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PubMed2002

Beta-adrenergic receptor polymorphisms: cardiovascular disease associations and pharmacogenetics.

The beta-adrenergic receptors (betaAR) play important roles in cardiovascular function and disease, and both agonists and antagonists are widely used in various settings for treatment of cardiovascular disease. Both the beta1AR and beta2AR genes have several polymorphisms that are common in the population and result in encoding of different amino acids. More importantly, in vitro functional studies suggest that these polymorphisms have functional significance. In this review we summarize the literature on the relationship between the betaAR polymorphisms and cardiovascular disease as well as the literature on the impact of these polymorphisms on drug response. Additionally, the polymorphisms in both the beta1AR and beta2AR genes are in linkage disequilibrium; thus, the relevance of single polymorphism vs. haplotype analysis is discussed. Further study of the betaAR genetic polymorphisms is likely to enhance our understanding of cardiovascular disease and improve our use of beta-agonists and beta-antagonists in treatment of cardiovascular disease.

Amino Acid Sequence↗

PubMed2001

Renin angiotensin system gene polymorphisms in pediatric renal transplant recipients.

Genetic variability in the renin angiotensin system may modify renal responses to injury and disease progression. We therefore examined whether the insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene, the Met235-->Thr polymorphism of the angiotensinogen (AGT) gene, and the A1166-->C polymorphism of the angiotensin II type 1 receptor gene (ATR1) were associated with disease progression and outcome after renal transplantation (Tx) in 100 Caucasian pediatric renal transplant recipients. The observed allele frequencies were: DD 31%, DI 41% and II 28%, for ACE; MM 42%, MT 37% and TT 21%, for the methionine (Met)235-->threonine (Thr) polymorphism of AGT; and AA 51%, AC 38% and CC 11%, for the adenine (A)1166-->cytosine (C) gene polymorphism. The slope of 1/creatinine was determined by linear regression analysis of a median of 12 points before and after renal Tx, and the population was divided in two equal groups, according to the slope, both before and after Tx. There were no statistically significant differences for AGT, ACE, and ATR1 polymorphisms with regard to the slope of 1/creatinine before renal Tx. After renal Tx, the ACE II genotype (p = 0.024, chi-square test) and the presence of the I allele (p=0.033, chi-square test) were associated with a favorable slope of 1/creatinine. There was no association of the AGT or the ATR1 polymorphism with outcome after renal Tx, and none of the genotypes were associated with hypertension before or after renal Tx. We suggest that the beneficial association of disease progression after renal Tx with the II genotype and/or the presence of the I allele in our pediatric cohort might be explained by a lower activity of the circulating ACE enzyme associated with the I allele.

Adolescent↗

PubMed2002

5 polymorphisms in the transforming growth factor-beta 1 gene (TGF-beta 1) in adult periodontitis.

OBJECTIVES: Transforming growth factor-beta (TGF-beta) represents a family of polypeptide growth factors, involved in inflammation and regulation of immune responses. The purpose of this study was to determine whether polymorphisms in the TGF-beta 1 gene may confer susceptibility to adult periodontitis. MATERIAL AND METHODS: We studied 90 patients with adult periodontitis together with 108 unrelated subjects. 3 polymorphisms located in the 5'region at positions -988 (C/A), -800 (G/A) and -509 (C/T) and 2 polymorphisms located at codons 10 (L10P) and 25 (R25P) of exon 1 were investigated by PCR methods. RESULTS: There was no statistically-significant difference in genotype or allele frequency distributions between patients and reference group for the -800G/A, -509C/T, L10P and R25P polymorphisms (p>0.05 in all cases). The -988 A polymorphism was present neither in our patients nor in unrelated subjects. Upon stratification for smoking status no significant differences were found in the TGF-beta 1 genotype or allele frequencies either between adult periodontitis smokers compared to control smokers, or between periodontitis non-smokers and control non-smokers. CONCLUSION: These data indicate that the mentioned polymorphisms of the TGF-beta 1 gene do not influence susceptibility to adult periodontitis. There was no association between any polymorphisms in the TGF-beta 1 gene, severity of periodontitis and the smoking status in our study.

Adult↗

PubMed2001

A polymorphism study of the human Agouti gene and its association with MC1R.

