Quantification by additive RT-PCR of HIV-1 RNA plasma levels in different stages of HIV-1 infection

Recent reports have shown an association between an intronic polymorphism of the presenilin-1 (PSEN1) gene and late-onset (age at onset > 65) familial and sporadic (no family history) Alzheimer disease (AD). The reported association was independent of the effect of the only previously identified gene associated with late-onset AD, APOE. Blood samples were obtained from members of 122 multiplex AD families, 42 unrelated cases of AD with positive family histories of dementia, 456 sporadic cases of AD, and 317 controls of similar ages at examination to the cases. These samples were genotyped for an intronic polymorphism of the PSEN1 gene, located 3' to exon 8, and the data analyzed for evidence of association or linkage. The samples were also genotyped for APOE and the data analyzed to see if the association or linkage changed when controlling for APOE genotype. There was no statistically significant increase (at alpha = .01) in allele 1 (199 bp) or genotype 1/1 in the sporadic AD cases, or in a random sample of one affected from each multiplex family, compared to controls. When examining the effect of the PSEN1 polymorphism while controlling for APOE genotype, APOE genotype was strongly associated with AD, but the PSEN1 polymorphism genotype was not. Model-trait dependent (lod score) and independent (Sim1BD) methods detected no evidence of linkage between PSEN1 and AD. In this independent dataset, the previously reported association between the intronic PSEN1 polymorphism and AD cannot be confirmed, and the conclusion that PSEN1 is a major susceptibility gene for late-onset AD is not supported.     

Confirmation of an association between a polymorphism in exon 3 of the low-density lipoprotein receptor-related protein gene and Alzheimer's disease

C766T, a polymorphism in exon 3 of the gene for the low-density lipoprotein receptor-related protein (LRP), was found to be associated with late-onset Alzheimer's disease (AD). We developed a PCR-restriction enzyme-based assay to analyze this allele in 234 AD patients and 103 controls. We confirmed that the LRP C766T polymorphism was in disequilibrium with AD--the C/C genotype was present in 76% of AD patients and 60% of controls (p < 0.01); however, the LRP polymorphism did not influence age at onset of AD.     

The plasma levels of endothelin in diabetic retinopathy and their changes after treatment with doxium

Apolipoprotein E (APOE) has been identified as a major susceptibility marker for Alzheimer's disease (AD) and it has been proposed that a common polymorphism in the alpha1-antichymotrypsin (ACT) gene increases the risk of developing AD, when the combination of ACT/AA genotype and APOE epsilon4 allele segregate together. The ACT polymorphism was analysed in 218 sporadic late-onset AD patients and 101 healthy control subjects from Eastern Finland. Samples of the ACT polymorphism were divided into three subgroups according to their APOE genotypes and the genotyping of samples was done using the polymerase chain reaction (PCR) method. Any association between the AD group and the controls was tested with the chi2 test. Our data failed to detect any effect of polymorphism in the ACT genotypes associated with the APOE alleles, suggesting that in this population ACT does not increase the risk of AD.     

Methylenetetrahydrofolate reductase gene polymorphism and ischemic stroke in Japanese

Hyperhomocyst(e)inemia has been identified as an independent risk factor for atherosclerotic and thromboembolic diseases such as coronary artery disease, cerebral artery disease, and venous thrombosis. Recently, the alanine/valine (A/V) gene polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR), one of the key enzymes that catalyzes the remethylation of homocysteine, was reported. The VV genotype is correlated with increased plasma homocyst(e)ine levels as a result of the reduced activity and increased thermolability of this enzyme. In this study, we examined the association between the V allele of the MTHFR gene and ischemic stroke in an elderly Japanese population. The diagnosis of cerebral infarction of all study patients was confirmed by CT of the brain. The MTHFR genotype was analyzed by polymerase chain reaction followed by HinfI digestion. In 256 stroke patients and 325 control subjects, the frequencies of the V allele were 0.45 and 0.32, respectively. The odds ratios and 95% confidence intervals adjusted for the other risk factors were, respectively, 1.51 (1.02 to 2.23) for the AV genotype and 3.35 (1.94 to 5.77) for the VV genotype compared with the AA genotype. Both of these effects were statistically significant (P=0.041 and P<0.001, respectively). In patients with multiple infarcts in particular, the allele frequency of the V mutation was 0.56, and the association between the V allele and stroke was highly significant. Plasma homocyst(e)ine levels were significantly higher in patients with the VV genotype than in patients with the AA or AV genotype, especially those with low plasma folate levels. The V allele of the MTHFR gene was significantly associated with cerebral infarction in an elderly Japanese population in a codominant manner. The VV genotype may contribute to risk for ischemic stroke through a predisposition to increased plasma homocyst(e)ine levels, and dietary folate supplementation may be of benefit, particularly to patients with this genotype.     

