SEARCH · PubMed Health

Results for “polymorphisms”

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 1,369 records · Page 76Linked to original sources

PubMed2007

Family trios analysis of common polymorphisms in the obestatin/ghrelin, BDNF and AGRP genes in patients with Anorexia nervosa: association with subtype, body-mass index, severity and age of onset.

Anorexia nervosa (AN) affects 0.3% of young girls with a mortality of 6%/decade and is strongly familial with genetic factors. Ghrelin is an upstream regulator of the orexigenic peptides NPY and AgRP and acts as a natural antagonist to leptin's effects on NPY/AgRP-expressing neurons, resulting in an increase in feeding and body weight. Obestatin which counteracts ghrelin action on feeding is derived from the same propeptide than ghrelin. BDNF has been involved in body weight regulation and its Val66Met polymorphism associated with AN. We therefore re-investigated the association between AN and the Leu72Met and Gln90Leu polymorphisms of the prepro-ghrelin/obestatin gene, the Ala67Thr polymorphism of AgRP and the Val66Met polymorphism of BDNF taking into account clinical subtypes (restrictive--ANR--and bingeing/purging--ANB--subtypes). Family trios study of these 4 single nucleotide polymorphisms were performed in 114 probands with AN and both their parents recruited in two specialized French centres. A transmission disequilibrium was observed for the Leu72Met SNP of the preproghrelin gene and for the Ala67Thr SNP of the AgRP gene. When stratified by clinical subtype, these two polymorphisms were preferentially transmitted for the trios with a bingeing/purging proband. An excess of transmission of the Gln90Leu72 preproghrelin/obestatin haplotype in patients with AN was observed. These results do not provide evidence for a preferential transmission of the 66Met allele of BDNF but support the hypothesis that ghrelin and AGRP polymorphisms confers susceptibility to AN. Further simultaneous analysis of genetic variants of the biological determinants of energy metabolism and feeding behaviour in very large populations should contribute to the understanding of the high degree of heritability of eating disorders and to the description of pathophysiological patterns leading to life-threatening conditions in a highly redundant system.

Adolescent↗

PubMed2005

Five NOTCH4 polymorphisms show weak evidence for association with schizophrenia: evidence from meta-analyses.

NOTCH4 initially received consideration as a risk gene for schizophrenia based on its location within a region on chromosome 6p that had previously shown strong evidence for genetic linkage with the illness. The initial published test for allelic association found strong evidence for involvement of this gene in schizophrenia, but subsequent studies failed to confirm this finding. Presently, we have used meta-analysis to derive a best estimate of the nature and magnitude of the associations between schizophrenia and five polymorphisms in and around the NOTCH4 gene. No significant association was detected between schizophrenia and repeat length of alleles at the (TAA)n, (CTG)n, or (TTAT)n polymorphisms, or between the disease and specific risk alleles at these polymorphisms or at the SNP1 or SNP2 polymorphisms. Heterogeneity and stronger evidence of association with the putative risk alleles of the (TAA)n, (CTG)n, SNP1, and SNP2 polymorphisms was observed in family-based studies than in case-control studies, suggesting that these polymorphisms may reliably influence risk for schizophrenia under certain circumstances. Since more consistent and robust associations with schizophrenia risk have been observed for haplotypes of these polymorphisms [especially those containing SNP2 and (CTG)n], additional large family-based or genomic-controlled studies would be helpful for definitively specifying the role of NOTCH4 haplotypes in risk for schizophrenia.

Alleles↗

PubMed2006

Genetic polymorphisms of the platelet receptors P2Y(12), P2Y(1) and GP IIIa and response to aspirin and clopidogrel.

