Non-carriers Of Allele Research Articles

Polymorphisms of the IL12B and IL23R Genes Are Associated with Psoriasis

Psoriasis is a common inflammatory and hyperproliferative skin disease with a multifactorial genetic basis. A recent study reported that psoriasis was associated with the IL12B haplotype rs3212227 (3'-untranslated region)-rs6887695 (60 kb, 5') and the IL23R haplotype rs7530511 (L310P)-rs11209026 (Q381R). We examined these four single-nucleotide polymorphisms (SNPs) for association with psoriasis in two groups of North American and German Caucasians: (1) 1,810 cases and 2,522 controls; and (2) 509 pedigrees. Both IL12B markers showed highly significant association with psoriasis in the case-control (rs3212227, odds ratio (OR)=1.62, P=1.7 x 10(-15); rs6887695, OR=1.49, P=2.7 x 10(-15)) and in the family-based analysis (rs3212227, P=2.2 x 10(-3); rs6887695, P=1.7 x 10(-3)). The IL23R SNPs also showed significant association in the cases and controls (rs7530511, OR=1.22, P=3.9 x 10(-3); rs11209026, OR=1.40, P=3.8 x 10(-4)). For both genes, common risk haplotypes were identified whose statistical significance approached (IL23R) or exceeded (IL12B) genome-wide criteria. We found no statistical evidence for interactions of these haplotypes with HLA-Cw6. Our results confirm associations between IL12B and IL23R and psoriasis in Caucasians, and provide a genetic basis for the clinical association between psoriasis and Crohn's disease.

Allelic polymorphism in IL-1 beta and IL-1 receptor antagonist (IL-1Ra) genes in inflammatory bowel disease.

Recent reports have shown that allele 2 of the IL-1 receptor antagonist (IL-1Ra) gene is over-represented in ulcerative colitis (UC). Healthy individuals carrying allele 2 of this gene have increased production of IL-1Ra protein. Since the final outcome of the biological effects of IL-1 beta may depend on the relative proportion of these two cytokines, we have studied if a TaqI polymorphism in the IL-1 beta gene, which is relevant to IL-1 beta protein production, may be involved in the genetic susceptibility to UC and Crohn's disease (CD), in association with the established IL-1Ra gene polymorphism. Polymorphisms in the closely linked genes for IL-1 beta and IL-1Ra were typed in 100 unrelated Dutch patients with UC, 79 with CD, and 71 healthy controls. The polymorphic regions in exon 5 of the IL-1 beta gene and in intron 2 of the IL-1Ra gene, were studied by polymerase chain reaction (PCR)-based methods. The IL-1 beta allele frequencies in UC and CD patients did not differ from those in healthy controls. In order to study if the IL-1 beta gene polymorphism might participate synergistically with the IL-1Ra gene polymorphism in susceptibility to UC and CD, individuals were distributed into carriers and non-carriers of allele 2 of the genes encoding IL-1 beta and IL-1Ra, in each of the patient groups and controls. Results indicated a significant association of this pair of genes, estimated by the odds ratio (OR) after performing Fisher's exact test, in the UC group (P = 0.023, OR = 2.81), as well as in the CD group (P = 0.01, OR = 3.79). Thus, non-carriers of IL-1 beta allele 2 were more often present in the subgroup of patients carrying the IL-1Ra allele 2. By contrast, no association of these alleles was detected in the group of healthy controls (P = 1.00, OR = 0.92). These results suggest that the IL-1 beta/IL-1Ra allelic cluster may participate in defining the biological basis of predisposition to chronic inflammatory bowel diseases.

