Relative risk of Alzheimer disease and age-at-onset distributions, based on APOE genotypes among elderly African Americans, Caucasians, and Hispanics in New York City.

Apolipoprotein-E epsilon 4 (APOE-epsilon 4) has been consistently associated with Alzheimer disease (AD) and may be responsible for an earlier age at onset. We have previously reported a diminished association between APOE-epsilon 4 and AD in African Americans. Using a new method, which allows inclusion of censored information, we compared relative risks by APOE genotypes in an expanded collection of cases and controls from three ethnic groups in a New York community. The relative risk for AD associated with APOE-epsilon 4 homozygosity was increased in all ethnic groups (African American relative risk [RR]=3.0; 95% confidence interval [CI]=1.5-5.9; Caucasian RR=7.3, 95% CI=2.5-21.6; and Hispanic RR=2.5, 95% CI=1.1-5.7), compared with those with APOE-epsilon 3/epsilon 3 genotypes. The risk was also increased for APOE-epsilon 4 heterozygous Caucasians (RR=2.9, 95% CI=1.7-5.1) and Hispanics (RR=1.6, 95% CI=1.1-2.3), but not for African Americans (RR=0.6, 95% Ci=0.4-0.9). The age distribution of the proportion of Caucasians and Hispanics without AD was consistently lower for APOE-epsilon 4 homozygous and APOE-epsilon 4 heterozygous individuals than for those with other APOE genotypes. In African Americans this relationship was observed only in APOE-epsilon 4 homozygotes. These results confirm that APOE genotypes influence the RR of AD in Caucasians and Hispanics. Differences in risk among APOE-epsilon 4 heterozygote African Americans suggest that other genetic or environmental factors may modify the effect of APOE-epsilon 4 in some populations.     

Genetic association between the apolipoprotein E (ApoE) gene alleles and various forms of Alzheimer's disease]

Allele epsilon 4 of the apolipoprotein E (APOE) gene is associated with higher risk of Alzheimer's disease (AD) in many, though not all, ethnic groups. The APOE allele and genotype frequency distributions were studied in 207 AD patients without cerebrovascular disorders, 62 AD patients with cerebrovascular disorders (combined AD), and 206 control individuals (ethnic Russians from the Russian population). The frequency of allele epsilon 4 in patients with early-onset and late-onset AD was three times higher than in control individuals (p < 0.000001). Compared with control people, patients with cerebrovascular disorders displayed a twofold higher frequency of allele epsilon 4; the difference between the two groups was significant (p = 0.0019). Relative risk of AD in carriers of allele epsilon 4 was five times higher than in carriers of alleles epsilon 2 and epsilon 3 (p < 0.000001). Allele epsilon 2 had a protective effect with respect to AD onset until 65 years of age (p = 0.015). Thus, APOE allele epsilon 4 proved to be a universal factor of early-onset, late-onset, and combined AD in ethnic Russians from Russia.     

Deficiency in mitochondrial aldehyde dehydrogenase increases the risk for late-onset Alzheimer's disease in the Japanese population

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) deficiency is caused by a mutant allele in the Mongoloids. To examine whether genetic constitutions affecting aldehyde metabolism influence the risk for late-onset Alzheimer's disease (LOAD), we performed a case-control study in the Japanese population on the deficiency in ALDH2 caused by the dominant-negative mutant allele of the ALDH2 gene (ALDH2*2). In a comparison of 447 patients with sex, age, and region matched nondemented controls, the genotype frequency carrying the ALDH2*2 allele was significantly higher in the patients than in the controls (48.1% vs 37.4%, P = 0.001). Logistic regression analysis indicates that carriage of the ALDH2*2 allele is an independent risk for LOAD of the epsilon4 allele of the apolipoprotein E gene (APOE-epsilon4) (P = 0.002). Moreover, the odds ratio for LOAD in carriers of the ALDH2*2 allele was almost twice that in noncarriers, irrespective of status with regard to the APOE-epsilon4 allele. Among patients homozygous for the APOE-epsilon4 allele, age at onset of LOAD was significantly lower in those with than without the ALDH2*2 allele. In addition, dosage of the ALDH2*2 allele significantly affected age at onset of patients homozygous for the APOE-epsilon4 allele. These results indicate that the ALDH2 deficiency is a risk for LOAD, synergistically acting with the APOE-epsilon4 allele.     

Association of the estrogen receptor alpha gene polymorphisms with sporadic Alzheimer's disease

Alzheimer's disease (AD) is a multifactorial disorder determined by the interaction of genetic, metabolic, and environmental factors. In the common late-onset familial and sporadic forms of AD apolipoprotein E type 4 allele (APOE-epsilon4) is now widely accepted as a major risk factor. The association of estrogen treatment with a reduction in the risk of AD together with the modulation by estrogen of the secretory metabolism of the amyloid precursor protein offers new possibilities for identification of other AD susceptibility genes, as those encoding for the estrogen receptors (ERs). A total of 193 patients with sporadic late-onset AD, meeting the NINCDS-ADRDA criteria, and a total of 202 control subjects, age and education matched, were included in this study. PvuII and XbaI ERalpha and HhaI APOE gene polymorphisms were evaluated in genomic DNA by Polymerase Chain Reaction (PCR). The frequency of the various ERalpha genotypes by the combination of P, p and X, x was calculated for controls and AD patients stratified based on ApoE typing. When the two ERalpha gene polymorphisms were analyzed in combination, 7 genotypes were recognized, with a significantly increased prevalence of PPXX genotype in AD patients compared to controls (P = 0.0001). Risk of AD increased by a factor of 7.6 (CI [1.10-62.3]) in homozygous APOE-epsilon4 individuals with PPXX ERalpha genotype. These results are consistent with a segregation of PPXX ERalpha genotype with a higher risk of developing late-onset sporadic AD in the Italian population. The ERalpha gene appears to interact with the APOE-epsilon4 genotype in determining AD susceptibility.     