INTRODUCTION: There is wide variability in the responses of individual patients to aspirin and clopidogrel. Polymorphisms of several platelet receptors have been related to increased platelet aggregation. We therefore aimed to evaluate whether these polymorphisms are related to altered response to aspirin or clopidogrel. MATERIALS AND METHODS: Patients (n=120) undergoing percutaneous coronary intervention who received aspirin for > or =1 week but not clopidogrel were included. Blood samples were drawn at baseline and 20-24h after a 300-mg clopidogrel dose. Aspirin insensitivity was defined as 5 microM ADP-induced aggregation > or =70% and 0.5 mg/mL arachidonic acid-induced aggregation > or =20%. Clopidogrel insensitivity was defined as baseline minus post-treatment aggregation < or =10% in response to 5 and 20 microM ADP. PlA polymorphism of glycoprotein IIIa, T744C polymorphism of the P2Y(12) gene and the 1622A>G polymorphism of the P2Y(1) gene were genotyped by polymerase chain reaction. RESULTS: There were no differences in polymorphism frequencies between drug-insensitive vs. drug-sensitive patients. There were also no significant differences in response to aspirin (assessed by arachidonic acid-induced aggregation) or to clopidogrel (assessed by ADP-induced aggregation or activation markers) when patients were grouped according to genotype. The only trend observed was lower reduction in PAC-1 binding following clopidogrel in PlA(2) carriers (P=0.065). CONCLUSIONS: We did not find an association between polymorphisms in the platelet receptors GP IIIa, P2Y(12) or P2Y(1) and response to aspirin or clopidogrel in cardiac patients. These findings suggest that the variability in response to anti-platelet drugs is multi-factorial and is not caused only by single gene mutations.

Aged↗

PubMed2006

Association of interleukin-1Ra gene polymorphism in patients with bladder cancer: case control study from North India.

OBJECTIVES: To evaluate whether polymorphism of interleukin (IL)-1beta gene (exon 5 and promoter region) and IL-1 receptor antagonist (Ra), 86-bp variable number tandem repeat, are associated with transitional cell carcinoma of the urinary bladder, because cytokines have been hypothesized to be important in cancer development. METHODS: The study included 120 patients with bladder cancer (age range 32 to 69 years) and 150 age-matched controls (age range 25 to 62 years). The polymorphisms were identified by polymerase chain reaction/restriction fragment length polymorphism method and IL-1Ra polymorphism by variable number of identical tandem repeat analysis. Genotype distribution and allelic frequencies between patients and controls were compared. RESULTS: A significant difference was found in the frequency distribution of the IL-1Ra gene polymorphism in patients with bladder cancer compared with the normal control group (P < 0.001), but no difference was found in the frequencies of the IL-1beta promoter region and exon 5 genotypes between patients with bladder cancer and controls (P = 0.112 and P = 0.953, respectively). CONCLUSIONS: This is perhaps the first report on polymorphic changes in gene encoding IL-1Ra in patients with bladder cancer from India. Our data suggest that IL-1Ra intron 2 polymorphism seems to play a prominent role among the IL-1 gene cluster with respect to bladder cancer, and the association studies appear to be plausible in determining the cancer susceptibility and risk.

Adult↗

PubMed2005

Distribution of paraoxonase PON1 gene polymorphisms in Mexican populations. Its role in the lipid profile.

Paraoxonase gene polymorphisms (PON1-55 and PON1-192) were determined in four Mexican populations (Mestizos, Nahuas, Teenek and Mayos) belonging to different ethnic groups. The role of these polymorphisms in the lipid profile in the Mestizo group was also analyzed. PON1 polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism. Comparison among Mexican populations showed increased frequencies of PON1-55 L allele and LL genotype and decreased frequencies of M allele and LM genotype in the three Amerindian populations when compared to Mestizos (P < 0.05). Mexicans together with Asian populations (from Japan and China) presented the highest frequencies of PON1-55 L allele (P < 0.05 when compared to Caucasian populations). Heterogeneous data were noted when PON1-192 polymorphism comparison was made. In summary, distribution frequencies of PON1 showed that Mexican populations are more related to Asians than Caucasians. This confirms previous studies with other genetic markers indicating that Native Americans have stronger genetic affinities to the Paleolithic people of North-East Asia than to other major world populations. In Mexican Mestizos, lack of correlation between PON1 polymorphisms and lipid profile was found, corroborating previous data in other populations. The present data could be helpful to understand the distribution of these polymorphisms and its role as genetic and evolutive markers in the Amerindian populations.

Adult↗

PubMed2000

Seven DNA polymorphisms at the candidate genes of atherosclerosis in Brazilian women with angiographically documented coronary artery disease.