Tumor Characteristics of Carriers and Noncarriers of the deCODE 8q24 Prostate Cancer Susceptibility Alleles

In collaboration with deCODE Genetics Inc. we previously reported on the association between genetic variants on chromosome 8q24 and prostate cancer susceptibility. Several prior studies have examined the relationship between these 8q24 alleles and clinical tumor features. In this study we examine the differences in clinical and pathological tumor features between carriers and noncarriers of these 8q24 alleles in patients with prostate cancer. We genotyped 551 white men who underwent radical prostatectomy or radiation therapy for clinically localized prostate cancer at single institution between 2002 and 2005. Of these men 177 (32.1%) were carriers of the -8 allele of the microsatellite marker DG8S737, the A allele of the single nucleotide polymorphism rs1447295 and/or the A allele of the rs16901979 (a surrogate single nucleotide polymorphism of HapC) 8q24 alleles. We used statistical analyses to compare the distribution of clinical characteristics and pathological outcomes between carriers and noncarriers. The -8, A and HapC surrogate single nucleotide polymorphism alleles were present in 77 (14%), 128 (23%) and 61 (14%) patients with prostate cancer, respectively. Carriers of the -8 or multiple 8q24 alleles were significantly more likely to have a Gleason score of 7 or greater and lymph node metastases. Among men with a family history of prostate cancer, carriers of the -8 allele had a significantly greater risk of high grade disease (64% vs 39%, p = 0.04). In our predominantly surgically treated population there was a significant association between 8q24 prostate cancer susceptibility alleles, particularly the -8 allele, and high grade disease. In men with a family history of prostate cancer the presence of 1 or more of these alleles also conferred a greater risk of some adverse pathological features.

Haplotypes of the EPCR gene, prothrombin levels, and the risk of venous thrombosis in carriers of the prothrombin G20210A mutation

Haplotypes A1 and A3 in the endothelial protein C receptor (EPCR) gene are tagged by 4678G/C and 4600A/G respectively. We assessed whether these haplotypes modify the risk of venous thromboembolism in carriers of the prothrombin 20210A allele. We genotyped 4678G/C and 4600A/G in 246 20210A carriers: 84 venous thromboembolism propositi and 162 relatives (13 symptomatic), and in 140 relatives not carrying the 20210A variant. Prothrombin and soluble EPCR (sEPCR) levels were also measured. Among propositi, the mean age at first onset was lower in carriers (35 +/- 8 years) than non-carriers of the 4600G allele (44 +/- 14 years) (p = 0.004). The probability of being free of thrombosis at age 40 was lower in 20210A carriers with the EPCR 4600G allele (p = 0.015). The frequency of the 4600G allele (p=0.002) and the levels of prothrombin antigen (p = 0.002) and sEPCR (p < 0.001) were higher in the propositi than in their asymptomatic relatives. Multivariate analyses showed that the presence of the 4600G allele (OR = 2.5, 95% confidence interval 1.3-5.0), sEPCR > 147 ng/mL (2.8, 1.5-5.2) and prothrombin > 129% (3.8, 1.8-8.3) all increased the thrombotic risk. In bivariate analysis, including the 4600G allele and sEPCR > 147 ng/mL, only the latter remained associated with risk. These results show that in 20210A carriers the venous thromboembolism risk is influenced both by the actual prothrombin levels and by the EPCR A3 haplotype, via its effect on sEPCR levels.

An observational study on the influence of the APOE-ε4 allele on the correlation between ‘free’ copper toxicosis and EEG activity in Alzheimer disease

Since many years the apolipoprotein E epsilon4 allele (APOE-ε4) is known to be associated with Alzheimer disease (AD) but the mechanisms of these associations remained unclear. In the last years, the potential pathogenetic role of ‘free’ copper (i.e. non-ceruloplasmin bound copper) has been evidenced in AD. Recently, elevated ‘free’ copper was found to be correlated with slowing of cortical electroencephalographic (EEG) rhythms. The present work aimed to check the hypothesis that the strength of the correlations between free-copper and alterations of cortical rhythms might be different in carriers and non-carriers of the APOE-ε4 allele. Fifty-four AD patients and 20 healthy controls were included in the study. In all of them 1) APOE genotyping was performed; 2) total serum copper and ceruloplasmin was determined in order to calculate the serum ‘free’ copper; and 3) resting eyes-closed EEG rhythms were recorded and spectral brain activity was estimated via LORETA. A ‘two correlation coefficients comparison’ test was used to test the strength of the correlation in APOE-ε4 carriers and non-carriers. ‘Free’ copper levels were higher in patients than in controls and correlated positively with parietal–temporal delta and negatively with parieto-temporal alpha-1 activities. The correlation between ‘free’ copper and temporal alpha-1 activity was stronger in APOE-ε4 carriers than in non-carriers. Peroxide levels correlated with higher temporal delta in the AD group. APOE-ε4 appears to modulate the effect of copper on the altered AD brain activities, suggesting that modulation of oxidative stress related to copper dysfunction may be one of the mechanisms that make APOE-ε4 a risk factor for AD.