To determine whether the Agouti Signalling Protein (ASP) gene is associated with skin and hair coloration in humans, the complete coding region of ASP was screened for polymorphisms. Analysis of ASP in Caucasian, African-American, Spanish Basque, Hispanic, Apache and Australian Aboriginal populations revealed no amino acid substitutions. A single polymorphism in the 3' untranslated region occurred at a frequency of 0.2 in African-Americans. Variants of the Melanocortin 1 Receptor (MC1R) gene have been found to be associated with red hair and fair skin in humans. Red hair individuals are usually compound heterozygotes or homozygous for one of a number of MC1R polymorphisms associated with red hair. Some individuals however are heterozygous for only one of these polymorphisms and dizygotic twins can be concordant for MC1R variants but discordant for hair colour. A recent study has also identified rare redheads carrying no MC1R variants indicating that polymorphisms of the human MC1R gene are required but not sufficient for the red hair phenotype. To address the question of whether ASP also contributes to the red hair phenotype, individuals previously identified as having unexpected MC1R genotypes were screened for polymorphisms at the ASP locus. No polymorphisms were found in any of these individuals. Results indicate that the human ASP gene is unlikely to function in normal human pigmentation in the same way as MC1R.

Agouti Signaling Protein↗

PubMed2003

Polymorphisms in the IL-10 and IL-12 gene cluster and risk of developing recurrent aphthous stomatitis.

BACKGROUND: Recurrent aphthous stomatitis (RAS) is a common, painful, ulcerative condition of the mouth. Although there is no clear genetic mode of inheritance, there is evidence that inheritance of specific gene polymorphisms may predispose individuals to RAS. AlsoTh1 cell mediated immune responses under the control of IL-10/IL-12 are thought to play an important role in its pathogenesis. OBJECTIVE: The objective of this study was to investigate the possibility that susceptibility to RAS is associated with the inheritance of specific gene polymorphisms for the T cell regulatory cytokines interleukin-10 (IL-10) and interleukin-12 (IL-12). PATIENTS AND METHODS: One hundred RAS patients and 91 ethnically matched controls were genotyped for the IL-10-592, and -1082 polymorphisms, and the IL-12 1188 polymorphism. Chi-square analysis was used to compare the allele frequencies and genotypes of cases and controls. RESULTS: No significant association was identified between inheritance of specific alleles or genotypes of the IL-10-592 and -1082 polymorphisms or IL-12 1188 polymorphism and susceptibility to RAS. CONCLUSIONS: We were unable to demonstrate an association between the inheritance of specific IL-10 or IL-12 gene polymorphisms and RAS susceptibility.

Adult↗

PubMed2005

The polyAT, intronic IVS11-6 and Lys939Gln XPC polymorphisms are not associated with transitional cell carcinoma of the bladder.

Chemical carcinogens from cigarette smoking and occupational exposure are risk factors for bladder transitional cell carcinoma (TCC). The Xeroderma Pigmentosum Group C (XPC) gene is essential for repair of bulky adducts from carcinogens. The Xeroderma Pigmentosum Group C gene polymorphisms may alter DNA repair capacity (DRC), thus giving rise to genetic predisposition to bladder cancer. Recent studies have demonstrated linkage disequilibrium between three polymorphisms in the XPC gene (polyAT, IVS11-6 and Lys939Gln) and these have been shown to influence the DRC, as well as to be associated with bladder cancer risk. We analysed all three XPC polymorphisms in 547 bladder TCC patients and 579 cancer-free controls to investigate the association between these polymorphisms and bladder cancer susceptibility, and we also attempted to assess gene-environmental interactions. We confirmed strong linkage disequilibrium among the polymorphisms (Lewontin's D' > 0.99). Using logistic regression adjusting for smoking, occupational and family history, neither the heterozygote nor the homozygote variants of these polymorphisms were associated with increased bladder cancer risk (adjusted odds ratio [95% confidence interval] for heterozygote 0.82 [0.63-1.07], 0.82 [0.63-1.08] and 0.83 [0.63-1.08] for PolyAT, IVS11-6 and Lys939Gln, respectively and homozygote variant, 0.98 [0.68-1.42], 0.99 [0.69-1.43] and 1.01 [0.70-1.46]). Moreover, we did not find any significant interaction between these XPC polymorphisms and environmental exposure to cigarette smoking and occupational carcinogens.

