Recessive Model (recessive + model)

Distribution by Scientific Domains


Selected Abstracts


Putative functional polymorphisms of MMP9 predict survival of NSCLC in a Chinese population

INTERNATIONAL JOURNAL OF CANCER, Issue 9 2009
Guangfu Jin
Abstract Matrix metalloproteinases (MMPs) play a crucial role in cancer progression and their over-expression is often associated with unfavorable survival of non-small cell lung cancer (NSCLC). Because genetic variants can alter expression level or biological activity of MMPs, we hypothesized that potentially functional single nucleotide polymorphisms (SNPs) in key MMP genes may be associated with the survival of NSCLC patients. We selected and genotyped 14 putative functional SNPs in six MMP genes (MMP1, MMP2, MMP3, MMP7, MMP9 and MMP12) using PCR-RFLP methods in 561 NSCLC patients. Kaplan-Meier method with the log-rank test and Cox proportional hazard models were used for the survival analyses. The C-1562T, Arg279Gln and Arg668Gln polymorphisms in MMP9 were significantly associated with survival of patients with NSCLC (log-rank p values = 0.032, 0.038 and 0.036, respectively). The C-1562T and Arg668Gln loci were in complete linkage disequilibrium (r2 = 1). Patients carrying the 668Gln allele had improved survival with a median survival time (MST) of 51.6 months, compared with 21.8 months for those with the 668Arg/Arg genotype (log-rank p = 0.010). In contrast, the 279Gln/Gln genotype was associated with a significantly shortened MST (17.3 months, log-rank p = 0.030) in the recessive model. In the final multivariate Cox regression model, 279Gln/Gln was identified as an independent prognostic factor with an adjusted hazard ratio of 1.60 (95% confidence interval 1.07,2.41). The MMP9 Arg279Gln and Arg668Gln SNPs are potential predictors of survival in NSCLC patients. © 2008 Wiley-Liss, Inc. [source]


A Haplotype-Based Analysis of the LRP5 Gene in Relation to Osteoporosis Phenotypes in Spanish Postmenopausal Women,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 12 2008
Lídia Agueda
Abstract LRP5 encodes the low-density lipoprotein receptor-related protein 5, a transmembrane protein involved in Wnt signaling. LRP5 is an important regulator of osteoblast growth and differentiation, affecting bone mass in vertebrates. Whether common variations in LRP5 are associated with normal BMD variation or osteoporotic phenotypes is of great relevance. We used a haplotype-based approach to search for common disease-associated variants in LRP5 in a cohort of 964 Spanish postmenopausal women. Twenty-four SNPs were selected, covering the LRP5 region, including the missense changes p.V667M and p.A1330V. The SNPs were genotyped and evaluated for association with BMD at the lumbar spine (LS) or femoral neck (FN) and with osteoporotic fracture, at single SNP and haplotype levels, by regression methods. Association with LS BMD was found for SNP 1, rs312009, located in the 5,-flanking region (p = 0.011, recessive model). SNP 6, rs2508836, in intron 1, was also associated with BMD, both at LS (p = 0.025, additive model) and FN (p = 0.031, recessive model). Two polymorphisms were associated with fracture: SNP 11, rs729635, in intron 1, and SNP 15, rs643892, in intron 5 (p = 0.007 additive model and p = 0.019 recessive model, respectively). Haplotype analyses did not provide additional information, except for haplotype "GC" of the block located at the 3,end of the gene. This haplotype spans intron 22 and the 3, untranslated region and was associated with FN BMD (p = 0.029, one copy of the haplotype versus none). In silico analyses showed that SNP 1 (rs312009) lies in a putative RUNX2 binding site. Electro-mobility shift assays confirmed RUNX2 binding to this site. [source]


Genetic Polymorphism of KCNH2 Confers Predisposition of Acquired Atrial Fibrillation in Chinese

JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 10 2009
QUN-SHAN WANG M.D.
Introduction: Nonfamiliar atrial fibrillation (AF) is usually associated with acquired structural heart disease, including valvular heart disease, coronary artery disease, and hypertension. Suggestive evidence indicates that these forms of acquired AF are more likely to occur in individuals with a genetic predisposition. We investigated the effect of the potassium channel voltage-gated subfamily member 2 (KCNH2) gene on the prevalence of acquired AF in a Chinese population. Methods: In a pair-matched, hospital-based case control study (297 vs 297) conducted in Chinese Hans, we investigated 4 tagging single nucleotide polymorphisms (tSNPs), rs1805120, rs1036145, rs3807375, and rs2968857 in the KCNH2 gene, and determined their association with AF acquired from structural heart diseases. Results: We did not observe the association of rs1036145, rs3807375, and rs2968857 with AF. However, we determined that the tSNP, rs1805120, in exon 6 confers the risk of AF in Chinese Hans. Both genotype and allele frequencies of rs1805120 were distributed differently in cases and controls (P = 0.0289 and P = 0.0172, respectively). The most significant association was observed under a recessive model for the minor GG genotype with a 1.45-fold risk of developing AF (95% confidence interval 1.09,1.93, P = 0.012). The significance remained after controlling for the covariates of age, smoking, BMI, hypertension, and diabetes. Conclusion: We report a new genetic variation (rs1805120) in the KCNH2 gene that predisposes Chinese Han individuals to the risk of acquired AF. Further genetic and functional studies are required to identify the etiological variants in linkage disequilibrium with this polymorphism. [source]