The possible association of genetic markers at the apolipoprotein E (HhaI polymorphism), apolipoprotein B (XbaI, EcoRI and Ins/Del polymorphisms), and low-density lipoprotein receptor (LDLR) (AvaII, HincII and PvuII polymorphisms) with coronary artery disease (CAD) was evaluated in 50 Brazilian women with CAD diagnosed by angiography and in 100 healthy women (controls). The frequency of E3/E4 genotype for HhaI polymorphism at the Apo E gene was significantly higher in CAD patients than in controls (40% vs. 14%, respectively, P<0.001). Similarly, the X-X- genotype for XbaI polymorphism was more frequent in CAD individuals than controls (42% vs. 12%, P<0.0001). The A+A+ and P1P1 genotypes for AvaII and PvuII polymorphisms at the LDLR locus were also higher in CAD subjects than controls (44% vs. 16%, P<0.001 and 64% vs. 39%, P<0.05, respectively). The estimated relative risks for CAD in women carrying the E3/E4, X-X-, A+A+ and P1P1 genotypes were 4.1 [95% confidence interval (CI), 3.0-5.6], 5.3 (95% CI, 3.8-7.5), 4.1 (95% CI, 3.0-5.5), and 2.8 (95% CI, 2.2-3.6), respectively. This study demonstrates that Apo E, Apo B and LDLR gene polymorphisms are associated with CAD in Brazilian Caucasian women.

Arteriosclerosis↗

PubMed2000

Renin-angiotensin system gene polymorphisms: potential mechanisms for their association with cardiovascular diseases.

Since the first description of the angiotensin-converting enzyme insertion/deletion polymorphism more than a decade ago, many hundreds of investigations have reported associations between this polymorphism and cardiovascular diseases. Subsequently, similar studies were performed in relationship with several other renin-angiotensin system gene polymorphisms, most notably the angiotensinogen M235T polymorphism and the angiotensin AT(1) receptor A1166C polymorphism. Surprisingly however, especially in view of the many contradictory results that have been obtained, very little attention has been paid to the mechanism(s) that may link these genetic variants and respective diseases. Here, we review the limited evidence that is currently available on the functional consequences (including compensatory mechanisms) of the above three renin-angiotensin system gene polymorphisms, in order to provide an explanation for the reported associations (or lack thereof) between these polymorphisms and cardiovascular diseases.

Animals↗

PubMed2001

Polymorphisms in the angiotensinogen gene are associated with carotid intimal-medial thickening in females from a community-based population.

BACKGROUND: Polymorphisms within genes of the renin-angiotensin system have been associated with an increased risk of cardiovascular disease. We investigated the association of polymorphisms in the angiotensinogen (AGT) and angiotensin II receptor type 1 (AGTR1) genes with increased intima-media thickness (IMT) and the presence of plaques in carotid arteries. METHODS: Subjects (1111) from the Perth Carotid Ultrasound Disease Assessment Study (CUDAS) were genotyped for three polymorphisms: two in the promoter of the AGT gene, G-6A and A-20C; and one in the AGTR1 gene, A1166C. RESULTS: Using multivariate generalised linear models, the AGT-6A allele (P<0.001) and the AGT-20C allele (P<0.03) were significantly associated with increased mean carotid IMT in females but not in males when adjusted for conventional risk factors. The AGTR1 A1166C polymorphism did not show any significant relationship to mean IMT. Results suggest that the I allele of the angiotensin converting enzyme insertion/deletion polymorphism may interact with the AGT-6G allele to increase mean carotid IMT in the population as a whole. None of the polymorphisms investigated were significantly associated with the presence of carotid plaques. CONCLUSION: This study shows that polymorphisms in the angiotensinogen gene are associated with an increased risk of carotid intimal-medial wall thickening in females.

Adult↗

PubMed2003

Influence of exonic polymorphisms in the gene for LDL receptor-related protein (LRP) on risk of coronary artery disease.