Aged↗

PubMedDate not supplied

Study of three intragenic polymorphisms in the Machado-Joseph disease gene (MJD1) in relation to genetic instability of the (CAG)n tract.

Intergenerational instability is one of the most important features of the disease-associated trinucleotide expansions, leading to variation in size of the repeat among and within families, which manifests as variable age at onset and severity, and is probably the basis for the occurrence of anticipation. Several factors are known to affect the degree of instability, namely the type of repeated sequence, its initial size, the presence or absence of interruptions in the repetitive tract and the gender of the transmitting parent. A recent study demonstrated the effect of an intragenic polymorphism (C987GG/G987GG) in the Machado-Joseph disease causative gene, immediately downstream of the CAG repeat, on the intergenerational instability of the expanded repeat. Surprisingly, there was an effect not only of the specific allele in cis to the disease chromosome, but also of the allele on the normal chromosome, suggesting the existence of an interaction between the normal and expanded alleles that affects the fidelity of replication of the (CAG)n tract. This effect could be a direct effect of the polymorphism studied or, alternatively, this polymorphism could be in disequilibrium with some other flanking sequence which affects the instability of the repetitive (CAG)n tract. In order to confirm the previous results in a different population and to distinguish between a direct and indirect effect of the CGG/GGG polymorphism, we typed 70 parent-progeny pairs for which the variation in the (CAG)n length in the MJD1 gene was known, for three intragenic polymorphisms: C987GG/G987GG and two additional, newly described ones, TAA1118/TAC1118 and A669TG/G669TG. We also typed a control population of 125 individuals for the A669TG/G669TG, C987GG/G987GG and TAA1118/TAC1118 polymorphisms, in an attempt to identify any association between haplotype and (CAG)n length in normal chromosomes, suggestive of an instability-predisposing effect of the repeat-flanking sequences, which could have led to the origin of the MJD mutation in the human population. We confirmed the effect of the C987GG/G987GG polymorphism on intergenerational instability when present in trans. Our results suggest that this effect is restricted to a small region of the gene, immediately downstream of the CAG repeat, which includes this particular nucleotide substitution and the stop codon of the MJD1 cDNA, and is not a more widespread chromosomal effect. The lack of a significant association of any specific intragenic haplotype with larger CAG repeats in normal chromosomes, together with the absence of an effect of the intragenic haplotype in cis on the intergenerational instability of the expanded (CAG)n in MJD families does not indicate the existence of an instability-predisposing haplotype.

Alleles↗

PubMed2002

Association of the tumour necrosis factor alpha -308G/A polymorphism with the risk of diabetes in an elderly population-based cohort.

Ample evidence supports a role for tumour necrosis factor alpha (TNFalpha) in the development of type 2 diabetes and cardiovascular disease. TNFalpha expression was found to be influenced by a -308G/A polymorphism in the promoter of the gene encoding TNFalpha (TNF). We investigated the contribution of this polymorphism to diabetes and cardiovascular mortality in a population-based cohort of 664 subjects aged 85 years and over (Leiden 85-plus Study). The -308G/A TNF promoter polymorphism was associated with the prevalence of diabetes in old age (P = 0.006). The risk of diabetes among subjects homozygous for the A-allele was estimated to be 4.6-fold (95% CI, 1.6-13.3) higher than among subjects homozygous for the common G-allele. The promoter polymorphism did not, however, predict mortality from all causes, cardiovascular diseases, cancer or infectious diseases during a 10-year follow-up period. In addition to the promoter polymorphism, TNFa and TNFc microsatellite genotypes were determined but these polymorphisms were not associated with morbidity or mortality. In conclusion, the -308G/A polymorphism in the TNF promoter is strongly associated with the risk of diabetes but not cardiovascular mortality in old age.

Aged↗

PubMed1997

Novel polymorphism of the human ob gene promoter in lean and morbidly obese subjects.

