While polymorphisms within CRP are associated with basal CRP levels in healthy men and women, less is known about the relationship of such genetic variants and the degree of CRP rise during and after acute ischemia. Plasma CRP is associated with increased rates of recurrent coronary events. We evaluated seven common genetic variants within CRP and assessed their relationship to the degree of rise in CRP levels immediately following an acute coronary syndrome in 1827 European American patients. Variants in the putative promoter region, ,757T > C and ,286C > T > A, were associated with the highest CRP elevations after ACS. Patients with two copies of the A allele of SNP ,286C > T > A had median CRP values of 76.6 mg/L, compared to 11.1 mg/L in patients with no copies of the rare variant (p-value <0.0001), post ACS. The lowest CRP values were found for patients with minor alleles of the exonic 1059G > C and the 3,untranslated region 1846G > A SNPs. For example, patients homozygous for the minor allele of 1059G > C had 71% lower median CRP values than those homozygous for the major allele [3.5 vs 12.0 mg/L, p < 0.0001]. These trends persisted in the chronic stable phase after ischemia had resolved, and after adjustment for infarct size by peak creatinine kinase levels and clinical status by Killip class. Assessment of CRP genetic variants identified patients with higher and lower CRP elevation after acute coronary syndrome. [source]

Genetic variation in the SMAD3 gene is associated with hip and knee osteoarthritis

ARTHRITIS & RHEUMATISM, Issue 8 2010
Ana M. Valdes
Objective Smad3 (or, MADH3) is a key intracellular messenger in the transforming growth factor , signaling pathway. In mice, Smad3 deficiency accelerates growth plate chondrocyte maturation and leads to an osteoarthritis (OA),like disease. We undertook this study to investigate the role of genetic variation in SMAD3 in the risk of large-joint OA in humans. Methods Ten tag single-nucleotide polymorphisms (SNPs) in the SMAD3 gene region were tested in a discovery set: 313 patients who had undergone total knee replacement, 214 patients who had undergone total hip replacement, and 520 controls from the UK. The SNP associated with both hip and knee OA was subsequently genotyped in 1,221 controls and 1,074 cases from 2 cohorts of patients with hip OA and 2,537 controls and 1,575 cases from 4 cohorts of patients with knee OA. Results A SNP (rs12901499) mapping to intron 1 of SMAD3 was associated with both knee and hip OA (P < 0.0022 and P < 0.021, respectively) in the discovery set. In all study cohorts, the major allele (G) was increased among OA patients relative to controls. A meta-analysis for knee OA yielded an odds ratio (OR) of 1.22 (95% confidence interval [95% CI] 1.12,1.34), P < 7.5 × 10,6. For hip OA, the OR was 1.22 (95% CI 1.09,1.36), P < 4.0 × 10,4. No evidence for heterogeneity was found (I2 = 0%). Conclusion Our data indicate that genetic variation in the SMAD3 gene is involved in the risk of both hip OA and knee OA in European populations, confirming the results from animal models on the potential importance of this molecule in the pathogenesis of OA. [source]

Role of the urate transporter SLC2A9 gene in susceptibility to gout in New Zealand M,ori, Pacific Island, and Caucasian case,control sample sets

ARTHRITIS & RHEUMATISM, Issue 11 2009
Jade E. Hollis-Moffatt
Objective To examine the role of genetic variation in the renal urate transporter SLC2A9 in gout in New Zealand sample sets of M,ori, Pacific Island, and Caucasian ancestry and to determine if the M,ori and Pacific Island samples could be useful for fine-mapping. Methods Patients (n= 56 M,ori, 69 Pacific Island, and 131 Caucasian) were recruited from rheumatology outpatient clinics and satisfied the American College of Rheumatology criteria for gout. The control samples comprised 125 M,ori subjects, 41 Pacific Island subjects, and 568 Caucasian subjects without arthritis. SLC2A9 single-nucleotide polymorphisms rs16890979 (V253I), rs5028843, rs11942223, and rs12510549 were genotyped (possible etiologic variants in Caucasians). Results Association of the major allele of rs16890979, rs11942223, and rs5028843 with gout was observed in all sample sets (P = 3.7 × 10,7, 1.6 × 10,6, and 7.6 × 10,5 for rs11942223 in the M,ori, Pacific Island, and Caucasian samples, respectively). One 4-marker haplotype (1/1/2/1; more prevalent in the M,ori and Pacific Island control samples) was not observed in a single gout case. Conclusion Our data confirm a role of SLC2A9 in gout susceptibility in a New Zealand Caucasian sample set, with the effect on risk (odds ratio >2.0) greater than previous estimates. We also demonstrate association of SLC2A9 with gout in samples of M,ori and Pacific Island ancestry and a consistent pattern of haplotype association. The presence of both alleles of rs16890979 on susceptibility and protective haplotypes in the M,ori and Pacific Island sample is evidence against a role for this nonsynonymous variant as the sole etiologic agent. More extensive linkage disequilibrium in M,ori and Pacific Island samples suggests that Caucasian samples may be more useful for fine-mapping. [source]

