Genetic variants in the 8q24 locus and risk of testicular germ cell tumors

Much evidence supports the premise that population genetic variation contributes significantly to the risk of testicular germ-cell tumor (TGCT). However, investigations of the association between genomic markers and TGCT susceptibility are scarce. Single nucleotide polymorphisms (SNPs) at the locus 8q24 have recently been found to be associated with prostate, colorectal and breast cancer. The US Servicemen’s testicular tumor environmental and endocrine determinants (STEED) study was used to investigate the association of 15 specific 8q24 SNPs with TGCT and its two main histologic groups of seminoma and nonseminoma. Conditional and unconditional logistic regression models, adjusted for the matching variables of year of birth, race/ethnicity and serum date, were utilized to produce odds ratios (OR) and 95% confidence intervals (95%CI). The analysis included 680 controls and 568 TGCT cases. In the TGCT analysis, no SNP was associated with risk in both heterozygotes and variant homozygotes. When stratified by histology the seminoma analysis also showed no association with the 8q24 SNPs. Conversely, the analysis of nonseminomas had three tentative associations (rs6470494, OR_{genotype AG} = 1.15, 95%CI: 0.86–1.54; OR_{genotype GG} = 1.68, 95%CI: 1.04–2.73; p for trend = 0.04) (rs13254738, OR_{genotype GT} = 1.04, 95%CI: 0.77–1.40; OR_{genotype TT} = 1.62, 95%CI: 1.06–2.49; p for trend = 0.07) (rs10505476, OR_{genotype CT} = 0.67, 95%CI: 0.50, 0.91; OR_{genotype TT} = 0.81, 95%CI: 0.47–1.39; p for trend = 0.04). There was no linkage disequilibrium between any of the 8q24 SNPs analyzed in this population. In conclusion, this study has found little evidence for an association between the reported 8q24 SNPs and TGCTs, although the findings for nonseminoma may be worth further investigation.     

Association of interleukin-13 gene polymorphisms with atopic bronchial asthma

A comparative analysis of allele and genotype distribution of C(−1055)T and R130Q IL13 gene polymorphisms has been performed in Russian patients from the Moscow region. In the study, 283 DNA specimens of atopic bronchial asthma (BA) patients and 227 DNA specimens of healthy donors were used. No association of these markers with atopic BA development as well as with total IgE concentration has been found. Haplotype frequency analysis did not reveal significant difference between samples. However, significant association of C(−1055)T polymorphism with the disease severity has been revealed (OR = 2.39, 95% confidence interval 1.44–3.98, p = 0.001). Therefore, C(−1055)T polymorphism was shown to be associated with atopic BA progression.     

心电图左心室劳损和左心室肥厚对主动脉瓣狭窄患者预后的影响

目的:探讨心电图左心室劳损(LV)和左心室肥厚(LVH)对无症状主动脉瓣狭窄患者预后的影响。方法:到我院治疗的主动脉瓣狭窄患者766例,心电图左心室劳损和左心室肥厚的预测值用Sokolow-Lyon(SL)电压标准和Cornell电压-时间(CVDP)标准评估,通过对其他预后协变量调整并进行评价。结果:心电图左心室劳损患者的心肌梗死的累计发生率显著高于非心电图劳损的患者(HR=2.7,95%CI:1.4-5.3,P=0.006)。与非心电图左心室肥厚的患者比较,SL标准与CVDP标准联用诊断的左心室肥厚患者心力衰竭的风险显著增加(95%CI:4.7-26.4,P0.001);行主动脉瓣置换术风险显著增加(95%CI:1.6-3.2,P0.001);非致死性梗死、心力衰竭或心血管死亡的复合终点风险也显著增加(95%CI:1.2-3.7,P0.05)。结论:心电图LV和LVH是无症状主动脉瓣狭窄患者预后不良的独立预测因子。     

Association of chromosome 8q24 variants with prostate cancer risk in the Siberian region of Russia and meta-analysis