Blunted β-adrenoceptor–mediated fat oxidation in overweight subjects: a role for the hormone-sensitive lipase gene

Obesity is associated with blunted β-adrenoceptor–mediated lipolysis and fat oxidation, which persist after weight reduction. We investigated whether dinucleotide (CA) n repeat polymorphisms in intron 6 (i6) or 7 (i7) and a C-60G promoter substitution of the hormone-sensitive lipase (HSL) gene are associated with a blunted in vivo β-adrenoceptor–mediated increase in circulating fatty acids and glycerol (estimation of lipolytic response) and fat oxidation in overweight-obese subjects. A total of 103 overweight (25 kg/m 2 ≤ body mass index < 30 kg/m 2) and obese (body mass index ≥30 kg/m 2) subjects (62 men, 41 women) were included. Energy expenditure, respiratory quotient (RQ), and circulating fatty acid and glycerol were determined after stepwise infusion of increasing doses of the nonselective β-agonist isoprenaline. The i6, i7 (CA) n repeat polymorphisms were determined by size-resolved capillary electrophoresis; and a C-60G promoter substitution was determined by restriction enzyme digestion assay. Female noncarriers of allele 184 i7 (n = 18) and female carriers of allele 240 i6 (n = 12) showed an overall reduced fat oxidation (as indicated by changes in RQ) after β-adrenoceptor–mediated stimulation, explaining, respectively, 6.9% and 20.8% of the variance in RQ. These effects were not seen in male subjects. In conclusion, our results suggest that variation in i7 and i6 of the HSL gene might be associated with a physiological effect on in vivo β-adrenoceptor–mediated fat oxidation, at least in overweight-obese female subjects.

Neuromedin Beta: P73t Polymorphism in Overweight and Obese Subjects

Neuromedin beta (NMB) is a member of the bombesin-like peptide family expressed in brain, gastrointestinal tract, pancreas, adrenals and adipose tissue. The aim of our study was to compare the frequency of P73T polymorphism in overweight and obese patients (37 men: age 50.6+/-11.7 years, BMI 41.1+/-7.8 kg/m(2); 255 women: age 49.0+/-11.9 years, BMI 37.9+/-6.8 kg/m(2)) with that of healthy normal weight subjects (51 men: age 28.2+/-7.1 years, BMI 22.3+/-2.0 kg/m(2); 104 women: age 29.1+/-9.1 years, BMI 21.5+/-1.9 kg/m(2)) and to investigate the polymorphism's influence on anthropometric, nutritional and psychobehavioral parameters in overweight/obese patients both at the baseline examination and at a control visit carried out 2.5 years later, regardless of the patient s compliance with the weight reduction program. No significant differences in the genotype distribution were demonstrated between normal weight and overweight/obese subjects. Male T allele non-carriers compared to T allele carriers had higher energy (p=0.009), protein (p=0.018) and fat (p=0.002) intakes and hunger score (p=0.015) at the beginning of treatment. Male T allele non-carriers had a more favorable response to weight management at the follow-up, as they exhibited a significant reduction in waist circumference, energy intake and depression score as well as a significant increase in dietary restraint. No significant differences between carriers and non-carriers were demonstrated in women at the baseline examination. Both female T allele carriers and non-carriers demonstrated similar significant changes in nutritional parameters and in restraint score at the follow-up. Nevertheless, only female non-carriers showed a significant decrease in the hunger score.

High Risk of Acute Myeloid Leukemia in Individuals with NAD(P)H:Quinone Oxidoreductase 1 (NQO1) and Cytochrome P450 A1 (CYP1A1) Gene Defects.

