SEARCH · PubMed Health

Results for “Polymorphism”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,603 records · Page 89Linked to original sources

PubMed2005

Polymorphisms in FcgammaRIIIA (CD16) receptor expression are associated with clinical response to rituximab in Waldenström's macroglobulinemia.

PURPOSE: Rituximab is an important therapeutic for Waldenstrom's macroglobulinemia (WM). Polymorphisms in FcgammaRIIIA (CD16) receptor expression modulate human immunoglobulin G1 binding and antibody-dependent cell-mediated cytotoxicity, and may therefore influence responses to rituximab. PATIENTS AND METHODS: Sequence analysis of the entire coding region of FcgammaRIIIA was undertaken in 58 patients with WM whose outcomes after rituximab were known. RESULTS: Variations in five codons of FcgammaRIIIA were identified. Two were commonly observed (FcgammaRIIIA-48 and FcgammaRIIIA-158) and predicted for amino acid polymorphisms at FcgammaRIIIA-48: leucine/leucine (L/L), leucine/arginine (L/R), and leucine/histidine (L/H). Polymorphisms at FcgammaRIIIA-158 were phenylalanine/phenylalanine (F/F), phenylalanine/valine (F/V), and valine/valine (V/V). A clear linkage between these polymorphisms was detected and all patients with FcgammaRIIIA-158F/F were always FcgammaRIIIA-48L/L, and patients with either FcgammaRIIIA-L/R or -L/H always expressed at least one valine at FcgammaRIIIA-158 (P < or = .001). The response trend was higher for patients with FcgammaRIIIA-48L/H (38.5%) versus -48L/R (25.0%) and LL (22.0%), and was significantly higher for patients with FcgammaRIIIA-158V/V (40.0%) and -V/F (35%) versus -158F/F (9.0%; P = .030). Responses for patients with FcgammaRIIIA-48L/L were higher when at least one valine was present at FcgammaRIIIA-158 (P = .057), thereby supporting a primary role for FcgammaRIIIA-158 polymorphisms in predicting rituximab responses. With a median follow-up of 13 months, no significant differences in the median time to progression and progression-free survival were observed when patients were grouped according to their FcgammaRIIIA-48 and -158 polymorphisms. CONCLUSION: The results of these studies therefore support a predictive role for FcgammaRIIIA-158 polymorphisms and responses to rituximab in WM.

Adult↗

PubMed2006

Functional characterization of polymorphisms in the kidney enhancer of the human renin gene.

The renin gene is regulated by an enhancer located 2.6 kb upstream of the transcription start site in the mouse and 11 kb upstream in humans. Despite extensive sequence conservation, the mouse renin enhancer is transcriptionally more active than the human renin enhancer. We report that the mechanism accounting for this is a result of sequence variation in the promoter proximal half-site of a retinoic-acid response element present in the enhancer. This sequence difference also prompted us to search for naturally occurring polymorphisms in the renin enhancer among normal and hypertensive human subjects. We sequenced the kidney enhancer from 90 samples derived from the Coriell Polymorphism Discovery Resource and 95 severely hypertensive Caucasian and African-American individuals. A single relatively frequent polymorphism (7, 2, and 7%, respectively in the Coriell, African-American, and Caucasian) was identified in the enhancer, one nucleotide downstream of the promoter distal half-site of the retinoic-acid response element. This variant was transcriptionally silent in transfection assays performed in renin-expressing As4.1 cells, a model of renal juxtaglomerular cells. A singleton polymorphism in the promoter was also identified in a single African-American individual. This polymorphism was located between binding sites for CBF1 and homeobox D10 but was also transcriptionally silent either in the presence or absence of the enhancer. Our study demonstrates the presence of silent polymorphisms in the renin promoter and enhancer, thus underscoring the critical importance of performing functional analyses before initiating expensive clinical studies seeking association between polymorphisms and complex diseases such as hypertension.

Animals↗

PubMed1986

Structural analysis of the polymorphic 3' region of the human chorionic gonadotropin-alpha gene in normal placenta and choriocarcinoma cells.