The low density lipoprotein (LDL) receptor-related protein (LRP) is a multifunctional receptor involved in numerous biological processes relevant to vascular biology including lipoprotein metabolism. Several polymorphisms in the LRP gene have been described and in this study we examined their influence on coronary artery disease (CAD). We compared the frequencies of the exon 3 (C766T), exon 6 (C663T), exon 22 (C200T), and four rarer and more recently described polymorphisms in approximately 600 Caucasian subjects aged <50 years with angiographic CAD and approximately 700 similarly aged subjects without symptomatic CAD randomly selected from the community. We found the distribution of exon 22 C200T genotypes to differ significantly between the CAD (CC: 52%, CT: 39%, TT: 9%) and control subjects (CC: 43%, CT: 46%, TT: 11%, P=0.005), with the CC genotype conferring an odds ratio (OR) for CAD of 1.5 (95% CI: 1.2-1.8, P=0.001) despite a lack of significant influence on plasma cholesterol or triglyceride. The other LRP polymorphisms were less common. Two showed an association with CAD; for the exon 3 C766T polymorphism the TT genotype was significantly lower (1.0 vs. 2.7%; OR: 0.36; P=0.04) and, for the exon 6 C663T polymorphism, the heterozygote frequency was higher (6.2 vs. 3.4%; OR: 1.9; P=0.03) in CAD subjects. In conclusion, LRP gene polymorphisms, particularly the relatively common exon 22 C200T polymorphism, are a significant risk factor for premature CAD in Caucasians.

Adult↗

PubMed1999

The p22 phox A640G gene polymorphism but not the C242T gene variation is associated with coronary heart disease in younger individuals.

BACKGROUND: Most recently, evidence has been presented that the NADH/NADPH oxidase p22 phox C242T, but not the A640G gene polymorphism is associated with a reduced risk of coronary artery disease (CAD). METHODS AND RESULTS: We analysed the relationships of both p22 phox gene polymorphisms to CAD in 2205 male Caucasians whose coronary anatomy was defined by means of coronary angiography. In the total population and in high and low risk groups the relative frequencies of the C242T alleles were essentially the same in patients without or with CAD and in individuals without or with myocardial infarction. In contrast, the G allele of the A640G polymorphism was significantly more frequent in subjects without CAD than in patients with CAD (Odds ratio (OR) 0.74 (0.57-0.98); P = 0.038 in multiple logistic regression (MLR)). Correspondingly, the AA genotype of A640G was preferentially found in patients with CAD. These associations did not disappear when the analyses were corrected for multiple comparisons for other gene polymorphisms (ACE I/D gene variation, angiotensinogen T174M and M235T gene polymorphisms, AT1 receptor gene variation, phox C242T gene polymorphism, paraoxonase PON54 and PON191 gene variations) (2p = 0.01 in MLR for the presence of CAD; 2p = 0.039 in multiple regression for the extent of CAD). The association of the A640G gene variation with the presence and extent of CAD was not only identified in the total sample, but was even stronger in various high risk subpopulations of younger individuals (e.g. with hypertension with or without increased apolipoprotein B plasma levels). CONCLUSIONS: Our observations allow the assumption that the p22 phox A640G gene polymorphism is independently associated with the presence and extent of coronary artery disease.

Adenine↗

PubMed1999

Contribution of apolipoprotein(a) size, pentanucleotide TTTTA repeat and C/T(+93) polymorphisms of the apo(a) gene to regulation of lipoprotein(a) plasma levels in a population of young European Caucasians.

Several studies indicate that the inter-individual variation in plasma concentrations of lipoprotein(a) (Lp(a)) is mainly under genetic control. To define the effect of three DNA polymorphisms on apolipoprotein(a) (apo(a)) expression, we have determined plasma Lp(a) concentrations, apo(a) isoform size, KpnI allele size, the TTTTA pentanucleotide repeat number in the 5' control region of the apo(a) gene and the +93 C/T polymorphism in a European Caucasian population. The simultaneous determination of the kringle 4 (K4) number by genotyping and by phenotyping revealed that the size distribution of non-expressed apo(a) alleles was markedly skewed towards alleles with greater than 25 K4 repeats. This is consistent with the inverse relationship frequently described between the kringle 4 number and the plasma Lp(a) level. Apportioning the Lp(a) concentration from the surface of the peaks on apo(a) phenotyping blots, we have observed that the Lp(a) plasma concentration associated with alleles having more than 25 K4 units does not exceed 400 mg/l, whereas the range of Lp(a) concentrations associated with smaller alleles was broad, from 0 to more than 1000 mg/l. It can thus be concluded that the number of K4 repeats is the main determinant of Lp(a) concentration when this number is more than 25, whereas other polymorphisms may be involved in the alleles with fewer than 26 K4. Analyses of the TTTTA repeat number and of the +93 C/T polymorphism were performed in subjects with KpnI alleles of the same length: low Lp(a) concentrations were shown to be preferentially associated with the presence of apo(a) alleles with more than eight pentanucleotide repeats while no association was revealed between Lp(a) plasma levels and the C/T polymorphism. These results demonstrate that the (TTTTA)(n) polymorphism affects the Lp(a) expression independently of apo(a) size polymorphism.