Study of functional variants of the BANK1 gene in rheumatoid arthritis

ARTHRITIS & RHEUMATISM, Issue 2 2009
Gisela Orozco
Objective To investigate 1 functional (rs17266594) and 2 potentially functional (rs10516487 and rs3733197) BANK1 variants, which were previously identified as systemic lupus erythematosus (SLE) susceptibility markers, to test whether they are associated with rheumatoid arthritis (RA). Methods Four different cohorts were included in the study: 1,080 RA patients and 1,368 healthy controls from Spain, 278 RA patients and 568 healthy controls from Sweden, 288 RA patients and 287 healthy controls from Argentina, and 288 RA patients and 288 healthy controls from Mexico. Samples were genotyped for BANK1 single-nucleotide polymorphisms (SNPs) using a TaqMan 5,-allele discrimination assay. Statistical analysis comparing allele and genotype distributions was performed with the chi-square test. Results We did not find a significant association between RA and the rs10516487 and rs17266594 BANK1 polymorphisms. However, there was an increase in the major alleles among RA patients. Similarly, for rs3733197, there was an increase in the major allele among patients in every cohort. Nevertheless, this skewing reached statistical significance in the Spanish (P = 0.01, odds ratio [OR] 1.17 [95% confidence interval (95% CI) 1.03,1.32]) and Argentinean (P = 0.04, OR 1.31 [95% CI 1.00,1.72]) populations. We found a significant association of rs10516487 (P = 0.005, OR 1.15 [95% CI 1.04,1.28]) and rs3733197 (P = 0.0009, OR 1.17 [95% CI 1.07,1.29]) with RA in the pooled analysis. In a 3-SNP haplotype analysis, we found that the major TGG haplotype was significantly associated with RA (P = 0.005, OR 1.14 [95% CI 1.04,1.25]). In addition, we found a common CAA haplotype that was protective against RA (P = 0.0004, OR 0.82 [95% CI 0.74,0.92]). Conclusion These results suggest that BANK1 SNPs and haplotypes may contribute to RA susceptibility with a low risk. [source]

Replication of the association between the C8orf13,BLK region and systemic lupus erythematosus in a Japanese population

ARTHRITIS & RHEUMATISM, Issue 2 2009
Ikue Ito
Objective Recent genome-wide association studies identified an association between single-nucleotide polymorphisms (SNPs) in the C8orf13 region of BLK, the B lymphoid tyrosine kinase gene, with systemic lupus erythematosus (SLE) in Caucasians. The purpose of this study was to evaluate the significance of this region in the genetic background of Japanese patients with SLE. Methods Fourteen tag SNPs in the C8orf13,BLK region were genotyped in 327 Japanese patients with SLE and 322 healthy Japanese controls. The population-attributable risk percentage (PAR%) of rs13277113 in Japanese was compared with that in Caucasians as well as with that of other SLE susceptibility genes in Japanese. Results As in Caucasians, rs13277113A demonstrated the strongest association in Japanese (P = 1.73 × 10,6 for the genotype frequency, P = 4.75 × 10,7 for the allele frequency, odds ratio [OR] 2.44 [95% confidence interval (95% CI) 1.43,4.16]). The association in Japanese was consistent with a recessive model (P = 2.74 × 10,7, OR 2.27 [95% CI 1.66,3.11]). In contrast to the Caucasian population, this risk allele was the major allele in the Japanese population. Because both the risk allele frequency and the OR were higher in Japanese than in Caucasians, the PAR% of rs13277113 was estimated to be much higher in Japanese (35.4%) than in Caucasians (16.2%), and the second highest among the 6 confirmed SLE susceptibility genes in Japanese. Conclusion The association of the C8orf13,BLK region with SLE was replicated in a Japanese population. Contribution of this region to the genetic predisposition to SLE appeared to be greater in Japanese than in Caucasians. [source]