Compelling evidence demonstrates the importance of chromosome 8q24 as a locus of susceptibility to prostate cancer. In this work, the association of common 8q24 variants, rs6983267 and rs1447295, with a sporadic risk of prostate cancer was analyzed in the Russian population of Siberia. For this purpose, the above polymorphisms were genotyped in 393 cases and 384 control individuals. The A allele of rs1447295 was significantly associated with prostate cancer risk (OR[CI 95%] = 1.74 [1.26–2.4], p = 7.8 × 10⁻⁴). The common G-A haplotype of rs6983267-rs1447295 also showed association with prostate cancer risk in Russians (OR[CI 95%] = 2.03 [1.1–3.75], p = 0.02). A meta-analysis combining our data with previously published results was performed to better evaluate the association between the SNPs studied and prostate cancer risk; its results strongly supported the association for both loci (p < 10⁻⁶). Thus, our study has confirmed the association of chromosome 8q24 with a risk of prostate cancer.     

ACE gene polymorphism and cardiac structure in patients with insulin resistance

Aims: Angiotensin-converting enzyme (ACE) is a key enzyme in the production of angiotensin II, thus may participate in the modulation of cardiac growth. The aim of our study is to analyze the ACE gene I/D polymorphisms in patients with insulin resistance (IR) and to evaluate its relationship to left ventricular mass and functions. Methods: Eighteen subjects (13 female and 5 male, mean age 39.8 ± 14) with IR were enrolled in the present study. Twenty-three healthy people without IR were recruited as the control group. ACE amplification of DNA was performed by polymerase chain reaction methodology. Fasting glucose and insulin, postprandial glucose, homeostasis model assessment (HOMA-IR) and HOMA-beta, lipid profile, anthropometric measurements were assessed. Left ventricular structure and functions were measured by echocardiography. Results: Distribution of I/D polymorphism of the ACE gene in the study group was as follows: genotype II–0%, ID–38.9%, DD–61.1% of patients. Distribution of individual genotypes was similar in patients with and without IR. No significant difference was found between genotype groups in terms of anthropometric measurements and metabolic parameters and blood pressure. Echocardiography showed no significant changes in left ventricular structure and functions in patients with IR. Conclusions: We considered that in patients with IR, there is no relationship between I/D polymorphism of the ACE gene and LVH.     

Genetic variability in the extracellular matrix protein as a determinant of risk for developing HTLV-I-associated neurological disease

Aggrecan, which is a well-known proteoglycan in joint cartilage, also exists in the spinal cord and plays an important role in maintaining water content in the extracellular matrix structure. In this study, we first examined the variable number of tandem repeat (VNTR) polymorphism of the aggrecan gene in 227 HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients, in 217 HTLV-I-infected healthy carriers (HCs), and in 85 normal controls. The VNTR allele 28 (1,630 bp) was more frequently observed in HAM/TSP patients than in HCs (χ ²=12.02, p=0.0005, odds ratio 1.79, 95% C.I. 1.29–2.50) and in controls (χ ²=13.43, p=0.0002, odds ratio 2.54, 95% C.I. 1.52–4.25), although this allele was not related to disease progression or to HTLV-I provirus load. We also found that the aggrecan concentration in cerebrospinal fluid (CSF) from rapidly progressive HAM/TSP patients was significantly higher than in slowly progressive patients (corrected p=0.0145) but not in infected non-inflammatory neurological other disease controls (OND) (corrected p=0.078). We then analyzed this aggrecan VNTR polymorphism in the different set of patients with HAM/TSP (n=58) and healthy carriers (n=70). This analysis, again, revealed that allele 28 was detected more frequently in HAM/TSP group than in HCs (χ ²=11.03, p=0.0009, odd ratio 3.04, 95% C.I. 1.55–5.97). The reproducibility of our study was regarded as a second- or third-class association by comparing combined p values and the Better Associations for Disease and GEnes (BADGE) system. Our results suggest that aggrecan polymorphism can be a novel genetic risk factor for developing HAM/TSP.Financial support: Grant in Aid for Research on Brain Science of the Ministry of Health, Labor and Welfare, Japan.     