Association between a PS-1 intronic polymorphism and late onset Alzheimer's disease

Previous work suggests an association between allele 1 and the 1-1 genotype of an intronic polymorphism in the presenilin-1 (PS-1) gene and late onset Alzheimer's disease. We found an excess of the 1-1 genotype in our late onset clinical sample (p = 0.006, one-tailed) but not in our postmortem confirmed sample, which instead exhibited an excess of allele 1 (p = 0.02, one-tailed). No interaction between PS-1 and ApoE genotype was detected and the findings remained significant when the effects of ApoE were taken into account (p = 0.03, one-tailed). These results suggest that the PS-1 polymorphism, or a locus in linkage disequilibrium with it, acts as a risk factor for late onset AD.     

Apolipoprotein E genotype as a risk factor in Japanese patients with early-onset and late-onset Alzheimer's disease

Recent studies have provided evidence of an association of apolipoprotein E (apoE) epsilon 4 allele and late-onset sporadic Alzheimer's disease (AD). Some studies have shown the possibility that apoE epsilon 4 is a risk factor of developing AD in early-onset type. We have analyzed the apoE gene polymorphism in a sample of 310 Japanese AD subjects and 237 age-matched Japanese controls. We divided the sporadic AD patients into two subgroups of 237 late-onset (> 65 years) and 73 early-onset (< or = 65 years) patients, and into three subgroups according to their apoE genotype, no epsilon 4, one epsilon 4, and two epsilon 4 alleles. Our data confirmed an association between epsilon 4 allele and early-onset AD and late-onset AD. The odds ratios (95% confidence interval) referred to no epsilon 4 allele for AD were 3.4 (1.7-7.0) for one epsilon 4 allele and 20.3 (2.5-166.6) for two epsilon 4 alleles in early-onset type, and 6.7 (3.9-11.3) for one epsilon 4 allele and 19.0 (2.5-145.6) for two epsilon 4 alleles in late-onset type. These ratios were significantly increased in both early-onset AD and late-onset AD. Kaplan-Meier survival analysis, which estimates the age of onset for subjects with no, one, and two epsilon 4 alleles in early-onset and late-onset type, revealed a significant dose effect where each additional epsilon 4 allele made the age of onset earlier (p < 0.0001). The age of onset is 9.7 years earlier for two epsilon 4 bearers and 3.9 years earlier for one epsilon 4 bearers than no epsilon 4 bearers in late-onset AD, 2.9 years earlier for two epsilon 4 bearers and 1.4 years earlier for one epsilon 4 bearers than no epsilon 4 bearers in early-onset AD. Moreover, we studied an association between apoE epsilon 2 allele and early-onset AD and late-onset AD. There was a significantly decreased frequency of apoE epsilon 2 allele in patients with late-onset AD (p = 0.026), although the frequency of apoE epsilon 2 was not changed significantly in early-onset AD (p = 0.360). The odds ratios referred to no epsilon 2 allele for AD were 1.9 (0.6-5.7) for one epsilon 2 allele in early-onset type, and 0.4 (0.2-0.9) for one epsilon 2 allele in late-onset type. Our study suggested the difference in the effect of apoE genotype on developing AD between early-onset and late-onset type in Japanese patients.     