OBJECTIVE: Leptin, the circulating product of the human ob gene, may play role in control of appetite and metabolic rate. We screened the proximal promoter area of the ob gene for mutations and common polymorphisms in order to find out whether genetic variation in the regulatory area of this gene plays a role in human obesity. DESIGN: The technique of single-strand-conformation polymorphism (SSCP) was applied to screen for the promoter area of the ob gene for genetic alterations in morbidly obese patients. SUBJECTS: A total of 249 morbidity obese (present or past body mass index [BMI] > or = 40 kg/m2) and 141 lean (BMI < or = 25 kg/m2) subjects. MEASUREMENTS: DNA analysis was carried out using a single-strand conformation polymorphism (SSCP) technique and PCR followed by digestion with the restriction enzyme BssHll. Leptin was determined by radioimmunoassay in obese subjects. Serum lipids, glucose and insulin concentrations in the obese subjects were also determined. RESULTS: A new polymorphism C(-188)A was identified in the promoter region of the ob gene. This polymorphism was detected with allelic frequencies of 0.06 in morbidly obese subjects and 0.09 in lean controls (P = 0.28). Initial studies failed to show an association of this polymorphism with serum leptin, response to treatment for obesity, history and extent of weight gain, or serum insulin, glucose of lipid concentrations. CONCLUSIONS: We have identified a common polymorphism in the promoter area of the human ob gene which appears to be very useful for genetic association and linkage studies. Further studies are needed to elucidate its potential role in the regulation of the human ob gene and in human metabolic disorders.

Adolescent↗

PubMed1998

Meta-analysis of the association of the Trp64Arg polymorphism in the beta3 adrenergic receptor with body mass index.

OBJECTIVE: As a result of efforts to isolate obesity-promoting genes, the Trp64Arg polymorphism in the beta3 adrenergic receptor locus, has been studied by many investigators. Results of the studies have varied in statistical significance and magnitude of the association of the polymorphism with body mass index (BMI: kg/m2). This has led to controversy about whether this polymorphism is associated with meaningful changes in BMI. To clarify the possible association, we conducted a meta-analysis. DESIGN: Meta-analytic study. MEASUREMENTS: For each genotype of the beta3 adrenergic receptor (Trp/Trp; Trp/Arg; Arg/Arg), we extracted the number of subjects, mean and standard deviation of BMI from 23 studies, including 36 different subgroups with a total of 7399 subjects. Other indices and obesity-related variables were not considered. RESULTS: No significant association of the Trp64Arg polymorphism with BMI was found. The weighted mean BMI difference between Trp/Trp homozygotes and Trp/Arg heterozygotes was 0.19 (s.e. = 0.11; P = 0.07). In addition, the distribution of effect sizes was not significantly heterogeneous (chi2=38.68; df 35; P = 0.31) suggesting that the variation of the effect sizes across the subgroups is not significant. A further weighted regression analysis, utilizing all three genotypes and adjusting for the random subgroup effect, also showed the effect of the polymorphism on BMI is not significant (F = 1.72, df = (2,54), P = 0.19). CONCLUSION: Based on existing data, the Trp64Arg polymorphism does not appear to be significantly associated with BMI. Moreover, we found no evidence for effect heterogeneity, suggesting that the effect of the polymorphism is not moderated by ethnicity or diabetic status.

Arginine↗

PubMed2001

Tumor necrosis factor-alpha--308 G/A polymorphism in obese Caucasians.