Influence of the inducible nitric oxide synthase gene (<Emphasis Type="Italic">NOS2A</Emphasis>) on inflammatory bowel disease susceptibility

The great amount of nitric oxide (NO) produced by the inducible isoform of NO synthase (iNOS) exerts deleterious effects, and iNOS expression is raised in the colonic mucosa of inflammatory bowel disease (IBD) patients. This is the first association analysis of polymorphisms within the NOS2A extended gene with IBD susceptibility. We analyzed 336 patients of Crohn’s disease (CD), 355 of ulcerative colitis (UC), and 536 healthy controls from a Spanish population. We tested a (CCTTT)n microsatellite, a (−/TAAA) insertion, and two single nucleotide polymorphisms (SNPs) flanking them (rs2779251 and rs2779248) in the NOS2A promoter, together with two SNPs in the coding region: one within exon 10, D385D (rs1137933), and another mapping to exon 16, S608L (rs2297518). Analysis of these markers evidenced differences among IBD patients and healthy controls. Allele (CCTTT) 13 is related to higher UC risk (p = 0.001; odds ratio [OR] [95% confidence interval, CI] = 1.64 [1.20–2.23]). Carriers of minor alleles of the two promoter SNPs analyzed showed an association with UC predisposition, and common allele homozygotes of the two exonic SNPs were more frequent among CD patients than among controls. Concordantly, one out of the three haplotypes carrying both exonic risk alleles was found to increase CD susceptibility (p = 0.007; OR [95%CI] = 1.74 [1.13–2.67]). Therefore, the NOS2A gene seems to be involved in IBD aetiology.     

Thymidylate synthase and methionine synthase polymorphisms are not associated with susceptibility to childhood acute lymphoblastic leukemia in Kurdish population from Western Iran

In order to determine the influence of polymorphism in thymidylate synthase (TS 28-bp repeat) and methionine synthase (MS A2756G) genes on the susceptibility to acute lymphoblastic leukemia (ALL), 73 children with ALL and 128 age and sex matched unrelated healthy individuals from the Kermanshah Province of Iran were screened. The genotyping of TS 28-bp repeat and MS A2756G polymorphisms were performed by polymerase chain reaction (PCR) and PCR–RFLP, respectively. The frequency of TS 2R allele in patients and controls were 41.5 and 38%, respectively (Odds ratios (OR) = 1.13, 95%CI 0.73–1.74, P = 0.56). The allelic frequency of G allele of MS was higher (25%) in patients compared with healthy subjects (23%) (OR = 1.09, 95%CI 0.67–1.75, P = 0.71). Considering MS AA and TS 3R3R genotypes as reference indicated that individuals with MS GG + TS 2R2R genotypes have 1.3-fold increase in the risk of ALL (OR = 1.3, 95%CI 0.6–2.7, P = 0.5). Our results showed that neither TS 28-bp repeat nor MS A2756G polymorphisms are risk factors for susceptibility to ALL in Western Iran.     

Genetic susceptibility to ischemic stroke in Russians

The frequencies of alleles and genotypes for ten functionally significant single-nucleotide polymorphisms were determined in the FGA, FGB, APOE, LPL, ACE, and CMA1 genes for Russian ischemic stroke (IS) patients and for a control group of Russians similar in gender and age distribution. The groups showed no significant differences in the frequencies of individual alleles or genotypes for any polymorphism studied. However, complex analysis of genetic susceptibility by the APSampler algorithm demonstrated that carriership of the APOE (−491A) allele predisposed to IS (p = 0.044, OR 3.8, 95% CI 1.0–15.1). Correspondingly, the APOE (−491T/T) genotype was associated with resistance to IS (p = 0.044, OR 0.26, 95% CI 0.07–1.0). The carriership of FGB (−249C) allele together with this genotype enhanced its protective potential, reducing the p value of the combination twofold (OR 0.17, 95% CI 0.04–0.8). Two more protective combinations were identified: biallelic APOE (−427C) + LPL (1595G) and triallelic APOE (−491C) + LPL (1595G) + CMA1 (−1903G). In both cases, p = 0.0052, OR 0.18, and 95% CI 0.05–0.66. Altogether, involvement in the formation of IS risk in Russians was evidenced for alleles of four genes: APOE, FGB, LPL, and CMA1; the APOE involvement was demonstrated for alleles of two polymorphic loci: −491T and −427C. Linkage analysis suggested that these loci were involved in IS resistance independently of each other.     