Adolescent↗

PubMed1996

Association analyses of the polymorphisms of angiotensin-converting enzyme and angiotensinogen genes with diabetic nephropathy in Japanese non-insulin-dependent diabetics.

To investigate predictive genetic markers for diabetic nephropathy, we studied the genetic polymorphisms of angiotensin-converting enzyme (ACE) and angiotensinogen (AGN) in Japanese subjects with non-insulin-dependent diabetes mellitus (NIDDM) with and without nephropathy. Genotype distributions were studied in 132 unrelated NIDDM patients of three groups with normoalbuminuria ([Normo] n = 53), microalbuminuria ([Micro] n = 54), and macroalbuminuria ([Macro] n = 25). The ACE insertion/deletion (I/D) polymorphism of intron 16 was identified by polymerase chain reaction, and the AGN M235T polymorphism was identified by restriction fragment length polymorphism analysis. There were no significant associations between AGN 235 allele or genotype and diabetic nephropathy. The D allele of ACE was significantly more frequent in the Micro (P = .003) and Macro (P = .009) group than in the Normo group. Overall frequencies of the ACE genotype did not differ significantly between the Micro and Macro groups. There were significant relationships between I/D polymorphism and plasma ACE activity; the DD genotype had the highest activity. A multiple logistic regression analysis revealed that the D allele is a strong and independent risk factor for abnormal albuminuria in NIDDM patients. These results suggested that ACE I/D polymorphism, but not AGN M235T polymorphism, is a possible genetic risk factor for diabetic nephropathy in Japanese NIDDM patients.

Aged↗

PubMed2003

Effect of apolipoprotein polymorphisms in renal transplant recipients.

Cardiovascular disease (CVD) is the main cause of mortality among long-term renal transplant recipients (RTR). On the other hand, allograft chronic nephropathy is the primary cause of graft loss among long-term RTR. Hyperlipidemia is a predisposing factor for both conditions. Polymorphisms of the apolipoproteins modulate lipid metabolism. The aim of the study was to evaluate the effect of apo A-I, apo A-IV and apo C-III genotypes on the long-term results of renal transplantation. Clinical assessment (renal allograft and patient survival) and genotyping for apo A-I (+83C/T), apo C-III (Sst I), and apo A-IV (Thr347Ser and Gln360His) polymorphisms were evaluated in 516 kidney transplant patients and correlated with the clinical evolution over 12 months. The distribution of the apo A-I (+83C/T) polymorphisms was: CC 91.9%, CT 7.9%, and TT 0.2%. The apo C-III genotype showed: S1S1 84.4%, S1S2 15.2%, and S2S2 0.4%. The apo A-IV (Pvu II) polymorphism was: GG 82%, GT 18%, and 0% TT. Finally, the frequency of apo A-IV (Hinf I) polymorphism was: AA 69%, AT 27%, and TT 4%. The frequency of polymorphisms was similar between men and women. In conclusion, there was no significant influence of apolipoprotein polymorphisms on renal and patient survival.

Apolipoprotein A-I↗

PubMed2001

Association of vitamin D receptor and 17 hydroxylase gene polymorphisms with benign prostatic hyperplasia and benign prostatic enlargement.