The Fc gammaRIIIA-158F allele is a risk factor for systemic lupus erythematosus

OBJECTIVE: To study whether the Fc gammaRIIIA-158V/F polymorphism, which affects IgG binding affinity, is a risk factor for systemic lupus erythematosus (SLE). METHODS: We genotyped a group of 70 Caucasian SLE patients for all known Fc gammaR polymorphisms. Of this group, 45 patients (64%) had nephritis. In 35 patients, this diagnosis was confirmed by renal biopsy. RESULTS: In the total group of 70 SLE patients, the frequency of the Fc gammaRIIIA-158F allele was 0.74, versus 0.57 in healthy controls (P = 0.003). The genotype distribution of the Fc gammaRIIIA-158V/F polymorphism was also significantly different from that of the control population (P = 0.004). The distribution of the other Fc gammaR polymorphisms--Fc gammaRIIA-131R/H, Fc gammaRIIIB-NA(1,2), and Fc gammaRIIIA-48L/R/H--was similar in SLE patients and controls. CONCLUSION: In our group of SLE patients, only the distribution of the alleles of the Fc gammaRIIIA-158V/F polymorphism was significantly different from that in the control group. This might indicate that macrophage expression of the Fc gammaRIIIA-158F isoform is involved in the disturbed clearance of immune complexes in patients with SLE.     

Aggravated decrease in the activity of nucleus basalis neurons in Alzheimer's disease is apolipoprotein E-type dependent

As reported before, the metabolic activity of nucleus basalis neurons is reduced significantly in Alzheimer patients. Because the apolipoprotein E (ApoE) epsilon4 genotype is a major risk factor for Alzheimer's disease (AD), we determined whether the decrease in metabolic activity in nucleus basalis neurons in AD is ApoE-type dependent. The size of the Golgi apparatus (GA) was determined as a measure of neuronal metabolic activity in 30 controls and 41 AD patients with a known ApoE genotype by using an image analysis system in the nucleus basalis of Meynert. A polyclonal antibody directed against MG-160, a sialoglycoprotein of the GA, was used to visualize this organelle. There was a very strong reduction in the size of the GA in the nucleus basalis of AD patients. Furthermore, a strong and significant extra reduction in the size of the GA was found in the nucleus basalis neurons of AD patients with either one or two ApoE epsilon4 alleles compared with Alzheimer patients without ApoE epsilon4 alleles. Our data show that the decreased activity of nucleus basalis neurons in AD is ApoE epsilon4 dependent and suggest that ApoE epsilon4 participates in the pathogenesis of AD by decreasing neuronal metabolism.     

Laparoscopic management of a noncommunicating uterine horn in a patient with an acute abdomen

INTRODUCTION: The presence of the apolipoprotein E4 allele (apoE4) has been recognized as a risk factor for the development of presenile and senile forms of Alzheimer's dementia (AD). MATERIAL AND METHODS: The apoE alleles frequency of 71 normal controls (NC), 60 demented controls (DC) and 50 senile type AD subjects was determined by polymerase chain reaction in order to get data about the apoE polymorphism of the Hungarian AD population. RESULTS: The apoE3/3 genotype was the most common in all groups. The apoE4 frequency was significantly higher (28%) in the AD group than that was (7% and 9%) in the NC and DC populations, respectively. No apoE4 homozygotes were found in the DC group and the number of heterozygotes was lower in the DC than in the AD group. CONCLUSION: The results are in good agreement with others in the literature and support the occurrence of an increased apoE4 allele frequency in Hungarian senile AD population.     

Apolipoprotein E-associated risk for Alzheimer's disease in the African-American population is genotype dependent

As a part of our ongoing study on Alzheimer's disease (AD) in elderly African Americans, we obtained clinical assessment and apolipoprotein E (ApoE) genotype data on 288 individuals (including 60 with AD). The ApoE epsilon4 allele frequency was significantly increased in AD patients compared with controls. The age-adjusted odds ratio (OR) for AD in epsilon4 homozygotes was 4.83 (95% confidence interval [CI], 1.71-13.64) compared with the epsilon3/epsilon3 genotype, but the OR for AD with the epsilon3/epsilon4 genotype did not reach significance (1.20; 95% CI, 0.58-2.45). These findings suggest that the association between ApoE epsilon4 and AD is weaker in African Americans than in whites.     