Serum and tissue levels of six trace elements and copper/zinc ratio in patients with cervical cancer and uterine myoma

The aim of this study is to investigate the relationship between trace elements and the incidence of cervical cancer. Tissue and serum levels of six elements (Cu, Zn, Fe, Mn, Ca, and Se) and the Cu/Zn ratio in 40 cases of patients with cervical cancer, 30 cases of uterine myoma, and 50 healthy subjects were measured by atomic absorption spectrophotometry; the selenium content was determined by atomic fluorescence spectrometry. The results showed that the tissue contents of Zn, Se, and Ca were significantly lower and the Cu and Fe concentrations and Cu/Zn ratio were significantly higher in cervical cancer tissue than that for paired nonlesion tissue (p<0.02 and p<0.001, respectively). The serum levels of Zn, Se, Ca, and Fe were lower and Cu and Mn levels and Cu/Zn ratio were higher in patients with cervical cancer than in healthy subjects (p<0.01 and p<0.001, respectively) and in the uterine myoma group compared with healthy subjects (p< 0.05–0.001). There are no significant differences in the contents of six elements and the Cu/Zn ratio between uterine myoma tissue and paired nonlesion tissue. The results showed also that the Fe level and Cu/Zn ratio were significantly higher and the Zn and Se levels were significantly lower in cervical cancer tissue than in uterine myoma tissue (p<0.01 and p<0.001, respectively). The serum Cu level and Cu/Zn ratio were significantly higher in the cervical cancer group than the uterine myoma group (p<0.01). Data were also analyzed using multivarate logistic regression. After adjustment for age, occupation, life habit, and other covariates for the development of cervical cancer, the odds ratios were 22.64 (95% confidence interval [CI]: 5.64–90.88, p=0.001) for Cu, 0.11 (95% CI: 0.034–0.373; p=0.005) for Zn, and 0.60 (95% CI: 0.36–0.99, p=0.01) for Se. Thus, the serum and tissue levels of Cu increase and the deficiency of Zn and Se may be risk factors for the development of cervical cancer.     

MTHFR 677 CT/MTHFR 1298 CC genotypes are associated with increased risk of hypertension in Indians

The goals of our present study were to measure plasma homocysteine levels and determine their association with methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms (C677T and A1298C) in essential hypertensive subjects. Plasma total homocysteine and folic acid levels were measured in essential hypertensive patients (n = 153) before and after oral supplementation with either 5 mg folic acid tablet/day or 5 mg placebo/day for 4 weeks and compared with age and sex matched normotensive controls (n = 133). MTHFR gene polymorphisms (C677T and A1298C) were studied by restriction fragment length polymorphism and correlated with plasma homocysteine levels. Homocysteine levels were significantly higher in hypertensive patients as compared to controls and showed a negative correlation with plasma folate levels. Folic acid supplementation (5 mg/day) for 4 weeks resulted in a significant decrease in plasma homocysteine concentrations in these patients. Patients carrying MTHFR 677T allele (OR = 1.90; 95%CI: 1.14–3.19) or MTHFR 1298C (OR = 2.6, 95%CI: 1.55–4.40) allele were at increased risk of hypertension. The frequency of co-occurrence of MTHFR 677 CT/1298 CC genotypes was significantly higher in the patients compared to controls (P < 0.05) and was associated with increased risk of hypertension (OR = 3.54, 95%CI: 0.37–4.30). Subjects with MTHFR 1298 CC genotype had significantly higher homocysteine levels compared to those with MTHFR 1298 AA genotype (P < 0.05). Our results indicate that MTHFR 677T and 1298C alleles and co-occurrence of MTHFR 677 CT/MTHFR 1298 CC genotypes are associated with increased risk of hypertension and MTHFR 1298 CC genotype is associated with higher homocysteine levels in our subjects.     