CHOP T/C and C/T haplotypes contribute to early-onset type 2 diabetes in Italians

JOURNAL OF CELLULAR PHYSIOLOGY, Issue 2 2008
*Article first published online: 4 AUG 200, Claudia Gragnoli
Type 2 diabetes (T2D) is characterized by impaired insulin secretion, insulin insensitivity and decreased beta-cell mass. Multiple genes contribute to T2D. The chromosome 12q13.1 region is in linkage to T2D in different populations, including our Italian dataset. CHOP is a candidate gene for the linkage, as it is located in the chromosome 12q13.1 region, and may contribute to T2D by increasing beta-cell apoptosis susceptibility and by impairing insulin sensitivity. Our goal was to identify any potential CHOP gene variants contributing to T2D in our Italian early-onset T2D families, which show linkage to the CHOP region. We directly sequenced the CHOP gene in 28 Italian probands of the linked T2D families and in 115 control subjects. We performed genotype and haplotype association tests with T2D of the identified single nucleotide polymorphisms (SNPs). We performed model-free and parametric association haplotype tests with T2D. We identified three SNPs [5,UTR-c.279T,>,C, 5,UTR-c.120A,>,G and,+,nt30C,>,T (F10F)] in CHOP. These SNPs are in complete linkage disequilibrium. The genotype association test showed an association trend with T2D of TT (F10F) and AG (-c.120A,>,G). The haplotype association test provided significant results for the haplotypes T/C (frequency,=,0.33) and C/T (frequency,=,0.01) (at 5,UTR-c.279T,>,C and,+,nt30C,>,T, respectively) under non-parametric analysis (P -value,=,0.0000), recessive model (P -value,=,0.0000) and additive model (P -value,=,0.0014). Our data show that CHOP described haplotypes T/C and C/T, as an additive and as a homozygous variant, contribute significantly to T2D in our Italian early-onset group. We conclude that the CHOP T/C and C/T haplotype contributes to our T2D linkage signal on chromosome 12q13.1. J. Cell. Physiol. 217: 291,295, 2008. © 2008 Wiley-Liss, Inc. [source]


Endothelial NOS G894 T and MMP-3 5A/6A gene polymorphisms and hypertension in Serbian population

JOURNAL OF CLINICAL LABORATORY ANALYSIS, Issue 6 2005
Tamara Djuri
Abstract The incidence of hypertension is increasing and it is more common in man than in women. Up to date, MMP-3 5A/6A polymorphism has been associated with artery stiffening and elevated blood pressure, whereas results considering association of endothelial NOS (eNOS) G894 T polymorphism with hypertension are controversial. The aim of our study was to analyze the possible association of eNOS G894 T and MMP-3 5A/6A gene polymorphisms with hypertension in Serbian population. Study sample consisted of 172 hypertensive and 200 normotensive subjects divided by gender. Both female and male group was truncated according to age. All subjects were genotyped for MMP-3 5A/6A and eNOS G894 T polymorphism. There was a significantly higher (P < 0.05) prevalence of 5A/5A genotype in hypertensive females compared to normotensive ones (19.30 % vs. 10.84%) even more pronounced in group ,50 years, according to its recessive effect. In young males (<40 years), we found 3.7-fold increased risk for hypertension associated with allele 6A (P < 0.01), and 8.1-fold with genotype 6A/6A (P = 0.01) according to recessive model. We found no association of eNOS G894 T polymorphism with hypertension. These results indicate that there were gender- and age-specific differences in association of MMP-3 5A/6A polymorphism with hypertension in Serbian population. J. Clin. Lab. Anal. 19:214,246, 2005. © 2005 Wiley-Liss, Inc. [source]


Novel pharmacogenetic markers for treatment outcome in azathioprine-treated inflammatory bowel disease