We previously examined the segregation patterns of two polymorphic restriction enzyme sites for EcoRI and HindIII in the 3'-flanking region of human CG-alpha gene in placenta and choriocarcinoma. We observed that a unique combination of restriction sites predominates in choriocarcinoma while this pattern was rare in placenta, suggesting a functionally important site in this region of genome. Genomic libraries were constructed from DNA derived from placenta and from the choriocarcinoma cell line JAr to examine the DNA sequence responsible for these polymorphic sites. Several clones were isolated; restriction fragments containing the polymorphic sites were subcloned into pBR322, and the stretch of DNA encompassing the polymorphic sites were sequenced. No apparent DNA rearrangements were observed; sequence analysis showed that both of the polymorphic sites were caused by single base pair mutation in the recognition sequence of each enzyme. Three new polymorphic sites were identified in the 3' region of the hCG-alpha gene. These data indicate that major DNA rearrangements in the 3' region of the gene are not associated with choriocarcinoma. However, analysis of the polymorphic sites revealed that there is a linkage disequilibrium among these sites which may extend to a putative oncogene which is responsible for developing choriocarcinoma.

Base Sequence↗

PubMed2004

Influence of SHBG gene pentanucleotide TAAAA repeat and D327N polymorphism on serum sex hormone-binding globulin concentration in hirsute women.

SHBG is the specific plasma transport protein for sex steroid hormones in humans. Plasma SHBG concentration follows a gender dimorphism but varies with nutritional and hormonal status in both sexes. In addition, a genetic influence on SHBG in humans has recently been suggested by family studies. We investigated the relationship between a point mutation (D327N) in SHBG gene exon 8 that delays human SHBG half-life and a pentanucleotide repeat polymorphism [PNRP (TAAAA)(n)] in the SHBG gene 5' untranslated region that influences transcription in vitro, on the one hand, and SHBG levels on the other, in a population of 303 women referred for hirsutism. Of these patients, 154 (51%) met the criteria for polycystic ovary syndrome (PCOS) and 124 (41%) were overweight [body mass index (BMI) > or = 25 kg/m(2)]. The two SHBG gene alleles for D327N substitution, wild-type (W) and variant (v), were identified by restriction fragment length polymorphism in the whole population, and the GeneScan method was used to identify PNRP alleles in 245 subjects. Six alleles of the pentanucleotide motif with six to 11 repeats were present in our population. Plasma SHBG concentration was related to PCOS status, non-SHBG-bound testosterone, BMI, fasting blood glucose level, fasting insulinemia, and D327N allele v. The v allele was associated with higher SHBG levels [36.9 +/- 15.9 nmol/liter for W/v (n = 52) and 43.5 +/- 3.5 nmol/liter for v/v (n = 2)] than was the wild-type W allele [31.1 +/- 16.1 nmol/liter (n = 249); P = 0.039]. Multivariate analysis showed that BMI, PCOS status, and D327N polymorphism influenced plasma SHBG concentrations, each of these parameters contributing independently of the others. Investigating the role of each allele of the TAAAA repeat polymorphism on SHBG levels was more complex because of the number of different genotypes (as many as 18 in our population) and the low frequency of some of them. Moreover, a strong disequilibrium linkage was found between D327N allele v and the eight-TAAAA repeat allele (P < 0.0001). This could mask the effect of the TAAAA repeat polymorphism on SHBG concentration in vivo. Nevertheless, SHBG levels in patients who were homozygous for six repeats (34.9 +/- 16.2 nmol/liter; n = 21) were significantly (P = 0.043) higher than in nine-repeat homozygous patients (21.5 +/- 13.0 nmol/liter; n = 8), and lay between the two for eight-repeat homozygous patients (28.5 +/- 15.8 nmol/liter; n = 44). Delineating the precise role of this PNRP polymorphism will need further investigation in a large healthy population. In summary, although BMI and PCOS status have a major influence on circulating SHBG levels in hirsute women, the present results support the notion that polymorphism(s) within the coding sequence and, potentially, in the regulatory sequence of the SHBG gene are associated with circulating SHBG levels and may represent part of the genetic background of sex steroid hormone activity in humans.

Adult↗

PubMed2004

Interleukin-13 gene polymorphisms confer the susceptibility of Japanese populations to Graves' disease.