The Glu318Gly mutation of the presenilin-1 gene does not necessarily cause Alzheimer's disease

In early-onset familial Alzheimer's disease (AD) pathogenic mutations have been found in the amyloid precursor protein (APP) gene and in the presenilin (PS)-1 and PS-2 genes. We screened for mutations in these genes in 20 patients with familial AD from the Finnish population. In addition, we sampled 41 sporadic AD patients and 59 controls to test for mutations identified in our familial AD cases. We detected an A-to-G transition in the PS-1 gene, resulting in a glutamic acid (Glu)-to-glycine (Gly) substitution at codon 318 in 2 familial and 2 sporadic AD patients. The Glu318Gly mutation has previously been reported to cause AD. We also found the Glu318Gly mutation in 4 healthy aged controls (range, 74-87 years). We thus conclude that the mutation is most likely a rare polymorphism not related to AD.     

Lack of association of trinucleotide repeat polymorphisms in very-low-density lipoprotein receptor gene with Alzheimer''s disease

Inheritance of the apolipoprotein E epsilon 4 allele is a risk factor for Alzheimer's disease (AD). A recent report studying Japanese patients suggested that a polymorphism of a trinucleotide repeat in the 5' untranslated region of an apolipoprotein E receptor, the very-low-density lipoprotein receptor, is genetically associated with AD, with overrepresentation of the allele containing five copies of the repeat. We determined the allele frequencies of the very-low-density lipoprotein receptor in 3 white populations totaling 469 individuals. In contrast to the previous report, we found no differences in allele frequencies between case patients and control subjects. The discrepancy could be due to differences in Japanese and white populations. Nonetheless, these data weaken the likelihood that this polymorphism in the very-low-density lipoprotein receptor gene is strongly associated with AD.     

Retroperitoneal round-cell liposarcoma associated with paraneoplastic pemphigus presenting as lichen planus pemphigoides-like eruption

OBJECTIVE: To investigate the relationship between angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism and the clinico-pathological manifestations in patients with immunoglobulin nephropathy (IgAN). METHODS: A flanking primer pair and an insertion-specific primer pair were used to perform two polymerase chain reactions so as to analyse the insertion/deletion polymorphism of ACE gene. RESULTS: There was a significantly higher genotype frequency for DD genotype in IgAN patients. The frequencies for DD genotype were also higher in those patients with hypertension and/or heavy proteinuria and/or severe glomerular sclerosis (P < 0.05). CONCLUSIONS: We observed a significant association of the deletion polymorphism of ACE gene with renal insufficiency, hypertension and severe glomerular lesions at biopsy. The deletion allele may play a role, at least to some extent, in the deterioration and progression in IgA nephropathy.     

The role of bronchial biopsy and washing in the diagnosis of allergic bronchopulmonary aspergillosis

A polymorphism in the angiotensin I-converting enzyme (ACE) gene has been associated with cerebrovascular diseases as a new potent risk factor. The purpose of this study was to investigate an association of the gene polymorphism with intracranial saccural aneurysmal patients. The study population consisted of 83 aneurysmal patients (age range 41-85 years) (the AN group) and 104 matched control subjects (age range 30-81 years) (the Control group). For detection of the ACE gene polymorphism, the standard PCR method was performed by using genomic DNA isolated from peripheral blood leukocytes. The PCR products were a 490-bp in the presence of the insertion (I) and a 190-bp fragment in the absence of the insertion (D). The ACE gene polymorphism was classified into three genotypes: I/I genotype (a 490-bp band); D/D genotype (a 190-bp band); or I/D genotype (both a 490-bp and a 190-bp band). The number of subjects with I/I, I/D, and D/D genotypes was 38, 40, and 5 in the AN group and 43, 45, and 16 in the Control group, respectively. The frequency of the D/D genotype in the AN group was significantly lower (5/83 = 0.06) than that in the Control group (16/104 = 0.15) (chi 2 = 4.06; p = 0.044). There was no significant difference between the genotype sof hypertensive patients and normotensive patients in the AN group. Thus, this present study suggests that genetic heterogeneity of the ACE gene may be correlated with the etiology of intracranial aneurysms.     