Acute myeloid leukemia (AML) has been linked to chronic exposure to benzene and tobacco's polycyclic aromatic hydrocarbons (PAH). NAD(P)H:quinone oxidoreductase 1 (NQO1) is an enzyme that detoxifies benzene-derived quinones and reduces oxidative stress in hematopoietic cells. A C→T substitution polymorphism at nucleotide 609 of the NQO1 gene has been linked to a decreased activity of the coded enzyme. On the other hand, PAH are bioactivated by the cytochrome P450 A1 (CYP1A1) enzyme. An A→G substitution polymorphism at nucleotide 4889 and a T→C substitution at nucleotide 6235 of the CYP1A1 gene lead to the production of an enzyme with increased activity in PAH metabolism. Moreover, environmental-related diseases resulting from exposure to benzene and tobacco-related diseases have been described as serious health problems in south-eastern Brazil. The aim of this study was to evaluate the influence of the NQO1 C609T and CYP1A1 A4889G and T6235C polymorphisms for AML risk in individuals of the south eastern region of Brazil. Genomic DNA from 133 AML patients (median age: 47 years, range: 17-89; female: 63, male: 70; Caucasians: 112, African-Americans: 21) and 133 gender and race-matched controls (median age: 53, range: 25–60; female: 63, male: 70; Caucasians: 116, African-Americans: 17) were analysed using the polymerase chain reaction (PCR) and enzymatic digestion with the Hinf1, MspI, and BsrDI, respectively. The differences between groups were calculated by the chi-square or Fischer exact test. Crude odds ratios (ORs) were calculated and were given within 95% confidence intervals (CI). Logistic regression analysis was used to obtain age-adjusted ORs. P≤ 0.05 were considered statistically significant. Control samples (X2= 3.69, P= 0.07), but not patient samples (X2= 6.52, P< 0.02), were in Hardy-Weinberg equilibrium at the NQO1 C609T locus. Both patient and control samples confirmed the Hardy-Weinberg expectations at the CYP1A1 A4889G (X2= 2.54, P= 0.12; X2= 0.89, P= 0.34) and T6235C (X2= 1.06; P= 0.30; X2= 0.04; P= 0.84) loci. The frequency of the NQO1 609CT+TT genotype (41.4% vs 28.6%, P= 0.04) and the CYP1A1 6235TC+CC genotype (51.1% vs 28.6%, P= 0.0001) was significantly higher in AML patients than in controls. Therefore, carriers of the NQO1 variant allele (T) were under a 1.7-fold increased risk of AML (95% CI: 1.01-2.89) and carriers of the CYP1A1 T6235C variant allele (C) were under a 2.8-fold increased risk of the disease (95% CI: 1.67–4.84). Similar frequencies of the CYP1A1 4889AG+GG genotype were seen in patients and controls (43.6% vs 30.8%, P= 0.10). Similar risks for the disease were seen in carriers and non-carriers of the variant allele (G) (95% CI: 0.92-2.60). The combined frequency of the variant genotypes NQO1 609CT+TT and CYP1A1 6235TC+CC and 4889AG+GG was higher in AML patients than in controls (8.3% vs 1.5%, P< 0.001). Carriers of the three variant alleles were under a 11.8-fold increased risk of AML (95% CI: 2.40-57.61). The results of our study suggest that the inherited genotypes of polymorphisms involved in the pathways of carcinogens metabolism, NQO1 C609T, and CYP1A1 A4889G and T6235C, substantially alter the risk for AML in individuals of south eastern Brazil. Financial support: CNPq

G-6A Polymorphism of Angiotensinogen Gene Modulates the Effect of Blood Pressure on Carotid Intima-Media Thickness: The Bogalusa Heart Study