Graves' disease (GD) is an autoimmune disorder with genetic predisposition. IL-13 is an important mediator of antiinflammatory immune responses and is expressed in the thyroid and orbit. The aim of the present study was to investigate whether IL-13 gene polymorphisms are associated with the development of GD. IL-13 gene polymorphisms were studied in Japanese GD patients (n = 310) and healthy control subjects without antithyroid autoantibodies or a family history of autoimmune disorders (n = 244). A C/T polymorphism at position -1112 of the promoter region was measured using the direct sequencing method, and an Arg(130)Gln (G2044A) polymorphism in exon 4 was examined using the PCR-restriction fragment length polymorphism method. There was a significant decrease in -1112T allele frequency in GD patients compared with controls (16% vs. 23%; P = 0.0019). The frequency of the 2044A allele on exon 4 also appeared lower in GD patients compared with controls. Haplotype analysis showed a significant decrease in the -1112T/2044A haplotype in GD patients. There was no association between IL-13 gene polymorphisms and ophthalmopathy, severity, or serum IgE levels. In conclusion, IL-13 gene polymorphisms are associated with GD susceptibility in Japan.

Adolescent↗

PubMed2005

The effect of cholesteryl ester transfer protein -629C->A promoter polymorphism on high-density lipoprotein cholesterol is dependent on serum triglycerides.

CONTEXT: The -629C-->A cholesteryl ester transfer protein (CETP) promoter polymorphism is a determinant of HDL cholesterol (HDL-C). The effect of the closely linked CETP TaqIB polymorphism on HDL-C has been suggested to be modified by obesity and hyperinsulinemia. OBJECTIVE: Because the CETP-mediated cholesteryl ester transfer out of HDL is stimulated by high triglycerides, we hypothesized that triglycerides modify the effect of the CETP -629C-->A promoter polymorphism on HDL-C. DESIGN: In 7083 nondiabetic subjects of the PREVEND population, the -629C-->A promoter polymorphism, HDL-C, serum triglycerides, waist circumference, and insulin resistance (HOMA(ir)) were determined. Serum apolipoprotein A-I was available in 6948 subjects. The TaqIB polymorphism was also assessed. SETTING: The study is set in the general community. RESULTS: HDL-C and serum apolipoprotein A-I were on average 0.14 mmol/liter and 0.05 g/liter higher in -629AA (22.9%) compared to -629CC (26.8%) homozygotes (P < 0.001 for both). This genotype effect on HDL-C was on average 0.15 mmol/liter in the lowest triglyceride tertile but only 0.08 mmol/liter in the highest tertile (P < 0.01). Multiple regression analysis showed that HDL-C was determined by the CETP promoter variant (P < 0.001), gender (P < 0.001), triglycerides (P < 0.001), and interactions between triglycerides and genotype (P < 0.05), between triglycerides and gender (P < 0.05), and between genotype and gender (P < 0.05), independently from waist, HOMA(ir), alcohol use, age, and use of lipid-lowering drugs. The TaqIB polymorphism also interacted with triglycerides on HDL-C. The -629C-->A promoter polymorphism did not interact with obesity and HOMA(ir) on HDL-C. CONCLUSIONS: The HDL-C-raising effect of the CETP -629A allele is diminished with higher triglycerides, which may be explained by a predominant effect of triglyceride-rich lipoproteins over circulating CETP itself on cholesteryl ester transfer out of HDL with rising triglycerides.

Adult↗

PubMed2005

Polymorphisms in the CLCN7 gene modulate bone density in postmenopausal women and in patients with autosomal dominant osteopetrosis type II.