Interleukin-10 and interleukin-18 promoter polymorphisms in an Italian cohort of patients with undifferentiated carcinoma of nasopharyngeal type

Purpose: Cytokines such as IL-10 and IL-18 seem to be involved in the inflammatory response of undifferentiated carcinoma of nasopharyngeal type (UCNT). The aim of this study was to evaluate the correlation between functional single nucleotide polymorphisms (SNPs) in the promoter region of IL-10 and IL-18 genes and the virological and clinical characteristics in a large case series of Caucasian patients suffering from UCNT, a tumor regularly associated with the Epstein Barr Virus (EBV). Methods: Eighty-nine patients with histologically confirmed UCNT and 130 healthy donors were included in our study. DNA was examined for the polymorphisms of IL-10 gene at positions –1082, −819, −592 by direct sequencing and IL-18 gene at position −607 and −137 by allele –specific PCR. EBV DNA serum viremia was evaluated by QC-PCR. Results: The distributions of the IL-10 and IL-18 genetic variants were not different between UCNT patients and healthy controls. The frequency of IL-10 –1082G allele, which is associated with high IL-10 expression, showed a nearly statistically significant increase in UCNT patients EBV DNA-negative as compared to healthy controls (OR=3.3 95% CI: 1.2–9.8). Subjects with C/C or C/G combined IL-18 genotypes showed an increased risk of being with Stages III-IV (OR=2.1 95% CI: 1.2–6.6). Conclusion: This study was performed to improve the definition of the pathogenetic factors implicated in UCNT by addressing the correlation between cytokine polymorphisms and clinical parameters. This is the first study investigating the possible role of the IL-18 and IL-10 polymorphisms in the development and outcome of UCNT. In our genetic analysis there is no evidence for involvement of IL-10 promoter polymorphisms alone in the genetic predisposition to this tumor. On the other hand, IL18 genetic variants may represent a genetic risk factor for tumor aggressiveness.     

Interaction of serum 70-kDa heat shock protein levels and <Emphasis Type="Italic">HspA1B</Emphasis> (+1267) gene polymorphism with disease severity in patients with chronic heart failure

Background Circulating heat shock protein 70 (Hsp70) is present in the circulation of healthy individuals and in patients with various disorders, including chronic heart failure (CHF). However, the source and routes of release of Hsp70 is only partially characterised in clinical samples. Aims The purpose of this study was to study the clinical and biological correlates of Hsp70 in a CHF population and, for the first time, to investigate the association of HspA1B (also known as Hsp70-2) +1267 alleles with serum Hsp70 levels. Methods A total of 167 patients (123 men, 44 women) with <45% left ventricular ejection fraction (LVEF) were enrolled; serum Hsp70 level was determined by enzyme-linked immunosorbent assay and HspA1B +1267 polymorphism by polymerase chain reaction–restriction fragment length polymorphism. Results Increased Hsp70 levels were present in patients with severe CHF (NYHA III–IV) as compared to the group of NYHA I–II (p = 0.003). Hsp70 levels correlated with LVEF, NT-proBNP, serum bilirubin, aspartate aminotransferase, alanine aminotransferase, γGT (p < 0.05) concentrations in patients with severe CHF, although no correlation was observed between Hsp70 and CRP, TNF-α, or IL-6. HspA1B allele G was associated with higher Hsp70 levels (p = 0.001) in patients in NYHA IV class as compared to carriers of allele A. Conclusions Serum Hsp70 levels were associated with disease severity in heart failure patients. An interaction with the presence of HspA1B +1267 allele G was observed for Hsp70 concentrations. Hsp70 correlates with markers of heart function and hepatic injury, but not with signs of inflammation.     