Alpha 1-antichymotrypsin gene polymorphism and risk for Alzheimer's disease

alpha 1-Antichymotrypsin (ACT), a component of the senile plaque of the Alzheimer's disease (AD) brain, has a possible role as a molecular chaperone in developing AD pathology. This study was a search for the possible association of the two structural polymorphisms of ACT, Ala15-->Thr and Met389-->Val in the Japanese population. In 101 AD patients, genotype and allele frequencies of the two polymorphisms did not differ from those of 104 age-matched healthy controls. However, in those subjects in which the apolipoprotein epsilon 4 allele was absent, the frequency of the Ala15 homozygote was significantly higher in the AD patients than in controls. This suggests that the Ala15 homozygote state may be a susceptibility marker for AD, interacting with apolipoprotein E genotype.     

Risk of left ventricular dysfunction in patients with probable Alzheimer's disease with APOE*4 allele

OBJECTIVE: To examine the association between the APOE genotype and cardiovascular disease in Alzheimer's disease (AD) patients. DESIGN: Case register study of 100 consecutive referrals to a Memory Clinic where type of dementia and cardiovascular comorbidity were diagnosed and APOE genotype was determined. SETTING: The Memory Clinic, University Hospital Rotterdam Dijkzigt. PARTICIPANTS: One hundred Memory Clinic patients, 59 to 91 years of age, who attended the Memory Clinic in the period between January 1994 and March 1996. MEASUREMENTS: Relative risk of cardiovascular morbidity in probable AD, based on clinical and ECG findings. RESULTS: The diagnosis of probable AD was more frequent in APOE*4 allele-carrying AD patients. When comparing homozygotes for APOE*4 with homozygotes for APOE*3, a nine-fold increase in prevalence of cardiac ischemia on ECG was found in the former. When grouping parameters of left ventricular dysfunction, the prevalence was 7.2 (95% confidence interval 1.2-42.6) times greater in probable Alzheimer patients with APOE4/4. CONCLUSIONS: In patients with probable AD, APOE*4 is associated with cardiac disease indicative of left ventricular dysfunction.     

The DD genotype of the angiotensin-converting enzyme gene is associated with increased mortality in idiopathic heart failure

OBJECTIVES: The aim of the present study was to investigate the association between the homozygous DD (deletion) genotype of the angiotensin-converting enzyme gene and survival and cardiac function in patients with idiopathic congestive heart failure. BACKGROUND: The DD genotype gene is a linkage marker for an etiologic mutation at or near the angiotensin-converting enzyme gene and has been associated with increased risk for the development of coronary artery disease, left ventricular hypertrophy and left ventricular dilation after myocardial infarction. We investigated the association between this angiotensin-converting enzyme genotype and mortality in a population-based cohort of patients with idiopathic congestive heart failure. METHODS: The genotype was determined in 193 patients recruited from a large unselected population of patients with congestive heart failure (n = 2,711). The patients were studied with echocardiography, and survival data were obtained after 5 years of follow-up. A control group from the general population (n = 77) was studied by a similar procedure. RESULTS: The frequency of the D allele was not significantly different in the study and control groups (0.57 vs 0.56, p = NS). Long-term survival was significantly worse in the patients with the DD genotype than in the remaining patients (5-year survival rate 49% vs. 72%, p = 0.0011 as assessed by log rank test). The independent importance of the DD genotype for prognosis was verified by a multivariate Cox proportional hazards analysis, by which the odds ratio for mortality and the DD genotype was 1.69 (95% confidence interval 1.01 to 2.82). The only significant difference in cardiac function data between the two groups was an increase in left ventricular mass index in the DD group (153 +/- 57 vs 134 +/- 44 g/m2, p = 0.019). CONCLUSIONS: Angiotensin-converting enzyme gene DD polymorphism was associated with poorer survival and an increase in left ventricular mass in patients with idiopathic heart failure. The results suggest a possible pathophysiologic pathway between angiotensin-converting enzyme gene polymorphism, angiotensin-converting enzyme activity, myocardial hypertrophy and survival. Therefore, the DD genotype may be a marker of poor prognosis in patients with congestive heart failure.     