CONTEXT: Genetic factors are important determinants of bone mineral density (BMD). The fact that mutations in the ClC-7 chloride channel cause autosomal dominant osteopetrosis (ADOII) make the CLCN7 gene an attractive candidate for the regulation of bone density. OBJECTIVE: The objective of the study was to investigate the association between polymorphisms in the CLCN7 gene and BMD in postmenopausal women and with clinical variability in ADOII. DESIGN: This was a genetic association study using five single-nucleotide polymorphisms and a variable number tandem repeat (VNTR) polymorphism in the CLCN7 gene. PARTICIPANTS: A total of 425 postmenopausal women aged 64 +/- 7 yr participated in the study. We also investigated an ADOII family with low penetrance comprising 18 mutation carriers. MAIN OUTCOME MEASURE(S): In our postmenopausal cohort, individual single-nucleotide polymorphism genotypes and haplotypes were analyzed for association with BMD at the lumbar spine and the femoral neck and with the bone resorption marker deoxypyridinoline (D-Pyr/Crea). The same polymorphisms on the nonmutated CLCN7 allele were investigated for association with the variability of the ADOII phenotype. RESULTS: Analysis by multiple linear regression revealed a significant association between the ss genotype of the VNTR and higher Z-score values (P = 0.029). The haplotype 4, which comprises the long allele of the VNTR, was found to be significantly associated with lower femoral neck Z-score values (P = 0.011). Furthermore, we found an association of the ss genotype of the VNTR with lower levels of the bone resorption marker D-Pyr/Crea (P = 0.015), whereas haplotype 4 was associated with higher D-Pyr/Crea levels (P = 0.039). In the ADOII family, we could demonstrate that haplotype 3, which contains the s-allele of the VNTR, is associated with a slightly higher probability that mutation carriers develop osteopetrosis (P = 0.029). In both cases the association seems largely to be driven by the VNTR genotype but is further strengthened if surrounding polymorphisms are added to the analysis. CONCLUSION: We observed a significant association of CLCN7 polymorphisms with the variance of BMD and bone resorption marker levels in postmenopausal women and with the variability of the ADOII phenotype.

Aged↗

PubMed2000

The A19G polymorphism in the 5' untranslated region of the human obese gene does not affect leptin levels in severely obese patients.

Recently, the presence of different polymorphisms in the regulatory region of the ob gene has been associated with variations in leptin levels. However, the results of these studies are still contradictory. The aim of the present investigation was to evaluate the presence of the A19G polymorphism in an Italian population of obese patients and to verify its association with leptin levels and anthropometric, metabolic, and clinical parameters. Two hundred five obese patients [body mass index (BMI) > 36 kg/m2; 135 women and 70 men; mean age, 46.9+/-14.23 yr] were screened for presence of the polymorphism; 61 normal-weight controls (mean BMI, 21.05 kg/m2; 53 women, 8 men) were also screened to compare polymorphism frequency. For obese patients, BMI, waist-to-hip ratio, resting energy expenditure, body composition, fasting leptin, total cholesterol, high-density lipoproteins, triglycerides, and caloric intake were determined. Genotype frequencies in obese and control subjects were compared using the contingency table chi-square test; in obese subjects an ANOVA was performed to evaluate association between the polymorphism and several clinical parameters. No significant differences in genotype distribution between control and obese subjects were found. No significant correlations were found between this polymorphism and serum leptin levels and the other parameters considered. These findings confirm the results obtained in both a Finnish and a French population; taken together, these observations might rule out a significant role for the A19->G polymorphism in the regulation of leptin levels and other clinical, anthropometric, and metabolic parameters.

5' Untranslated Regions↗

PubMed2000

Lack of association of nonautoimmune hyperfunctioning thyroid disorders and a germline polymorphism of codon 727 of the human thyrotropin receptor in a European Caucasian population.

Constitutively activating mutations of the human TSH receptor (hTSHR) gene have been implicated as a major cause of hyperfunctioning nonautoimmune thyroid disease. However, significant geographic differences in the prevalence of these mutations have been observed. Recently, a high frequency of a germline polymorphism at codon 727 of the cytoplasmic tail of the hTSHR has been demonstrated in patients with toxic multinodular goiter. In the present study we assessed whether the codon 727 polymorphism is associated with hyperfunctioning thyroid adenomas. PCR followed by restriction enzyme digestion were used to genotype a total of 128 European Caucasian patients with toxic nonautoimmune thyroid disease (83 with toxic adenoma, 31 with toxic multinodular goiter, and 14 with disseminated autonomy) and to compare their codon 727 polymorphism frequencies with those of 99 healthy controls and 108 patients with Graves' disease. All individuals were drawn from an identical ethnic background. Sequencing of PCR products was used to confirm the mutation analysis. We found no significant differences in codon 727 polymorphism frequencies between patients with autonomously functioning thyroid disorders (13.3%) and the healthy control group (16.2%; P = 0.57). Moreover, the subtypes of toxic nonautoimmune thyroid disease (toxic adenoma, 13.2%; multinodular goiter, 9.6%; disseminated autonomy, 21.4%) were not related to significant differences in codon 727 polymorphism frequencies compared with the healthy control group (P = 0.67, P = 0.40, and P = 0.70, respectively). Additionally, there were no significant differences between patients with Graves' disease (21.3%) and healthy controls (P = 0.38). In conclusion, our data do not support an association between the codon 727 polymorphism of the hTSHR and toxic thyroid adenomas or toxic multinodular goiter in our study population. Thus, the codon 727 polymorphism of the hTSHR does not appear to be involved in the evolution of autoimmune or nonautoimmune hyperthyroidism in the European Caucasian population.