The adverse association between blood pressure and carotid artery intima-media thickness (IMT), a surrogate measure of subclinical atherosclerosis, is well-known. However, whether the G-6A polymorphism of the angiotensinogen (AGT) gene, a candidate gene of hypertension and vascular remodeling, modulates this relationship is unknown. In 662 white and black subjects aged 25 to 43 years (73.4% white, 39.7% male), common carotid IMT was measured by B-mode ultrasonography. The variant A-6 allele frequency was higher in blacks than in whites (0.850 v 0.448, P < .0001). In a bivariate analysis, there were no differences in mean arterial blood pressure and common carotid IMT between carriers and noncarriers of the G allele in whites, blacks, or the total sample, after adjusting for gender, age, and race. In a multivariable regression analysis that included the status of the G allele (carriers versus noncarriers) along with gender, age, mean arterial blood pressure, body mass index, LDL cholesterol, triglycerides:HDL cholesterol ratio, homeostasis model assessment of insulin resistance, smoking, and race (in the total sample), mean arterial blood pressure was significantly and adversely associated with common carotid IMT in whites, blacks, and the total sample. This adverse positive relationship between mean arterial blood pressure and common carotid IMT was noted among noncarriers but not carriers of the G allele (comparison of slopes, P = .02) in the total sample. Although the interaction was not significant (P = .2 and P = .05 in whites and blacks, respectively), a trend similar to that in the total sample was found in both races. In a recessive manner, the genetic variant (G-6A) of the AGT gene modulates the association between blood pressure and carotid IMT in young adults.

Variation in the IGF1 gene and growth in foetal life and infancy. The Generation R Study

The objective of this study was to examine whether variants of the IGF1 gene are associated with growth patterns from foetal life until infancy. This study was embedded in the Generation R Study, a population-based prospective cohort study of foetal life. Foetal growth (head circumference, abdominal circumference, femur length, estimated foetal weight) was assessed by ultrasound in early, mid- and late pregnancy. Growth in infancy was assessed at birth (weight) and at the ages of 6 weeks, 6 months and 14 months (head circumference, length, weight). The IGF1 promoter region genotype was determined in 738 children. Eight alleles of the IGF1 promoter region were identified. In total, 43% of the subjects were homozygous for the most common 192-bp allele (wild-type), 45% were heterozygous, and 12% were noncarriers of the 192-bp allele. No differences were found in birthweight between the three groups. However, noncarriers had a lower estimated foetal weight in mid-pregnancy (P = 0.040), followed by an increased growth rate until 6 months (P < 0.005) in comparison to the 192-bp homozygotes. A similar difference in growth rate was found for length (P < 0.001). Variants of the IGF1 promoter region are not associated with birthweight. However, noncarriers of the 192-bp allele tend to have a smaller foetal size, followed by an increased growth rate from mid-pregnancy to early infancy. Studies in larger cohorts are necessary to replicate our findings and to examine whether these effects persist throughout childhood.

CCR5-Δ32 genetic polymorphism associated with benign clinical course and magnetic resonance imaging findings in Brazilian patients with multiple sclerosis

The CCR5 chemokine receptor has been implicated in the pathogenesis of multiple sclerosis (MS). This research was carried out to investigate the association between the CCR5-Delta32 deletion in 124 patients with MS from Southern Brazil. Ninety-eight (79.0%) patients presented with relapsing-remitting MS (RR-MS), 17 (13.7%) secondary progressive MS (SP-MS), 8 (6.5%) primary progressive MS (PP-MS) and one (0.8%) clinically isolated syndrome (CIS). The control group consisted of 127 healthy blood donors from the same geographic region. The disease severity was assessed clinically using the Expanded Disability Status Scale (EDSS). Genomic DNA was extracted from peripheral blood cells and the genetic polymorphism was evaluated by polymerase chain reaction. Of the MS patients, 85 (68.5%) were females (p=0.0093). The CCR5-Delta32 frequency among the controls was 5.5%, and did not differ from that observed among the MS patients (4.8%) (p=0.7337). The mean (+/-SD) age at disease onset among the carriers and non-carriers of the CCR5-Delta32 allele was 31.7 (+/-11.1) and 36.6 (+/-12.0) years, respectively (p=0.1312). The duration (+/-SD) of the disease was 11.2 (+/-12.9) and 7.7 (+/- 5.6) years among the CCR5-Delta32 heterozygous, and CCR5 wild type, respectively (p=0.396). The mean (+/-SD) EDSS among the MS patients carriers and non-carriers of the CCR5-Delta32 allele was 2.4+/-1.2 and 2.67+/-2.2, respectively (p=0.9796). The MRI findings in MS patients with the CCR5-Delta32 genotype exhibited lower positive gadolinium enhancing-imaging (p=0.0013) and lower brain atrophy (p=0.1333) than MS patients with the CCR5 wild-type genotype. Despite that the differences were not significant, the results suggested that the disease onset and progression to disability may be prolonged in MS carriers of CCR5-Delta32, and CCR5-Delta32 could be considered a favorable prognostic biomarker of MS. Further studies comprising larger numbers of individuals carrying non-wild-type haplotypes are needed to determine CCR5-Delta32 involvement in the specific process of MS pathology and pathogenesis.