The modifying effect of C-reactive protein gene polymorphisms on the association between central obesity and endometrial cancer risk

CANCER, Issue 11 2008
Wanqing Wen MD
Abstract BACKGROUND. Obesity is a major risk factor for endometrial cancer. Obesity, particularly central obesity, is considered as a systemic inflammatory condition and is related strongly to insulin resistance. C-reactive protein (CRP) is the most recognized biologic marker of chronic systematic inflammation, and it is conceivable that the CRP gene may work together with obesity in the development of endometrial cancer. METHODS. On the basis of a population-based case,control study in a Chinese population, the authors obtained obesity measurements and data on 6 CRP single-nucleotide polymorphisms (SNPs) from 1046 patients with newly diagnosed endometrial cancer (cases) and from 1035 age frequency-matched controls. The association of the CRP SNPs with endometrial cancer risk and their modification on the association between obesity and endometrial cancer risk were evaluated. RESULTS. Although CRP SNPs alone were not associated with endometrial cancer, the associations of endometrial cancer with central obesity, measured as the waist-to-hip ratio (WHR) and the waist circumference, seemed to be stronger in women who were homozygous for the major allele of reference SNP (rs)1130864 (cytidine [C]/C) than in women who had the C/thymidine (T) and T/T genotypes (interaction test: P = .013 for WHR; P = .083 for waist circumference). When the women were stratified further by menopausal status, the observed interactions persisted mainly in premenopausal women (interaction test: P < .001 for WHR; P = .002 for waist circumference). CONCLUSIONS. The current results suggested that, in the Chinese population that was studied, obesity-related insulin resistance and proinflammatory effects may play an important role in endometrial cancer risk, and these effects were modified significantly by the CRP SNP rs1130864. Cancer 2008. © 2008 American Cancer Society. [source]

Apolipoprotein AI-CIII-AIV gene cluster polymorphisms in relation to cholesterol gallstone

JOURNAL OF DIGESTIVE DISEASES, Issue 1 2007
You Gui YAO
OBJECTIVE: To investigate the frequency of variants at Xmn I, Msp I sites of apolipoprotein (Apo), A I-CIII-AIV gene cluster, and its relation to cholesterol gallstones in Chinese patients. METHODS: Restriction fragment length polymorphisms (RFLP) at Xmn I, Msp I sites of ApoAI-CIII-AIV gene cluster were studied using a polymerase chain reaction (PCR) in 161 patients with cholesterol gallstones and 94 healthy subjects from a Chinese population in Sichuan Province. RESULTS: In both the cholesterol gallstone group and the healthy control group, X1 and M1 alleles were the major alleles and homozygous X1X1 and M1M1 genotypes were the most frequent. However, the frequency of X2 allele mutation in female patients of the cholesterol gallstones group was significantly higher than that in women in the healthy control group (P < 0.05), but no difference was found in the frequency of M2 alleles mutation (P > 0.05). CONCLUSION: The data showed that Xmn I RFLP of ApoAI-CIII-AIV gene cluster is associated to some extent with cholesterol gallstones in female Chinese patients. [source]

Least-Square Deconvolution: A Framework for Interpreting Short Tandem Repeat Mixtures,

JOURNAL OF FORENSIC SCIENCES, Issue 6 2006
Tsewei Wang Ph.D.
ABSTRACT: Interpreting mixture short tandem repeat DNA data is often a laborious process, involving trying different genotype combinations mixed at assumed DNA mass proportions, and assessing whether the resultant is supported well by the relative peak-height information of the mixture sample. If a clear pattern of major,minor alleles is apparent, it is feasible to identify the major alleles of each locus and form a composite genotype profile for the major contributor. When alleles are shared between the two contributors, and/or heterozygous peak imbalance is present, it becomes complex and difficult to deduce the profile of the minor contributor. The manual trial and error procedures performed by an analyst in the attempt to resolve mixture samples have been formalized in the least-square deconvolution (LSD) framework reported here for two-person mixtures, with the allele peak height (or area) information as its only input. LSD operates on the peak-data information of each locus separately, independent of all other loci, and finds the best-fit DNA mass proportions and calculates error residual for each possible genotype combination. The LSD mathematical result for all loci is then to be reviewed by a DNA analyst, who will apply a set of heuristic interpretation guidelines in an attempt to form a composite DNA profile for each of the two contributors. Both simulated and forensic peak-height data were used to support this approach. A set of heuristic guidelines is to be used in forming a composite profile for each of the mixture contributors in analyzing the mathematical results of LSD. The heuristic rules involve the checking of consistency of the best-fit mass proportion ratios for the top-ranked genotype combination case among all four- and three-allele loci, and involve assessing the degree of fit of the top-ranked case relative to the fit of the second-ranked case. A different set of guidelines is used in reviewing and analyzing the LSD mathematical results for two-allele loci. Resolution of two-allele loci is performed with less confidence than for four- and three-allele loci. This paper gives a detailed description of the theory of the LSD methodology, discusses its limitations, and the heuristic guidelines in analyzing the LSD mathematical results. A 13-loci sample case study is included. The use of the interpretation guidelines in forming composite profiles for each of the two contributors is illustrated. Application of LSD in this case produced correct resolutions at all loci. Information on obtaining access to the LSD software is also given in the paper. [source]