Adenoma↗

PubMed1999

Dopamine D2 receptor gene polymorphism and the risk of levodopa-induced dyskinesias in PD.

OBJECTIVE: To investigate whether polymorphisms in the genes for dopamine receptors D1 and D2 are associated with the risk of developing peak-dose dyskinesias in PD. BACKGROUND: Peak-dose dyskinesias are the most common side effects of levodopa therapy for PD. The identified predictors may only partially account for the risk of developing peak-dose dyskinesias because a substantial proportion of patients never develop peak-dose dyskinesias. Genetic factors could play a role in determining the occurrence of peak-dose dyskinesias. METHODS: A case-control study of 136 subjects with sporadic PD and 224 population control subjects. We studied three polymorphisms involving the dopamine receptor D1 gene and one intronic short tandem repeat polymorphism of the dopamine receptor D2 gene. RESULTS: The polymorphisms of the dopamine receptor D1 gene were not associated with the risk of developing PD or peak-dose dyskinesias. The 15 allele of the polymorphism of the dopamine receptor D2 gene was more frequent in parkinsonian subjects than in control subjects. More important, the frequency of both the 13 allele and the 14 allele of the dopamine receptor D2 gene polymorphism was higher in nondyskinetic than in the dyskinetic PD subjects. The risk reduction of developing peak-dose dyskinesias for PD subjects carrying at least 1 of the 13 or 14 alleles was 72% with respect to the PD subjects who did not carry these alleles. CONCLUSIONS: Certain alleles of the short tandem repeat polymorphism of the dopamine receptor D2 gene reduce the risk of developing peak-dose dyskinesias and could contribute to varying susceptibility to develop peak-dose dyskinesias during levodopa therapy.

Adult↗

PubMed2001

The COMT L allele modifies the association between MAOB polymorphism and PD in Taiwanese.

OBJECTIVE: Reports suggest that catechol-O-methyltransferase (COMT(L/L)) (Val(158)/Met) and monoamine oxidase B (MAOB) intron 13 genotype polymorphism is associated with PD. To understand the ethnicity-specific effects of genetic polymorphism, we performed a case-control study of the association between PD susceptibility and polymorphism of MAOB and COMT, both separately and in combination, in Taiwanese. METHODS: Two hundred twenty-four patients with PD and 197 controls, matched for age, sex, and birthplace, were recruited. MAOB and COMT polymorphism genotyping was performed by using PCR-based restriction fragment length polymorphism (RFLP) analyses. chi(2), OR, and Fisher's exact tests were used to compare differences in allelic frequencies and genotypes. RESULTS: The MAOB G genotype (G in men and G:/G in women) was associated with a 2.07-fold increased relative risk of PD. COMT polymorphism, considered alone, showed no correlation with PD risk; however, a significant synergistic enhancement was found in PD patients harboring both the COMT(L) and MAOB G genotypes. CONCLUSIONS: These results suggest that, in Taiwanese, PD risk is associated with MAOB G intron 13 polymorphism, and this association is augmented in the presence of the COMT(L) genotype, indicating an interaction of these two dopamine-metabolizing enzymes in the pathogenesis of sporadic PD. However, the relatively low frequencies of these combined genotypes in our study necessitates confirmation with a larger sample size.