Basic Genetic Statistics Are Necessary in Studies of Functional Associations in Anesthesiology

Basic Genetic Statistics Are Necessary in Studies of Functional Associations in Anesthesiology

Rapid screening for potentially relevant polymorphisms in the human fatty acid amide hydrolase gene using Pyrosequencing™

Introduction Fatty acid amides such as the endocannabinoid anandamide serve as mammalian lipid transmitters in various physiological and pathophysiological processes including inflammation. They are rapidly degraded by the fatty acid amide hydrolase (FAAH). Non-functional FAAH resulted in reduced inflammatory and nociceptive responses. Evidence suggests that human genetic FAAH variants modulate pain and addiction but their clinical role is still poorly known. We therefore developed reliable high-throughput screening assays for FAAH polymorphisms to facilitate research of their clinical role. Materials and methods Six simplex Pyrosequencing™ assays were developed for FAAH polymorphisms dbSNP rs932816, rs4141964, rs324420, rs324419, rs2295633 and rs12029329 spanning the whole FAAH gene. They are frequent or have been functionally associated. Assays were established and validated in DNA samples from 350 healthy unrelated Caucasians. Results In all 350 DNA samples the six FAAH polymorphisms were identified correctly as verified by control samples obtained by conventional sequencing. The observed frequencies of homozygous, heterozygous and non-carriers of the minor alleles were in agreement with the Hardy–Weinberg equilibrium. Minor allelic frequencies were: rs932816G > A = 0.26, rs4141964C > T = 0.37, rs324420C > A = 0.20, rs324419C > T = 0.15, rs2295633G > A = 0.35 and rs12029329G > C = 0.25. SNPs were in high linkage except between rs324419 and rs12029329. One single haploblock was identified, spanning either the whole gene range or excluding rs12029329 in the 3′ region, depending on the statistical procedure of haloblock assignment. Conclusion The presently developed Pyrosequencing™ assays allow for quick and reliable detection of FAAH genotypes and may facilitate investigations of FAAH genetic functional associations.

The CDC2 I-G-T haplotype associated with the APOE ɛ4 allele increases the risk of sporadic Alzheimer's disease in Sicily

The cell division cycle 2 (CDC2) gene is a candidate susceptibility gene for Alzheimer's disease (AD). We investigated the CDC2 genotype, and allele and haplotype frequencies in AD patients and matched controls, distinguishing between apolipoprotein E (APOE) ɛ4 allele carriers and non-carriers. APOE ɛ4 is an established predictor of AD risk. APOE and CDC2 genotypes were examined in 109 sporadic AD patients and in 110 healthy age- and sex-matched controls from Sicily. The ɛ4 allele of APOE was predictive of AD risk in our study group (odds ratio: 5.37, 95% CI 2.77–10.41; P < 0.0001). Genotype and allele frequencies of the three tested CDC2 polymorphisms (Ex6 + 7I/D, Ex7–15 G > A, Ex7–14 T > A) were not significantly different between AD patients and controls. However, a significant different distribution of a specific CDC2 haplotype (I-G-T) was found between AD patients and controls when analyzing APOE ɛ4-positive subjects ( P = 0.0288). Moreover, the combined presence of the I-G-T haplotype and the ɛ4 allele almost doubled the risk of AD (odds ratio: 10.09, 95% CI 3.88–26.25; P < 0.0001) compared to carriers of ɛ4 alone. This study suggests that the I-G-T haplotype of the CDC2 gene increases the risk of AD in APOE ɛ4 carriers.