CYP1B1 (4326C > G), CYP2F1 (c.14_15insC), CYP2J2 (?76G > T), and CYP2S1 (13106C > T and 13255A > G) polymorphisms and genetic predisposition to chronic respiratory diseases induced by smoking and occupational factors

The contribution of the polymorphic markers of cytochrome P450 genes to respiratory diseases caused by smoking and occupational factors has been assessed. For this purpose, PCR-RFLP analysis of the CYP1B1 (rs1056836, 4326C > G), CYP2F1 (rs11399890, c.14_15insC), CYP2J2 (rs890293, -76G > T), and CYP2S1 (rs34971233, 13106C > T and rs338583, 13255A > G) gene polymorphisms has been performed. The analysis has shown that CYP1B1 (rs1056836, 4326C > G) and CYP2F1 (rs11399890, c.14_15insC) polymorphisms may contribute to the development of occupational chronic bronchitis. The proportion of CYP1B1*1*3 heterozygotes in the group of patients with occupational chronic bronchitis is considerably greater than in the group of healthy workers (69.16% versus 53.29%; χ² = 5.94, p = 0.02, p _cur = 0.04, OR = 1.97, the 95% CI is 1.13–3.42). Patients with occupational chronic bronchitis and healthy workers significantly differed from each other in the CYP2F1 genotypes frequency distribution (rs11399890, c.14_15insC) (χ² = 6.18, d.f. = 2, p = 0.05). CYP2F1 wild type/ins heterozygous genotype frequency is higher in healthy workers (36.08%) than in patients (22.22%) (χ² = 5.48, p = 0.02, p _cur = 0.04, OR = 0.51, the 95% CI is 0.28–0.90). No association has been found between the CYP2J2 (rs890293, −76G > T) or CYP2S1 (rs34971233, 13106C > T, and rs338583, 13255A > G) gene polymorphisms and respiratory diseases.     

Effect of Gastric Banding on Aminoterminal Pro‐brain Natriuretic Peptide in the Morbidly Obese

Objective: Aminoterminal pro‐brain natriuretic peptide (NT‐proBNP), like brain natriuretic peptide, might have diagnostic utility in detecting left ventricular hypertrophy and/or left ventricular dysfunction. The aim of the study was to investigate the relationship between morbid obesity and NT‐proBNP and the effect of weight reduction on this parameter. Research Methods and Procedures: A total of 34 morbidly obese patients underwent laparoscopic adjustable gastric banding (LAGB). NT‐proBNP levels were measured before and 12 months after the surgery. Results: Metabolic features and systolic and diastolic blood pressure were significantly decreased (p < 0.00001 for both) after a cumulative weight loss of 19.55 kg 1 year after LAGB. NT‐proBNP concentration was significantly higher in morbidly obese patients before LAGB than in normal‐weight control subjects (341.15 ± 127.78 fmol/mL vs. 161.68 ± 75.78 fmol/mL; p < 0.00001). After bariatric surgery, NT‐proBNP concentration decreased significantly from 341.15 ± 127.78 fmol/mL to 204.87 ± 59.84 fmol/mL (p < 0.00, 001) and remained statistically significantly elevated (204.88 ± 59.84 fmol/mL vs. 161.68 ± 75.78 fmol/mL; p = 0.04) compared with normal‐weight subjects. Discussion: This investigation demonstrates higher levels of NT‐proBNP in morbidly obese subjects and a significant decrease during weight loss after laparoscopic adjustable gastric banding. In obesity, NT‐proBNP might be useful as a routine screening method for identifying left ventricular hypertrophy and/or left ventricular dysfunction.     

Further evidence for a synergistic association between APOEɛ4 and BCHE-K in confirmed Alzheimer’s disease