Aged↗

PubMed2004

Pharmacogenomics of drug transporters: a new approach to functional analysis of the genetic polymorphisms of ABCB1 (P-glycoprotein/MDR1).

In the 21st century, emerging genomic technologies (i.e., bioinformatics, functional genomics, and pharmacogenomics) are shifting the paradigm of drug discovery research and improving the strategy of medical care for patients. In order to realize the personalized medicine, it is critically important to understand molecular mechanisms underlying inter-individual differences in the drug response, namely, pharmacological effect vs. side effect. Evidence is now accumulating to strongly suggest that drug transporters are one of the determinant factors governing the pharmacokinetic profile of drugs. Effort has been made to identify genetic variation in drug transporter genes. In particular, genetic variations of the human ABCB1 (P-glycoprotein/MDR1) gene have been most extensively studied. Hitherto more than fifty single nucleotide polymorphisms (SNPs) and insertion/deletion polymorphisms in the ABCB1 gene have been reported. However, at the present time, information is still limited with respect to the actual effect of those genetic polymorphisms on the function of ABCB1. In this context, we have undertaken functional analyses of ABCB1 polymorphisms. To quantify the impact of genetic polymorphisms on the substrate specificity of ABCB1, we have developed a high-speed screening system and a new structure-activity relationship (SAR) analysis method. This review addresses functional aspects of the genetic polymorphism of ABCB1 and provides the standard method to evaluate the effect of polymorphisms on the function.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Association between HaeIII polymorphism of scavenger receptor class B type I gene and plasma HDL-cholesterol concentration.

BACKGROUND: Evidence has recently been found for significant associations between genetic variation within the scavenger receptor class B type I gene (SR-BI), plasma lipids and anthropometric measurements in healthy Caucasians. The present case-control study was conducted to determine whether there is an association between three polymorphisms identified by the restriction endonucleases HaeIII, AluI and ApaI of SR-BI and coronary artery disease (CAD) in Korean subjects. METHODS: DNA was extracted from 137 subjects with CAD and 124 age-matched controls; it was amplified using the polymerase chain reaction. Individual alleles at each of the three polymorphic sites were identified by digestion with the appropriate restriction enzyme. RESULTS: Only a single allele was identified at the AluI and ApaI polymorphic sites. The frequency of the common (+) allele at the HaeIII polymorphic site was higher in CAD patients than in the controls (P = 0.001). The concentrations of plasma HDL-cholesterol and apolipoprotein AI also varied significantly among HaeIII genotypes in the CAD patients. The common (+) allele of the HaeIII polymorphism was associated with a lower body mass index in female controls. CONCLUSIONS: Allele frequencies of the AluI and ApaI polymorphisms in this study were different to those in a Caucasian population studied previously, suggesting a difference in the genetic background. Further comparative studies of SR-BI polymorphism in other racial or ethnic groups should therefore prove to be of value.

Aged↗

PubMed2003

T+31C polymorphism (M235T) of the angiotensinogen gene and home blood pressure in the Japanese general population: the Ohasama Study.

The angiotensinogen (AGT) gene polymorphism M235T (a methionine to threonine amino acid substitution) has been investigated in association with essential hypertension (EHT) based on conventional measurement of blood pressure (BP); however, the results have been inconsistent. Recently, we have been conducting lines of genetic analysis on a general population of Ohasama Town in Iwate Prefecture, Japan, who measured their BP at home (Ohasama genetic analysis and home BP project). We here assessed the association between AGT M235T polymorphism and hypertension within the same population (1,245 subjects aged 40 years and over). AGT M235T polymorphism was determined by genotyping the AGT T+31C polymorphism, which has complete disequilibrium with the AGT M235T polymorphism. We defined subjects as hypertensive if they were being treated with antihypertensive medication and/or had home BP values of more than 135 mmHg in systole and/or 85 mmHg in diastole. The genotype frequencies were similar to those in previous Japanese studies. There was no significant difference among the genotypes in home BP values (p = 0.63/0.74 for systolic/diastolic blood pressure) or in prevalence of hypertension (MM: 44.7%; MT: 42.3%; TT: 39.6%; p = 0.61). No difference was noted in the frequency of familial history of hypertension. Pulse pressure, however, was significantly different among the genotypes (p = 0.049), and this association was prominent in the older (age260) population (p = 0.0018), but not noted in the younger population (60 > age > or = 40). In conclusion, the present analysis confirmed the lack of a significant effect of AGT M235T polymorphism on blood pressure level, but the difference in pulse pressure in the older population suggests that further investigations of this polymorphism should be made in the Japanese population.