OBJECTIVE: Tumor necrosis factor-alpha (TNF-alpha) is expressed primarily in adipocytes, and elevated levels of this cytokine have been linked to obesity and insulin resistance. Recently, the A allele of a polymorphism in the 5'-flanking region of the TNF-alpha gene (G-308A) has been reported to be more frequent in obese than in lean subjects and has also been associated with increased expression of this cytokine in fat tissue and influences fat mass and insulin resistance. We, therefore, examined the relationship between this variant and obesity in a German Caucasian population. SUBJECTS AND METHODS: We genotyped 176 index subjects recruited within the framework of the BErG (Berlin Ernährung Geschwister)- Study for the TNF-alpha-G-308A polymorphism. Subjects were characterized for weight, height, waist and hip circumference, body mass index (BMI), body composition, glucose tolerance, leptin and angiotensinogen levels. RESULTS: The frequency of the -308A allele (0.18) was similar to that reported previously and genotype distribution was in Hardy-Weinberg equilibrium (GG, n=118; GA, n=53; AA, n=5). There was a significant difference in allele frequencies of the polymorphism by BMI quartiles (I,<27.3 kg/m2; II, 27.3-31.9 kg/m2; III, 31.9-36.5 kg/m2; IV,>36.5 kg/m2, in each quartile n=44) with -308A allele carriers having a higher BMI than G allele carriers (P=0.013). Despite previous smaller studies that have related insulin resistance to the G-308A polymorphism, we found no relationship between glucose and insulin response during an oral glucose tolerance test (OGTT) and the polymorphism. Furthermore, none of the plasma parameters were related to the polymorphism. CONCLUSION: Our findings support the hypothesis that the G-308A polymophism of the TNF-alpha gene is associated with BMI. The G-308A polymorphism may, therefore, represent a genetic marker for increased susceptibility for obesity in Caucasians.

Alleles↗

PubMed2004

GNB3 gene C825T and ACE gene I/D polymorphisms in essential hypertension in a Kazakh genetic isolate.

The Kazakh inhabitants living in Barkol pasture of northeast China belong to a genetic isolate characterized by ethnically homogeneous and a communal pastoral lifestyle. To investigate whether the polymorphisms in the G-protein beta-3 subunit (GNB3) gene and angiotensin-converting enzyme (ACE) gene are associated with essential hypertension (EH), we carried out a case-control study of 290 hypertensive subjects and 244 normotensive (NT) controls randomly selected from Kazakh populations of Barkol. A previous medical history of diabetes and hypertension, and body mass index (BMI) was recorded. Plasma glucose, triglyceride, and cholesterol were measured. The insertion/deletion (I/D) polymorphism of the ACE gene and the C825T polymorphism of the GNB3 gene were determined by the polymerase chain reaction (PCR) technique. The distributions of genotypes and alleles for the two polymorphisms did not differ significantly between the case and control populations, and odds ratio of EH related to the ACE gene D allele and GNB3 gene T allele was not significantly different from 1.0. Logistic regression analysis shows the variation at the GNB3 and ACE did not have any statistically significant synergistic effect on blood pressure (BP). Stratification of NT and untreated hypertensives according to I/D polymorphism of ACE gene and C825T polymorphism of GNB3 gene disclosed no significant difference across genotypes with respect to BMI, glucose, triglyceride, cholesterol, systolic and diastolic BP. In conclusion, the polymorphisms in the GNB3 gene and ACE gene, solely or combined, did not confer a significantly increased risk for the development of EH in the Kazakh isolate of northeast China.

Adult↗

PubMed2005

Endothelial nitric oxide synthase polymorphism, nitric oxide production, salt sensitivity and cardiovascular risk factors in Hispanics.

Mutations in the endothelial nitric oxide synthase (eNOS) gene may be associated with abnormal nitric oxide (NO) production and cardiovascular diseases. In this study, we investigated the prevalence of two eNOS polymorphisms, the Glu298Asp variant on exon 7, and the 4a/b variable number of tandem repeats (VNTR) on intron 4, and their association with blood pressure (BP), NO production, salt sensitivity and cardiovascular risk factors in healthy Venezuelans. The prevalence of both polymorphisms in Venezuelans was comparable to that described for Caucasians, but significantly different from that known for African-Americans and Japanese. The 4a/b genotype was associated with reduced levels of NO metabolites (25% decrease), larger BP lowering in response to salt restriction (9.0 vs 4.8 mmHg, P<0.05), greater prevalence of salt sensitivity (39% in 4a/b and 27% in 4b/b; P<0.05) and with higher LDL-cholesterol levels. The Glu298T polymorphism did not affect NO production, nor it was associated with salt sensitivity. Glu298Asp polymorphism was positively associated with higher weight, triglycerides and LDL-cholesterol. Neither polymorphism was associated with changes in fasting or postload serum glucose, BP, obesity and albuminuria. In conclusion, the prevalence of eNOS polymorphisms is strongly determined by ethnic factors. The 4a/b gene polymorphism could be a genetic susceptibility factor for the BP response to salt intake and for the genetic control of NO production. The reduced NO production in subjects with the 4a/b genotype may be responsible for the increased sensitivity of their BP to salt.