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2009
M. A. SMITH
Summary Background, Azathioprine (AZA) pharmacogenetics are complex and much studied. Genetic polymorphism in TPMT is known to influence treatment outcome. Xanthine oxidase/dehydrogenase (XDH) and aldehyde oxidase (AO) compete with TPMT to inactivate AZA. Aim, To assess whether genetic polymorphism in AOX1, XDH and MOCOS (the product of which activates the essential cofactor for AO and XDH) is associated with AZA treatment outcome in IBD. Methods, Real-time PCR was conducted for a panel of single nucleotide polymorphism (SNPs) in AOX1, XDH and MOCOS using TaqMan SNP genotyping assays in a prospective cohort of 192 patients receiving AZA for IBD. Results, Single nucleotide polymorphism AOX1 c.3404A > G (Asn1135Ser, rs55754655) predicted lack of AZA response (P = 0.035, OR 2.54, 95%CI 1.06,6.13) and when combined with TPMT activity, this information allowed stratification of a patient's chance of AZA response, ranging from 86% in patients where both markers were favourable to 33% where they were unfavourable (P < 0.0001). We also demonstrated a weak protective effect against adverse drug reactions (ADRs) from SNPs XDH c.837C > T (P = 0.048, OR 0.23, 95% CI 0.05,1.05) and MOCOS c.2107A > C, (P = 0.058 in recessive model, OR 0.64, 95%CI 0.36,1.15), which was stronger where they coincided (P = 0.019). Conclusion, These findings have important implications for clinical practice and our understanding of AZA metabolism. [source]


Polymorphisms in IL13 pathway genes in asthma and chronic obstructive pulmonary disease

ALLERGY, Issue 4 2010
B. Beghé
To cite this article: Beghé B, Hall IP, Parker SG, Moffatt MF, Wardlaw A, Connolly MJ, Fabbri LM, Ruse C, Sayers I. Polymorphisms in IL13 pathway genes in asthma and chronic obstructive pulmonary disease. Allergy 2010; 65: 474,481. Abstract Background:, Asthma and chronic obstructive pulmonary disease (COPD) are chronic respiratory diseases involving an interaction between genetic and environmental factors. Interleukin-13 (IL13) has been suggested to have a role in both asthma and COPD. We investigated whether single nucleotide polymorphisms (SNPs) in the IL13 pathway may contribute to the susceptibility and severity of asthma and COPD in adults. Methods:, Twelve SNPs in IL13 pathway genes ,IL4, IL13, IL4RA, IL13RA1, IL13RA2 and STAT6, were genotyped in subjects with asthma (n = 299) and in subjects with COPD or healthy smokers (n = 992). Genetic association was evaluated using genotype and allele models for asthma severity, atopy phenotypes and COPD susceptibility. Linear regression was used to determine the effects of polymorphism on baseline lung function (FEV1, FEV1/FVC). Results:, In asthmatics, three IL13 SNPs , rs1881457(,1512), rs1800925(,1111) and rs20541(R130Q) , were associated with atopy risk. One SNP in IL4RA1 [rs1805010(I75V)] was associated with asthma severity, and several IL13 SNPs showed borderline significance. IL13 SNPs rs1881457(,1512) and rs1800925(,1111) were associated with better FEV1 and FEV1/FVC in asthmatics. IL13 SNPs rs2066960(intron 1), rs20541(R130Q) and rs1295685(exon 4) were associated with COPD risk and lower baseline lung function in the recessive model. In females, but not in males, rs2250747 of the IL13RA1 gene was associated with COPD and lower FEV1. Conclusion:, These data suggest that IL13 SNPs (promoter and coding region) and, to a lesser extent, IL4RA SNPs may contribute to atopy and asthma. We also provide tentative evidence that IL13 SNPs in the coding region may be of significance in COPD susceptibility. [source]


Sequence variation in ,-methylacyl-CoA racemase and risk of early-onset and familial prostate cancer

THE PROSTATE, Issue 14 2007
Albert M. Levin
Abstract BACKGROUND Expression of the ,-methylacyl-CoA racemase (AMACR) gene has been established as a sensitive and specific biomarker for the diagnosis of prostate cancer. An initial study has also suggested that the risk of familial (but not sporadic) prostate cancer may be associated with germline variation in the AMACR gene. METHODS In a study of brothers discordant for the diagnosis of prostate cancer (including 449 affected and 394 unaffected men) from 332 familial and early-onset prostate cancer families, we used conditional logistic regression and family-based association tests to investigate the association between prostate cancer and five single nucleotide polymorphisms (SNPs) tagging common haplotype variation within the coding and regulatory regions of AMACR. RESULTS The strongest evidence for prostate cancer association was for SNP rs3195676, with an estimated odds ratio of 0.58 (95% confidence interval,=,0.38,0.90; P,=,0.01 for a recessive model). This non-synonymous SNP (nsSNP) results in a methionine-to-valine substitution at codon 9 (M9V) in exon 2 of the AMACR gene. Three additional nsSNPs showed suggestive evidence for prostate cancer association (P,,,0.10). CONCLUSIONS Our results confirm an initial report of association between the AMACR gene and the risk of familial prostate cancer. These findings emphasize the value of studying early-onset and familial prostate cancer when attempting to identify genetic variation associated with prostate cancer. Prostate 67: 1507,1513, 2007. © 2007 Wiley-Liss, Inc. [source]