Aged↗

PubMed2002

Genetic susceptibility in Dupuytren's disease. TGF-beta1 polymorphisms and Dupuytren's disease.

Dupuytren's disease is a benign fibroproliferative disease of unknown aetiology. It is often familial and commonly affects Northern European Caucasian men, but genetic studies have yet to identify the relevant genes. Transforming growth factor beta one (TGF-beta1) is a multifunctional cytokine which plays a central role in wound healing and fibrosis. It stimulates the proliferation of fibroblasts and the deposition of extracellular matrix. Previous studies have implicated TGF-beta1 in Dupuytren's disease, suggesting that it may represent a candidate susceptibility gene for this condition. We have investigated the association of four common single nucleotide polymorphisms in TGF-beta1 with the risk of developing Dupuytren's disease. A polymerase chain reaction-restriction fragment length polymorphism method was used for genotyping TGF-beta1 polymorphisms. DNA samples from 135 patients with Dupuytren's disease and 200 control subjects were examined. There was no statistically significant difference in TGF-beta1 genotype or allele frequency distributions between the patients and controls for the codons 10, 25, -509 and -800 polymorphisms. Our observations suggest that common TGF-beta1 polymorphisms are not associated with a risk of developing Dupuytren's disease. These data should be interpreted with caution since the lack of association was shown in only one series of patients with only known, common polymorphisms of TGF-beta1. To our knowledge, this is the first report of a case-control association study in Dupuytren's disease using single nucleotide polymorphisms in TGF-beta1.

Adult↗

PubMed1999

Angiotensin-converting enzyme gene polymorphism: is there a link to nephropathy in patients with type 1 diabetes?

OBJECTIVE: To evaluate the association between the angiotensin-converting enzyme (ACE) gene polymorphism and diabetic nephropathy in patients with type 1 diabetes. DATA SOURCES: Citations were selected using the MEDLINE database. Only those citations involving human subjects and available in English were selected. Key search words included angiotensin-converting enzyme (ACE), polymorphism, nephropathy, and type 1 diabetes. STUDY SELECTION: Selection criteria consisted of all MEDLINE-referenced clinical trials, review articles, and editorial comments assessing the potential link between the ACE gene polymorphism and diabetic nephropathy in insulin-dependent diabetes mellitus published between January 1990 and February 1998. DATA SYNTHESIS: Because diabetic nephropathy is a serious complication of type 1 diabetes, focus has been placed on the early identification of and intervention with patients genetically susceptible to this complication. Because the ACE gene polymorphism has an effect on plasma ACE concentration variations among individuals, it has been investigated as a potential genetic marker for diabetic nephropathy. The best studies to date are reviewed in order to assess the utility of the ACE polymorphisms as a genetic marker of diabetic nephropathy in patients with type 1 diabetes, and to determine what implications this holds for drug treatment. CONCLUSIONS: Although the ACE gene polymorphism's potential link to diabetic nephropathy in patients with type 1 diabetes has been debated, the most definitive studies show that an association exists. Large epidemiologic studies must now be conducted to determine the implications this polymorphism holds for the best treatment strategies in the care of these patients.

Clinical Trials as Topic↗

PubMed2004

The influence of an insulin-like growth factor I gene promoter polymorphism on hip bone geometry and the risk of nonvertebral fracture in the elderly: the Rotterdam Study.