Adult↗

PubMed2001

Serotonin transporter polymorphisms: no association with response to antipsychotic treatment, but associations with the schizoparanoid and residual subtypes of schizophrenia.

The human serotonin transporter gene (5-HTT) demonstrates two polymorphisms with possible functional impact: a 44-bp insertion/deletion polymorphism of the promoter region and a 17-bp variable number of tandem repeat polymorphism (VNTR) in intron 2 (STin2). Such genetic polymorphisms in the serotoninergic system may increase the susceptibility to schizophrenia or may serve as predictors of therapeutic response. We therefore analyzed these polymorphisms as susceptibility factors for schizophrenia by comparison of 684 schizophrenic inpatients with 587 healthy controls. We furthermore compared the therapeutic outcome of schizophrenic patients differentiated by the 5-HTT genotypes. Schizo-affective patients were more frequently homozygous for the 44-bp insertion allele (Odds ratio, OR: 1.6, 95% confidence interval, CI: 1.1--2.3, P < 0.03) than were all other schizophrenic patients and controls. The 17-bp VNTR alleles found were: STin2.7, 9, 10, and 12. Sequence analysis revealed seven different sequence motifs with an invariable arrangement. Patients with schizo-paranoid schizophrenia were more frequently homozygous for the STin2.12 allele than were controls (OR: 1.4, CI: 1.1--1.8, P < 0.007) and all other schizophrenic patients (OR: 1.6, CI: 1.2--2.3). The STin2.9 allele represented a risk factor for the residual subtype of schizophrenia (OR: 6.4, CI: 2.5--16.2, P < 0.001). On the basis of global clinical impressions, as well as measurements with the positive and negative syndrome scale we found no association of the polymorphisms with therapeutic response. In conclusion, the 44-bp polymorphism may be associated with the schizo-affective and the 17-bp VNTR with the residual and schizo-paranoid subtype of schizophrenia, findings which require further biochemical and epidemiological confirmation.

Adolescent↗

PubMed2005

Meta-analysis reveals association between serotonin transporter gene STin2 VNTR polymorphism and schizophrenia.

The serotonin transporter gene (SLC6A4) is a candidate gene for schizophrenia based on serotonin transporter's crucial role in serotonergic neurotransmission. However, association studies have produced conflicting results regarding the association between two common SLC6A4 gene polymorphisms, the promoter insertion/deletion (5-HTTLPR) and the intron 2 VNTR (STin2 VNTR) polymorphisms, and schizophrenia susceptibility. To further elucidate the putative association between the two SLC6A4 gene polymorphisms and schizophrenia susceptibility, we performed a meta-analysis based on all original published association studies between schizophrenia and the 5-HTTLPR and STin2 VNTR polymorphisms published before April 2004. Our analyses showed no statistically significant evidence for the association between the Short allele of the 5-HTTLPR polymorphism and schizophrenia (random-effects pooled odds ratio (OR)=0.99, 95% Confidence Interval (CI)=0.92-1.07, Z=-0.23, P=0.82) from 19 population-based association studies consisting of 2990 case and 3875 control subjects. However, highly significant evidence for association between the STin2.12 allele of the STin2 VNTR polymorphism (random-effects pooled OR=1.24, 95% CI=1.11-1.38, Z=3.82, P=0.00014) and schizophrenia was found from 12 population-based association studies consisting of 2177 cases and 2369 control subjects. Our meta-analysis suggests that the STin2.12 allele of the STin2 VNTR polymorphism is likely a risk factor for schizophrenia susceptibility. Our data imply that following completion of the International HapMap Project, a comprehensive evaluation of a set of markers that fully characterize the linkage disequilibrium relationships at the SLC6A4 gene should be tested in large well-characterized clinical samples in order to understand the role of this gene in schizophrenia susceptibility.

Chromosome Mapping↗

PubMed2004

Thrombospondin-4 A387P polymorphism is not associated with coronary artery disease and myocardial infarction in the Chinese Han population.