Sequence variation at the human ABO locus

ANNALS OF HUMAN GENETICS, Issue 1 2002
S. P. YIP
The ABO blood group is the most important blood group system in transfusion medicine. Since the ABO gene was cloned and the molecular basis of the three major alleles delineated about 10 years ago, the gene has increasingly been examined by a variety of DNA-based genotyping methods and analysed in detail by DNA sequencing. A few coherent observations emerge from these studies. First, there is extensive sequence heterogeneity underlying the major ABO alleles that produce normal blood groups A, B, AB and O when in correct combination with other alleles. Second, there is also extensive heterogeneity underlying the molecular basis of various alleles producing ABO subgroups such as A2, Ax and B3. There are over 70 ABO alleles reported to date and these alleles highlight the extensive sequence variation in the coding region of the gene. A unifying system of nomenclature is proposed to name these alleles. Third, extensive sequence variation is also found in the non-coding region of the gene, including variation in minisatellite repeats in the 5, untranslated region (UTR), 21 single nucleotide polymorphisms (SNPs) in intron 6 and one SNP in the 3, UTR. The haplotypes of these variations reveal a specific relationship with the major ABO alleles. Fourth, excluding the common alleles, about half of the remaining alleles are due to new mutations and the other half can better be explained by intragenic recombination (both crossover and gene conversion) between common alleles. In particular, the recombination sites in hybrid alleles can be quite precisely defined through haplotype analysis of the SNPs in intron 6. This indicates that recombination is equally as important as point mutations in generating the genetic diversity of the ABO locus. Finally, a large number of ABO genotyping methods are available and are based on restriction analysis, allele specific amplification, mutation screening techniques or their combinations. [source]

Molecular characterization of CTX-M-15-producing clinical isolates of Escherichia coli reveals the spread of multidrug-resistant ST131 (O25:H4) and ST964 (O102:H6) strains in Norway

APMIS, Issue 7 2009
UMAER NASEER
Nationwide, CTX-M-producing clinical Escherichia coli isolates from the Norwegian ESBL study in 2003 (n=45) were characterized on strain and plasmid levels. BlaCTX-M allele typing, characterization of the genetic environment, phylogenetic groups, pulsed field gel electrophoresis (PFGE), serotyping and multilocus sequence typing were performed. Plasmid analysis included S1 -nuclease-PFGE, polymerase chain reaction-based replicon typing, plasmid transfer and multidrug resistance profiling. BlaCTX-M-15 (n=23; 51%) and blaCTX-M-14 (n=11; 24%) were the major alleles of which 18 (78%) and 6 (55%), respectively, were linked to ISEcp1. Thirty-two isolates were of phylogenetic groups B2 and D. Isolates were of 29 different XbaI-PFGE-types including six regional clusters. Twenty-three different O:H serotypes were found, dominated by O25:H4 (n=9, 20%) and O102:H6 (n=9, 20%). Nineteen different STs were identified, where ST131 (n=9, 20%) and ST964 (n=7, 16%) were dominant. BlaCTX-M was found on ,100 kb plasmids (39/45) of 10 different replicons dominated by IncFII (n=39, 87%), FIB (n=20, 44%) and FIA (n=19, 42%). Thirty-nine isolates (87%) displayed co-resistance to other classes of antibiotics. A transferable CTX-M phenotype was observed in 9/14 isolates. This study reveals that the majority of CTX-M-15-expressing strains in Norway are part of the global spread of multidrug-resistant ST131 and ST-complex 405, associated with ISEcp1 on transferrable IncFII plasmids. [source]