Recent reports on a potential association between the K-variant of the gene for butyrylcholinesterase (BCHE-K) and Alzheimer’s disease (AD) are discordant. An initial finding of association through a synergistic enhancement of risk of APOEɛ4 with late-onset AD has not been confirmed by others. We have conducted a case-control study of histopathologically confirmed AD (n=135) and non-AD (n=70) cases (age of death ≥60 years), in which we have genotyped for APOEɛ4, BCHE-K, and BCHE-A1914G, a silent polymorphism 299 bp downstream of the BCHE-K mutation. The allelic frequency of BCHE-K was 0.13 in the controls and 0.23 in the AD cases, giving a carrier odds ratio (OR_c) of 2.1 (95% C.I. 1.1–4.1) for BCHE-K in confirmed AD. The allelic frequency for the BCHE-1914G variant was 0.19 and 0.33 in controls and AD cases, respectively (OR_c=2.4; 95% C.I. 1.3–4.5). In an older sub-sample of 27/70 controls and 89/135 AD patients with ages of death ≥75 years, the OR_c was increased to 4.5 (95% C.I. 1.4–15) for BCHE-K and 2.7 (95% C.I. 1.0–7.2) for BCHE–1914G carriers. The BCHE-K association with AD became even stronger in carriers of at least one APOEɛ4 allele. Only three out of 19 controls compared with 39/81 AD cases carried BCHE-K in addition to APOEɛ4, giving an odds ratio of confirmed AD of 5.0 (95% C.I. 1.3–19) for BCHE-K carriers within APOEɛ4 carriers. Five out of 19 controls and 52/81 AD cases carried BCHE-1914G, giving the same odds ratio of confirmed AD of 5.0 (95% C.I. 1.6–16) for BCHE-1914G carriers within APOEɛ4 carriers. In addition, our results suggest strong linkage disequilibrium between BCHE-K and BCHE-1914G but no major association of the sole BCHE-1914G chromosome with AD. We conclude that BCHE through its K-variant, rather than a nearby marker, is a susceptibility factor for AD and enhances the AD risk defined by APOEɛ4 alone in an age-dependent manner. Received: 29 September 1998 / Accepted: 29 December 1998     

Genetic polymorphisms in transforming growth factor beta-1 (TGFB1) and childhood asthma and atopy

Transforming growth factor beta-1 (TGFB1) may influence asthma by modulating allergic airway inflammation and airway remodeling. The role of single nucleotide polymorphisms (SNPs) of TGFB1 in asthma remains inconclusive. We examined TGFB1 SNPs in relation to asthma risk and degree of atopy among 546 case-parent triads, consisting of asthmatics aged 4–17 years and their parents in Mexico City. Atopy to 24 aeroallergens was determined by skin prick tests. We genotyped five TGFB1 SNPs, including two known functional SNPs [C-509T (rs1800469), T869C (rs1982073)] and three others (rs7258445, rs1800472, rs8179181), using TaqMan and Masscode assays. We analyzed the data using log-linear and polytomous logistic methods. Three associated SNPs, including the two known functional SNPs, were statistically significantly related to asthma risk. Individuals carrying the T allele of C-509T had an increased risk of asthma [relative risk (RR) = 1.42, 95% confidence interval (CI) = 1.08–1.87 for one copy; RR (95%CI) = 1.95 (1.36–2.78) for two copies]. For T869C, the RRs (95%CI) were 1.47 (1.09–1.98) for one and 2.00 (1.38–2.90) for two copies of the C allele. Similar results were found for rs7258445. The haplotype containing all three risk alleles conferred an increased risk of asthma (RR = 1.48, 95% CI = 1.11–1.95 for one copy; RR = 1.77, 95% CI = 1.22–2.57 for two copies). These three SNPs were also related to the degree of atopy. This largest study to date of genetic variation in TGFB1 and asthma and atopy adds to increasing evidence for a role in these disorders.     

Case-control Studies on the Relationship between Onchocerciasis and Epilepsy: Systematic Review and Meta-analysis

Objective

A systematic review and meta-analysis of all available case-control studies on the relationship between onchocerciasis and epilepsy. Because age and level of onchocerciasis endemicity in the area of residence are major determinants for infection, an additional analysis was performed, restricted to studies achieving control of these confounding factors.

Data sources

Medical databases, the “African Neurology Database, Institute of Neuroepidemiology and Tropical Neurology, Limoges,” reference lists of relevant articles, commercial search engines, up to May 2012.

Methods

We searched for studies examining infection status with Onchocerca volvulus in persons with epilepsy (PWE) and without epilepsy (PWOE) providing data suitable for the calculation of pooled odds ratios (OR_p) and/or standardized mean differences (SMD) using random-effects models.