Assignment of the locus for arachnomelia syndrome to bovine chromosome 23 in Simmental cattle

ANIMAL GENETICS, Issue 6 2009
J. Buitkamp
Summary Arachnomelia syndrome is a lethal inherited malformation mainly of the limbs, vertebral column and skull in cattle, which poses a severe impairment to farmers and breeders. Recently, a number of cases of arachnomelia syndrome have occurred in the Simmental breed and some sires with excellent breeding values had been shown to be carriers of the disease. We herein report the genetic mapping of the mutation underlying arachnomelia in cattle. The disease was mapped using a two-stage genome scan. A first round autosomal genome-wide screening using a limited number of cases identified three chromosomal regions with lod-scores > 1. The position of the arachnomelia syndrome locus was identified to be on BTA 23 by genotyping an additional, independent set of animals with markers that provided positive lod-scores in the course of the initial genome-wide screen. Using a denser set of regional microsatellites, the locus could be mapped to a region about 9 cM in length. The most significant linkage signal with arachnomelia syndrome was obtained with marker NRKM-17 (lod-score > 20) using a recessive model. Interestingly, different genes seem to be responsible for the disease in Brown Swiss and Simmental breeds, as arachnomelia syndrome was mapped to a different location in Brown Swiss. The results provide sufficient information for the development of a genetic test system and also allow the identification of positional candidate genes. [source]


Detecting linkage disequilibrium in the presence of locus heterogeneity

ANNALS OF HUMAN GENETICS, Issue 3 2006
D. Wang
Summary Locus heterogeneity is a common phenomenon in complex diseases and is one of the most important factors that affect the power of either linkage or linkage disequilibrium (LD) analysis. In linkage analysis, the heterogeneity LOD score (HLOD) rather than LOD itself is often used. However, the existing methods for detecting linkage disequilibrium, such as the TDT and many of its variants, do not take into account locus heterogeneity. We propose two novel likelihood-based methods, an LD-Het likelihood and an LD-multinomial likelihood, to test linkage disequilibrium (LD) that explicitly incorporate locus heterogeneity in the analysis. The LD-Het is applicable to general nuclear family data but requires a working penetrance model. The LD-multinomial is only applicable to affected sib-pair data but does not require specification of a trait model. For affected sib-pair data, both methods have similar power to detect LD under the recessive model, but the LD-multinomial model has greater power when the underlying model is dominant or additive. [source]


The FAS ,670A>G polymorphism influences susceptibility to systemic sclerosis phenotypes

ARTHRITIS & RHEUMATISM, Issue 12 2009
J. Broen
Objective To investigate the possible role of the FAS ,670A>G functional polymorphism in the genetic predisposition to systemic sclerosis (SSc) susceptibility or clinical phenotype. Methods A total of 2,900 SSc patients and 3,186 healthy controls were included in this study. We analyzed the genotype and allele frequencies of the FAS ,670A>G polymorphism in 9 distinct ethnic cohorts, including 6 cohorts of European ancestry (a Spanish cohort of 228 SSc patients and 265 controls, a Dutch cohort of 203 SSc patients and 277 controls, a German cohort of 313 SSc patients and 247 controls, an Italian cohort of 323 SSc cases and 89 controls, a British cohort of 269 SSc patients, and a Swedish cohort of 182 patients) and 3 distinct ethnic cohorts from the US (a cohort of 1,047 white patients and 692 controls, a cohort of 159 Hispanic patients and 137 controls, and a cohort of 176 black SSc patients and 194 controls). Genotyping was performed using a TaqMan 5, allelic discrimination assay. Results In the British, Italian, and American white cohorts we observed an association of the FAS ,670G allele with limited cutaneous SSc (lcSSc) (odds ratios [ORs] 1.25, 1.43, and 1.18, respectively). A meta-analysis comprising all 9 cohorts revealed an association of both the FAS ,670G allele (OR 1.10) and the FAS ,670GG genotype (OR 1.13) with the lcSSc phenotype. In a meta-analysis including only white subjects, both the FAS ,670G allele and the FAS ,670GG genotype remained associated with lcSSc (allele OR 1.12; genotype OR 1.16). In addition, a recessive model of the ,670GG genotype exhibited a strong association with SSc, lcSSc, and anticentromere antibody,positive lcSSc (OR 1.23, OR 1.33, and OR 1.45, respectively). Conclusion Our data show that the FAS ,670A>G polymorphism plays a role in lcSSc susceptibility. A similar trend has been observed in other autoimmune diseases. [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]