UNLABELLED: The absence of the wildtype allele of a promoter polymorphism of the IGF-I gene is associated with increased risk (1.5; 95% CI, 1.1-2.0) of fragility fracture in women (n = 4212) but not in men (n = 2799). An approximation of hip bone geometry (from DXA) suggested the polymorphism is associated with bone strength and stability in gender-specific ways. INTRODUCTION: Previously, we found a CA-repeat promoter polymorphism in the insulin-like growth factor I (IGF-I) gene associated with IGF-I levels and BMD in postmenopausal women, but the relationship with fractures is unclear. In this large population-based study of elderly men and women, we examined the association between this IGF-I promoter polymorphism with parameters of bone geometry and the occurrence of fractures. MATERIAL AND METHODS: Within the Rotterdam Study, a prospective population-based cohort, the IGF-I polymorphism was analyzed in relation to incident nonvertebral fractures in 2799 men and 4212 women followed on average for 8.6 years. Furthermore, we estimated structural parameters of hip bone geometry indirectly from DXA outputs of the femoral neck in 2372 men and 3114 women. We studied neck width, cortical thickness, and the cortical buckling ratio and the section modulus as indexes of bone stability and bending strength. RESULTS: Women heterozygotes and noncarriers of the allele had, respectively, 1.2 (95% CI, 1.0-1.5) and 1.5 (95% CI, 1.1-2.0) increased risk of having a fragility fracture at older age compared with homozygotes for the 192-bp allele (p trend = 0.0007). In men, fracture risk was not influenced by the polymorphism. Compared with homozygotes for the 192-bp allele, noncarrier males had approximately 1% narrower femoral necks and 2.2% lower section moduli (p trend < 0.05). Noncarrier females had 1.7% thinner cortices and 1.6% higher buckling ratios (p trend < 0.05) but no significant differences in femoral neck widths and section moduli. In women with low body mass index, genotype differences in bone strength (section modulus) and fracture risk were accentuated (p interaction = 0.05). The genotype-dependent differences in hip bone geometry did not fully explain the genotype-dependent differences in fracture risk. CONCLUSIONS: The CA-repeat promoter polymorphism in the IGF-I gene is associated with the risk for fragility fracture at old age in women and with bone structure in both genders.

Aged↗

PubMed1999

Effects of genetic polymorphism on ex vivo and in vivo function of beta2-adrenoceptors in asthmatic patients.

BACKGROUND: Genetic polymorphism determines agonist-induced down-regulation and desensitization of beta2-adrenoceptors. OBJECTIVES: The aim of the present study was to investigate the effects of genetic polymorphism on ex vivo (lymphocytes) and in vivo (bronchoprotection) function of beta2-adrenoceptors in asthmatic patients, having been washed out of previous beta2-agonist exposure. METHODS: Sixty patients with stable mild-to-moderate asthma were evaluated, with a post hoc analysis of genotype performed at end of study. Having withheld treatment with long-acting beta2-agonists for > or = 48 h and short-acting beta2-agonists for > or = 12 h, measurements of lymphocyte beta2-adrenoceptors were made for binding density, binding affinity, basal cyclic adenosine monophosphate (cAMP), and maximal cAMP response to isoproterenol (Emax). In addition, in 48 of these patients who were methacholine responsive (PD20 < 1,000 microg), the acute protective effect of formoterol as a 24-microg single dose (at 1 h) was also evaluated. Comparisons were made according to homozygous and heterozygous (Het) polymorphisms at codon 16 and codon 27. RESULTS: There were no significant differences in age, FEV1 percent predicted, or inhaled corticosteroid dose, when comparing mean values for polymorphisms at either codon-16 or codon 27. There were also no significant differences between polymorphisms for any of the measured lymphocyte beta2-adrenoceptor parameters apart from basal cAMP between Glu-27 and Het-27. Mean values for Emax (after-before isoproterenol as pmol/10(6) cells) were as follows: Gly-16 (3.4), Arg-16 (3.5), Het-16 (4.0), Glu-27 (3.9), Gln-27 (3.5), and Het-27 (3.7). Polylorphism had no significant effect on formoterol protection as doubling dose shift in methacholine PD20 (geometric mean): Gly-16 (5.3), Arg-16 (5.4), Het-16 (4.6), Glu-27 (5.3), Gln-27 (5.3), Het-27 (4.5). CONCLUSIONS: Our results show that genetic polymorphism at codon 16 or 27 does not influence stimulated coupling of lymphocyte beta2-adrenoceptors and similarly did not influence the degree of functional antagonism exhibited by formoterol. Thus, a single dose of beta2-agonist when used on demand affords equal protection against bronchoprotection regardless of genetic polymorphism.

Adenylyl Cyclases↗