Recently, conflicting data have been reported regarding the possible contribution of the TSP-4 (thrombospondin-4) A387P polymorphism to CAD (coronary artery disease) or MI (myocardial infarction). To investigate a possible association between the A387P polymorphism and CAD or MI in the Chinese Han population, we conducted a case-controlled study including 817 patients with angiographically verified CAD or those who survived an acute MI and 847 control subjects. The TSP-4 A387P polymorphism was determined by PCR and PCR-RFLP (restriction-fragment-length polymorphism) analysis. The prevalence of the 387P allele was 3.8% in the healthy controls, which was less frequent than those in Western populations (19.6-23.2%). No association of the A387P polymorphism with an altered risk of CAD, MI or premature MI was found in our present study (CG+CC compared with GG, P (CAD)=0.51, P (MI)=0.13, P (Premature MI)=0.17 respectively). We concluded that a relationship between the TSP-4 A387P polymorphism and CAD or MI was unlikely in our population. Additional investigations should be performed in populations at different risk of coronary events in order to elucidate further the possible contribution of this polymorphism to cardiovascular disease.

Adult↗

PubMed1998

Ultraviolet B induced suppression of induction of contact sensitivity in human skin is not associated with tumour necrosis factor-alpha-308 or interleukin-10 genetic polymorphisms.

Low doses of ultraviolet B (UVB) can induce localized immunosuppression in skin. This effect may be important in the induction of skin cancers and is thought to be mediated by tumour necrosis factor (TNF) alpha and interleukin (IL) 10 in conjunction with other factors. In humans a transition polymorphism in the TNF-alpha gene may affect TNF-alpha secretion and the promoter region of the IL-10 gene contains a CA repeat polymorphism which may affect gene function. We have therefore investigated the association of these polymorphisms with UVB-induced immunosuppression in humans. Volunteers (n = 42) were irradiated with UVB then sensitized on irradiated skin with diphenylcyclopropanone (DPCP) and subsequently antigen challenged with DPCP. DNA was extracted from blood samples and volunteers genotyped for the TNF-alpha polymorphism by polymerase chain reaction (PCR) and restriction digestion. The CA repeat polymorphism was amplified by PCR and sized by gel electrophoresis. Twenty-four volunteers were susceptible to UVB-induced immunosuppression and 18 were resistant. The association of allele frequencies and phenotype was statistically tested using a chi2-test. For both the TNF-alpha and IL-10 polymorphisms, there was no statistically significant association between allele types and response to UVB. These results indicate that variation in the immune response to UVB in humans is not associated with the TNF-alpha-308 transition or IL-10 CA repeat polymorphisms, although other as yet undetected DNA sequence variants of these genes may be involved.

Alleles↗

PubMed2003

Cytokine gene polymorphisms in atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) and psoriasis are genetically determined inflammatory skin disorders characterized by abnormal cytokine production. From association studies there is evidence that functionally relevant cytokine gene polymorphisms contribute to the genetic basis of psoriasis. Association studies in AD have mostly been limited to polymorphisms of T-helper 2-type cytokines, which dominate in acute AD lesions. Unexpectedly, the results of recent genome scans indicate linkage of AD to psoriasis susceptibility loci. Therefore, AD may also be influenced by genes that modulate cutaneous inflammation independently from atopic mechanisms. OBJECTIVES: To investigate further the role of cytokine gene polymorphisms in AD. METHODS: Polymorphisms in the genes encoding tumour necrosis factor-alpha (TNFA-238 G/A, -308 G/A), interleukin (IL)-1beta (IL1B-511 T/C, +3953 T/C), IL-6 (IL6-174 C/G), IL-10 (IL10-1082 A/G) and the IL-1 receptor antagonist (IL1RN intron 2) were investigated in German patients with AD (n = 94) and in healthy nonatopic individuals (n = 214) by polymerase chain reaction-based methods and direct cycle sequencing. RESULTS: No association was found between AD and any of the polymorphisms analysed. This is in contrast to the recently described association between psoriasis and the TNFA-238 and IL1B-511 polymorphisms. CONCLUSIONS: Our data indicate that cytokine gene polymorphisms may act as specific markers of inflammatory skin diseases rather than contribute to a general disposition towards cutaneous inflammation.

Adolescent↗