Results

Eleven studies providing data of qualitative skin biopsies for diagnosis of onchocerciasis were identified. Combined analysis on the total sample of 876 PWE and 4712 PWOE resulted in an OR_p of 2.49 (95% confidence interval (95%CI): 1.61–3.86, p<0.001). When this analysis was restricted to those studies achieving control for age, residence and sex (367 PWE, 624 PWOE), an OR_p of 1.29 (95% CI: 0.93–1.79; p = 0.139) was found. Presence of nodules for diagnosis of onchocerciasis was analyzed in four studies (225 PWE, 189 PWOE; OR_p 1.74; 95%CI: 0.94–3.20; p<0.076), including two studies of the restricted analysis (106 PWE, 106 PWOE; OR_p 2.81; 95%CI: 1.57–5.00; p<0.001). One study examined quantitative microfilariae counts in patients without preceding microfilaricidal treatment and demonstrated significantly higher counts in PWE than in PWOE.

Interpretation

Our results strengthen the hypothesis that, in onchocerciasis foci, epilepsy and infection with O. volvulus are associated. Analysis of indicators giving information on infection intensity, namely nodule palpation and quantitative microfilaria count in untreated patients, support the hypothesis that intensity of infection with O. volvulus is involved in the etiology of epilepsy.     

ACE and AGTR1 Polymorphisms in Pathogenesis of Human Left Ventricular Hypertrophy

The A2350G polymorphism of exon 17 of the angiotensin I-converting enzyme gene (ACE) and the A1166C polymorphism of the 3-untranslated region (3-UTR) of the angiotensin II type 1 receptor gene (AGTR1) were tested for association with left ventricular hypertrophy (LVH) in patients with essential hypertension (EH) or arterial hypertension (AH) combined with diabetes mellitus type 2 (DM2). The patients with EH or AH + DM2 did not differ significantly in ACE or AGTR1 allele or genotype frequencies from healthy subjects. Both polymorphisms were associated with LVH in EH. AGTR1 allele 1166C was more frequent in patients with LVH than without (33.6 vs. 20.7%) and affected the left ventricular mass index (LVMI) in patients with EH (p = 0.007). The frequency of ACE allele 2350G in EH patients with LVH was 1.5 times higher, and that of genotype GG was 3.5 times higher, than in patients without LVH. LVMI differed significantly (p = 0.002) between patients with different ACE genotypes, being maximum in homozygotes GG and minimum in homozygotes AA. Thus, AGTR1 allele 1166C and ACE allele 2350G were identified as predisposing to LVH in EH. The two polymorphisms were not associated with the incidence or severity of LVH in patients with AH and DM2.     

Assessment of Recanalization of Chronic Total Occlusions on Left Ventricular Function in Patients With or Without Previous Myocardial Infarction by Real-time Three-Dimensional Echocardiography

The changes of left ventricular ejection fraction (LVEF) were assessed after successful recanalization of chronic total occlusions (CTO) with or without previous myocardial infarction (MI) by real-time three-dimensional echocardiography (RT3DE). 32 patients with a successfully recanalyzed CTO were included in the present prospective study. The patients were divided into group 1 without previous MI and group 2 with previous MI in the territories of total occlusion vessel that was recanalized. In addition, there was a subgroup composed of 14 patients with collateral flow or retrograde flow in group 2. In all patients, LVEF was determined by RT3DE at baseline and after 6 weeks. In group 1, the evolution of LVEF increased significantly from 59.9 ± 7.2–67.5 ± 8.7% (P < 0.05). In group 2, the evolution of LVEF increased from 48.6 ± 6.1–50.1 ± 6.4%, however, it was without statistic significance (P > 0.05). The evolution of LVEF increased from 46.8 ± 7.1–53.0 ± 7.2% (P < 0.05) in the subgroup of group 2. Left ventricular function in patients with CTO can be feasibility and actually evaluated by RT3DE. The influence of recanalization of CTO on the improvement of left ventricular function was different between MI and non-MI patients. The left ventricular function did not improve in MI patients, but improved significantly in the patients having rich collateral circulation.