Genotype–Environment Interactions: Cognitive Aging and Social Factors

The possibility of genotype-environment interaction for memory performance and change was examined in 150 monozygotic (MZ) twin pairs from the Swedish Adoption Twin Study of Aging (SATSA). We used an MZ twin pair difference approach to examine the possibility that genotype was associated with intrapair variability and thus suggestive of genotype-nonshared environment interactions. Multiple 'variability genes' were found for longitudinal change in a semantic memory task including candidates coding for apolipoprotein E (APOE) and estrogen receptor alpha (ESR1) as well as serotonin candidates (HTR2A and 5HTT). One candidate also related to variability in change in episodic memory (5HTT). Of the significant associations observed, generally results indicated that MZ pairs who carry putative risk alleles were less variable than noncarriers, suggesting that noncarriers may be more sensitive to environmental contexts. We sought to 'contextualize' the possible nonshared environmental influences for found gene-environment (G x E) effects by considering intrapair differences in measured social and stress factors, including social support, life events and depressive symptoms. Results suggested that nonshared environmental influences associated with depressive symptoms may moderate the G x E relationship observed for ESR1 and APOE and longitudinal semantic memory change whereby noncarriers of putative risk alleles may be relatively more sensitive to depressionevoking environmental contexts than carriers of the risk allele. Thus, the contexts that facilitate or reduce depressive symptoms may affect semantic memory resiliency dependent on genotype. Further work ought to consider larger sample sizes as well as consider additional social and contextual factors.

Dopamine D2 receptor gene polymorphisms predict well the response to dopamine antagonists at therapeutic dosages in patients with schizophrenia

Previous reports have shown that both A1 allele carriers of TaqI A and Del allele non-carriers of -141C Ins/Del for dopamine D(2) receptor (DRD(2)) gene polymorphisms have a better antipsychotic drug response. The present study aimed to examine the validity of a combination of these two DRD(2) polymorphisms as predictors for response to DRD(2) antagonists. The subjects consisted of 49 acutely exacerbated inpatients with schizophrenia treated with bromperidol (30 cases, 6-18 mg/day) or nemonapride (19 cases, 18 mg/day) for 3 weeks. Brief Psychiatric Rating Scale and Udvalg for Kliniske Undersøgelser side-effects rating scale were used for clinical assessments. DRD(2) genotypes were determined using a polymerase chain reaction method. In the overall 49 subjects, combined DRD(2) polymorphisms weakly predicted the response to DRD(2) antagonists (Fisher exact test, P = 0.049), that is, good response in A1(+) or Del(-) subjects and poor response in A1(-) plus Del(+) subjects. In the former subjects, non-responders with A1(+) or Del(-) showed higher scores of psychic, extrapyramidal and total side-effects. At therapeutic doses (6-8 mg/day haloperidol equivalent dose) in 30 subjects, the predictability of response was greatly increased (Fisher exact test, P < 0.0045) with higher positive and negative predictive values (78.3% and 85.7%, respectively). These findings suggest that combined DRD(2) polymorphisms can be used as a pretreatment marker for response to DRD(2) antagonists at therapeutic doses, and that A1(+) or Del(-) subjects are highly sensitive to DRD(2) antagonists, expressed as either treatment responders or non-responders vulnerable to extrapyramidal symptoms.

Pro12Ala Polymorphism of the PPARγ2 Locus Modulates the Relationship Between Energy Intake and Body Weight in Type 2 Diabetic Patients

We explore the relationship among BMI, habitual diet, and the Pro12Ala polymorphism in the peroxisome proliferator-activated receptor (PPAR)gamma2. The Pro12Ala variant was characterized in 343 unrelated type 2 diabetic patients who were consecutively seen at the outpatient clinic of a health district of the province of Naples. Anthropometric and laboratory parameters were measured; habitual diet was assessed by a validated semiquantitative food frequency questionnaire. The overall frequency of Ala12 was 12% (n = 42). BMI was significantly higher in Ala carriers than non-Ala carriers, whereas total daily energy intake or macronutrient composition of the diet were similar in the two groups. For further analysis, participants were stratified according to genotype and sex-specific quartiles of energy intake. BMI increased in both genotype groups with increasing energy intake (P < 0.03). BMI was similar in Ala carriers and non-Ala carriers (30.0 vs. 30.1 kg/m2, P > 0.10) in the lower quartile of energy intake but significantly higher in Ala carriers in the upper quartile (36.0 vs. 32.1 kg/m2, P < 0.001). Average daily energy intake and diet composition were comparable within each quartile for carriers or noncarriers of the Ala allele. Relative to the noncarriers, Ala carriers had a significantly lower energy intake per kilogram body weight, thus suggesting that the Ala allele is associated with a higher food efficiency. The confounding role of medications, glucose control, and physical exercise was ruled out. This study provides evidence of a differential susceptibility to fat accumulation, and, hence, weight gain, in response to habitual high energy intake for Ala carriers compared with Pro/Pro homozygotes.