The Gln-Arg191 polymorphism of the human paraoxonase gene (HUMPONA) is not associated with the risk of coronary artery disease in Finns

The human paraoxonase gene (HUMPONA) is codominantly expressed as alleles A and G. The A allele codes for glutamine (A genotype) and the G allele for arginine (B genotype) at position 191 of the paraoxonase enzyme. This genetic polymorphism has been suggested to be associated with the predisposition to coronary artery disease (CAD). We investigated the frequency of paraoxonase A and G alleles in 380 well-characterized CAD patients and in 169 controls. The most common genotype in both the patients with CAD (211/380) and in healthy Finnish individuals (87/169) was AA (Gln/Gln). The heterozygous AM (Gln/Arg) genotype was present in 140 of the patients and in 75 controls. The frequency of the A allele was 0.74 in both patients and controls. The genotype distribution between the two groups did not differ (P = 0.12, chi2 test). The genotype distributions were also similar to those reported earlier in other caucasoid populations. In conclusion, we found no association between the Gln-Arg 191 polymorphism of the human paraoxonase gene and coronary artery disease in Finns.     

Left ventricular hypertrophy, blood pressure and ACE genotype in untreated hypertension

It has been suggested that the deletion polymorphism of the angiotensin-converting enzyme (ACE) genotype may be important in the development of left ventricular hypertrophy (LVH). In order to test this hypothesis we investigated the interaction between blood pressure (BP), LVH and ACE genotype in 86 previously untreated hypertensive patients. Each underwent two-dimensional and Doppler echocardiography and ACE genotyping. There were no significant differences in BP, the parameters of left ventricular structure (including left ventricular mass index) or diastolic function between the three genotype groups. Additionally, there were no significant differences in the relationship between systolic BP and left ventricular mass index among the three genotype groups (II genotype, r = 0.46, P = 0.02; ID genotype, r = 0.42, P = 0.01; DD genotype, r = 0.34, P = 0.10; F = 0.38). In contrast to some previous studies, we have found in this group of previously untreated hypertensive subjects no evidence to suggest that the deletion polymorphism of the ACE genotype is important in the development of LVH.     

Polymorphism within the cyclin D1 gene is associated with prognosis in patients with squamous cell carcinoma of the head and neck

We have examined the correlation of a frequent A/G polymorphism within exon 4 of the cyclin D1 gene (CCND1) with genetic susceptibility and clinical outcome in 384 patients with squamous cell carcinoma (SCC) of the head and neck. CCND1 genotype frequencies were similar in the cases and 191 controls. Furthermore, the CCND1 genotype was not associated with susceptibility to SCC of the larynx, pharynx, or oral cavity. The influence of the CCND1 genotype on clinical outcome was also assessed. We found no correlation between genotype and tumor size (T1-T4), the involvement of nodes at presentation, or patient age and gender. However, the distribution of CCND1 genotypes in cases with poorly differentiated tumors was significantly different to that in patients with well-/moderately differentiated tumors (P = 0.016; chi2(2) = 8.71). Homozygosity for CCND1*G (GG genotype) was associated with poorly differentiated tumors (G3). We used Cox's proportional hazards model to investigate the influence of the CCND1 genotype on disease-free interval. CCND1 GG was associated with reduced disease-free interval [P = 0.001; hazard ratio (HR) = 2.95; 95% confidence interval (CI) = 1.54-5.63]. This remained significant after correction for tumor differentiation (P = 0.013; HR = 2.34; 95% CI = 1.2-4.6) and tumor stage (P = 0.005; HR = 2.64; 95% CI = 1.34-5.19). Analysis of the data from patients with tumors at different sites showed that the CCND1 GG genotype was associated with reduced disease-free interval in laryngeal (P = 0.004; HR = 3.63; 95% CI = 1.44-8.83) and pharyngeal (P = 0.006; HR = 3.48; 95% CI = 1.43-8.46) tumors. This is the first report of an association between CCND1 polymorphism and prognosis in SCC of the head and neck. These data show that the CCND1 GG genotype is an independent prognostic indicator of disease-free interval and supports initial observations in non-small cell lung cancer, that polymorphism within CCND1 influences tumor behavior.