OBJECTIVES: To determine whether polymorphisms in 17 hydroxylase (CYP17) and vitamin D receptor (VDR) genes have an association to prostate volume/histology and endocrine patterns in elderly men with lower urinary tract symptoms (LUTS). METHODS: Elderly men with LUTS underwent the following investigations: International Prostate Symptom Score (IPSS), uroflowmetry, serum prostate-specific antigen (PSA) assessment of prostate volume, and an endocrine study. Polymorphisms of CYP17 (T-->C substitution in the 5' promoter region) and VDR (T1055C) genes were detected by polymerase chain reaction followed by restriction-length polymorphism analysis, using DNA from peripheral white blood cells. Clinical and endocrine parameters and the prostate stroma/epithelial ratio were correlated to CYP17 and VDR genotypes. RESULTS: A total of 148 (mean +/- SD, 67.0 +/- 9.7 years) patients were analyzed. IPSS (17.8 +/- 7.0), prostate volume (41.9 +/- 17.9 cc), maximum flow rate (10.9 +/- 5.8 mL/s), and PSA (4.7 +/- 4.7 ng/mL) indicate a typical LUTS population. Mean endocrine levels were consistently within age-specific reference values. Neither CYP17 nor VDR gene polymorphisms revealed an association to prostate size, PSA, clinical parameters, and endocrine parameters. Men who had the A1/A1 CYP17 genotype had on average a greater stromal/epithelial ratio than men with the A1/A2 or A2/A2 genotypes, yet after adjusting for multiple testing, this significance disappeared. CONCLUSIONS: Gene polymorphisms of CYP17 and VDR have no association to prostate volume, clinical parameters, and endocrine parameters in elderly men. The association of CYP17 polymorphism and prostate histology warrants further studies. Assessment of gene polymorphisms might provide new insights into the pathogenesis of benign prostatic hyperplasia and benign prostate enlargement and may hold promise as genetic biomarkers of this disease.

Aged↗

PubMed2002

Serotonin 5-HT(2A) receptor gene polymorphism, 5-HT(2A) receptor function and personality traits in healthy subjects: a negative study.

BACKGROUND: Central serotonin-2A (5-HT(2A)) receptor dysfunction is regarded as an important factor in the etiology of affective disorders. The relations between some personality traits and the vulnerability of affective disorders are also implicated. Moreover, there are several reports which describe the association between 5-HT(2A) receptor gene polymorphisms and mental disorders. We therefore examined the relationship between personality traits, the 5-HT(2A) receptor function, and 5-HT(2A) receptor gene polymorphisms. METHODS: 5-HT-induced intraplatelet calcium (Ca) mobilization, 5-HT(2A) receptor gene polymorphisms (A-1438G, T102C, T516C, C1340T, C1354T), and Temperament and Character Inventory (TCI) scores were examined in 133 healthy subjects. RESULTS: Neither 5-HT-induced Ca mobilization nor 5-HT(2A) receptor gene polymorphisms (A-1438G, T102C) appear to be associated with seven personality dimensions including Harm Avoidance. There was no significant difference in the Ca response among the subjects with -1438A/A, A/G and G/G genotypes. Since the appearance of the other types of the 5-HT(2A) receptor gene polymorphisms (T516C, C1340T and C1354T) was quite rare in our sample, we were unable to examine the relationship between these polymorphisms, and the TCI score or the Ca response. LIMITATIONS: Our failure to find a significant association may reflect the false negative results due to the small sample size and low statistical power. Further studies in depressed patients may clarify the complicated relationship between personality traits and the vulnerability of affective disorders. CONCLUSIONS: Personality traits detected by TCI may not be directly related to the 5-HT(2A) receptor function or 5-HT(2A) receptor gene polymorphism which may be involved in the vulnerability of affective disorders.

Adult↗

PubMed2003

Polymorphisms of DRD4 and DRD3 and risk of avoidant and obsessive personality traits and disorders.

We investigated whether polymorphisms of the dopamine D4 receptor (DRD4) and polymorphisms of the dopamine D3 receptor (DRD3) were associated with personality disorder symptomatology rather than with personality traits such as novelty seeking. DNA was obtained from 145 depressed patients in a clinical trial. These patients were assessed for the presence of personality disorder symptoms and disorders. The 2-repeat allele of the DRD4 exon III polymorphism was associated with increased rates of avoidant and obsessive personality disorder symptomatology. The T,T genotype of the DRD4 -521 C>T polymorphism was also associated with increased rates of avoidant and obsessive personality disorder symptomatology. The Gly9,Gly9 genotype of the DRD3 Ser9Gly polymorphism was associated with increased rates of obsessive personality disorder symptomatology. None of these three polymorphisms were associated with novelty seeking or other temperament traits on the Temperament and Character Inventory. Our results suggest that genetic polymorphisms of DRD4 and DRD3 may well be associated with personality traits, and that conflicting findings to date may arise from the problem of phenotype definition.