Decreased cerebral blood flow velocity in apolipoprotein E ɛ4 allele carriers with mild cognitive impairment

The aim of this study was to investigate the changes in cerebral blood flow velocity (CBFV) and its relation to apolipoprotein E (apoE) epsilon4 allele in mild cognitive impairment (MCI). Thirty MCI and 30 controls were assessed using Mini-Mental State Examination (MMSE) and Cambridge Cognitive Examination-Chinese version (CAMCOG-C), and then insonated in the anterior (ACA), middle (MCA) and basilar (BA) cerebral arteries using transcranial Doppler ultrasonography. Compared with controls, MCI showed significant decreases in the mean (V(m)), systolic (V(s)) and diastolic (V(d)) CBFV, bilaterally in MCA and ACA (P < 0.05-0.001), but not in BA. Compared with 17 apoE epsilon4 allele non-carriers, 13 carriers in MCI showed significant CBFV decreases, bilaterally in MCA (P < 0.05-0.001). Our findings, the decreased CBFV in apoE epsilon4 allele carriers with MCI, suggest that a large sample and longitudinal study in CBFV and cognitive changes may have the implications on early diagnosis of Alzheimer's disease.

β1-ADRENERGIC RECEPTOR GENE MODULATES THE EFFECT OF HEART RATE ON ARTERIAL STIFFNESS: THE BOGALUSA HEART STUDY.

Introduction Heart rate and sympathetic nervous activity are important determinants of arterial stiffness. However, whether the relationship between heart rate and arterial stiffness is modulated by β1-adrenergic receptor (β1-AR) gene variation is not known. This study examines the genetic modulation by β1-AR gene polymorphism (Arg389Gly) on the effect of heart rate on arterial stiffness in young adults. Methods The study cohort included 183 blacks and 502 whites aged 19 to 44 years enrolled in the Bogalusa Heart Study. Aortofemoral pulse wave velocity (af-PWV) was measured by echo-Doppler. Results Heart rate was significantly associated with af-PWV in blacks, whites, and the total sample. However, there was no difference in heart rate between carriers and noncarriers of Gly389 allele in both blacks and whites. Carriers versus noncarriers of the Gly389 allele showed higher values of af-PWV (5.29 m/sec vs 5.19 m/sec, p Conclusions β1-AR gene modulates arterial stiffness and its association with heart rate in young adults.

The Effect of Borderline Diabetes on the Risk of Dementia and Alzheimer’s Disease

To verify the hypothesis that borderline diabetes may increase the risk of dementia and Alzheimer's disease, a community-based cohort of 1,173 dementia- and diabetes-free individuals aged >or=75 years was longitudinally examined three times to detect patients with dementia and Alzheimer's disease (Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria). Borderline diabetes was defined as a random plasma glucose level of 7.8-11.0 mmol/l. Data were analyzed using Cox proportional hazards models. During the 9-year follow-up, 397 subjects developed dementia, including 307 Alzheimer's cases. At baseline, 47 subjects were identified with borderline diabetes. Borderline diabetes was associated with adjusted hazard ratios (95% CIs) of 1.67 (1.04-2.67) for dementia and 1.77 (1.06-2.97) for Alzheimer's disease; the significant associations were present after additional adjustment for future development of diabetes. Stratified analysis suggested a significant association between borderline diabetes and Alzheimer's disease only among noncarriers of APOE epsilon4 allele. There was an interaction between borderline diabetes and severe systolic hypertension on the risk of Alzheimer's disease (P = 0.04). We conclude that borderline diabetes is associated with increased risks of dementia and Alzheimer's disease; the risk effect is independent of the future development of diabetes. Borderline diabetes may interact with severe systolic hypertension to multiply the risk of Alzheimer's disease.