Adult↗

PubMed2002

Relationship of the tumor necrosis factor-alpha -308 A/G promoter polymorphism with insulin sensitivity and abdominal fat distribution in Japanese patients with type 2 diabetes mellitus.

We investigated the relationship of the A/G variant of the tumor necrosis factor-alpha (TNF-alpha) gene promoter at position -308 with insulin resistance and abdominal fat distribution in type 2 diabetic patients in the Japanese population. The TNF-alpha polymorphism was evaluated by polymerase chain reaction-restriction fragment length polymorphism in 142 healthy volunteers and 132 type 2 diabetic patients. Insulin sensitivity was assessed by homeostasis model assessment (HOMA) index in healthy subjects and hyperinsulinemic euglycemic clamp in type 2 diabetic patients. Abdominal fat distribution was evaluated by computed tomography (CT) scanning in diabetic patients. The TNF-alpha polymorphism was detected in three healthy volunteers and three type 2 diabetic patients, all of them being heterozygotes. There was no significant difference in allele frequencies of the -308 polymorphism between healthy subjects (0.0106) and type 2 diabetic patients (0.0114). HOMA index was no significant difference between healthy subjects with and without polymorphism (1.09 +/- 0.03 vs. 1.02 +/- 0.05). Glucose infusion rate (GIR), an index of insulin sensitivity, was not significantly different between diabetic patients with and without TNF-alpha polymorphism (40.4 +/- 4.1 vs. 45.0 +/- 1.8 micromol/kg per min). Moreover, no remarkable effect of TNF-alpha polymorphism on abdominal fat distribution was observed in diabetic patients. These results suggest that A/G heterozygotes of the TNF-alpha gene promoter at position -308 play no major role in the pathogenesis of insulin resistance or abdominal fat distribution in Japanese type 2 diabetic patients.

Abdomen↗

PubMed1999

CTLA4 gene polymorphism correlates with the mode of onset and presence of ICA512 Ab in Japanese type 1 diabetes.

Recently, the association of CTLA4 gene polymorphism with type 1 diabetes and AITD has been reported in several populations. CTLA4 was originally reported to regulate T-cell activity and T-B cognate interaction. To investigate the role of CTLA4 in autoimmune diseases, we examined the correlation between CTLA4 gene polymorphism and the clinical characteristics of Japanese patients with type 1 diabetes, including the mode of onset of diabetes and presence of islet-specific autoantibodies (GAD, ICA 512 Ab) in the serum. We studied 111 patients with type 1 diabetes and 445 normal subjects. CTLA4 exon 1 position 49 (A/G: codon 17: Thr/Ala) polymorphism was defined, employing PCR-RFLP. Sixty-three (57%) patients had AITD. The allele frequencies of G and A in both 111 patients (G: 65%; A: 35%) and 63 patients (G: 62%; A: 38%) were not significantly different from the control subjects (G: 63%; A: 37%). Serum samples of 69 patients were obtained within a year after onset and used for pancreas specific autoantibodies analysis. These samples were also used for further analysis between CTLA4 gene polymorphism and clinical characteristics. The allele frequencies of G and A in patients who presented with diabetic ketoacidosis (DK+) (G: 75%; A: 25%) were significantly different from those in DK- patients (G: 50%, A: 50%, P = 0.003). Allele and genotype analyses showed significant differences between DK+ patients and control subjects (P = 0.014, P = 0.046, respectively). Allele frequencies of G and A were not significant between patients who were positive and negative for GAD Ab, but significant for ICA 512 Ab (G: 83%, A:17% versus G: 59%, A: 41%: positive patients versus negative patients, P = 0.004). Our results showed a significant correlation between CTLA4 gene polymorphism and ICA 512 Ab. Our results also indicated that CTLA4 gene polymorphism is associated with the onset mode of Japanese type 1 diabetes and the presence of ICA512 Ab. Further analysis of this polymorphism is necessary to fully understand the pathogenesis and progression of type 1 diabetes.

Abatacept↗