Coenzyme Q, Vitamin E and Apo-E alleles in Alzheimer Disease

Neurodegenerative Diseases represent the most common cause of Dementia, about 5-10% of the population aged above 65 years and about 30% above 80 years. A study about Apo-E alleles, Coenzyme Q and Vitamins E as biological indicators was performed in plasma samples of patients aged from 30 to 85 years, affected by Neurodegenerative Diseases. The results were compared with control subjects of approximately the same ages as the reference group. A frequency of 21.7% of epsilon4 allele in control group was estimated, against 15.8% observed in patients. The frequency of epsilon2 and epsilon3 alleles was 13.0% and 65.2% in the control group against 10.5% and 73.7% in patients. No significant differences were observed between the frequency of epsilon3/epsilon3 genotype and epsilon3/epsilon4 genotype in the control group compared to patients' group. The frequencies observed in epsilon2/epsilon3 genotype groups were 8.7% vs 15.8% and of e2/e4 genotype 17.4% vs 5.3%. The epsilon2/epsilon2 and epsilon4/epsilon4 genotypes were not identified in any groups. Plasma CoQ10 concentrations were similar in patient and control groups and no differences were found even taking into account the distribution of male and female subjects in the two groups. Also, vitamin E did not provide evidence of any differences between groups and the analysis among sexes revealed that again vitamin E concentrations were similar in between subgroups.     

Genetic variation in α1-antichymotrypsin and its association with Alzheimer's disease

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by extracellular neuritic plaques and intracellular neurofibrillary tangles in brain parenchyma. Alpha-1-antichymotrypsin (ACT) is a component of plaque cores, can bind to Abeta, and has been proposed as a possible candidate gene for AD susceptibility. The genetic association between the ACT codon -17*A allele of the signal peptide polymorphism and AD has been shown in some, but not in all studies. One hypothesis is that the ACT codon -17*A allele is in linkage disequilibrium with unknown functional mutation(s) in the ACT gene. This study was undertaken to identify new mutation(s) in the ACT gene by PCR-SSCP-sequencing and, in conjunction with known mutations, to assess their role in affecting the risk of AD. A total of seven new point mutations were observed: 5'UTR(A-->G), Asp128Asn(G-->A), Ser250Ser(C-->T), Leu301Pro(T-->C), Thr324Thr(A-->G), G-->A in intron 4, and 3'UTR C-->A. Of these, mutations at codon 250, codon 324, intron 4 and 3'UTR showed a frequency of 1% or more. Of the known mutations, Thr-17Ala(A-->G), Lys76Lys(A-->G) and Leu241Leu(G-->A) occur at a polymorphic level. The ACT codon -17*A allele was associated with increased risk of AD (OR for AA vs TT: 1.71; 95% CI: 1.16-2.53; P=0.007), especially in the presence of the APOE*4 allele (OR for AA vs TT: 2.35; 95% CI: 1.13-4.85; P=0.02). The codon 241*A allele and the codon 250*T allele were associated with protective effects against AD (OR: 0.36; 95% CI: 0.13-0.86; P=0.02) (OR:0.39; 95% CI: 0.18-0.85; P=0.02). irrespective of the APOE*4 status. The codon 324*G allele was associated with a marginal protective effect (OR:0.57; 95% CI: 0.26-1.26; P=0.17). While the codon 241*A allele was in linkage disequilibrium with the codon -17*A allele, the codon 250*T and codon 324*G alleles were non-randomly associated with the codon -17*T allele. In contrast, the codon 76*G (OR:1.34; 95% CI: 0.92-1.95; P=0.13), codon 227*G (OR:3.96; 95% CI: 0.83-18.8; P=0.08) and intron 4*G (OR:1.47; 95% CI: 0.88-2.29; P=0.15) alleles were associated with a modest risk of AD, and all were in linkage disequilibrium with the codon -17*A allele. EH-based haplotype analysis showed that certain haplotypes are associated with either higher or lower risk of AD. Our data indicate that the ACT gene harbors several potentially important variable sites, which are associated with either an increased or decreased risk of AD. The non-random combination of risk and protective alleles may explain, in part, why the association studies regarding the ACT codon -17*A have been inconsistent, especially if the frequency of other ACT mutations varies between populations.     

Polymorphism of Apolipoproteine E in Relation with Alzheimer and Vascular Dementia

Summary 1. The epsilon 4 allele of the apolipoprotein E gene increases the risk of late onset familial and sporadic Alzheimer disease. Relation of epsilon 4 allele of the apolipoprotein E gene to various types of dementia and the onset of dementia were analyzed in the present study.2. The study comprised 139 patients (50 men and 89 women) with dementia, mean age 73.61 years (range 47–98). The diagnosis of dementia was made according to Diagnostic and Statistical Manual of Mental Disorders, and subtypes diagnoses were made according to NINCDS-ADRDA and NINDS-AIREN criteria. Minimental State Examination (MMSE) was used for the screening of dementia. Apolipoprotein E polymorphism was determined by the PCR-RFLP technique-polymerase chain reaction and subsequent digestion with specific restriction endonuclease. For statistical analyses chi-square test and the crude Gart′s odds ratio (OR) and 95% confidence intervals (CI) were used.3. From 139 dementia patients (MMSE ≤24 points) in 61 (45%) Alzheimer disease (AD) was present, in 44 patients (31%) vascular dementia (VD), and in 34 (24%) mixed dementia (MD) were revealed. In comparison with control group the presence of at least one ApoE-ɛ4 allele was significantly higher only in the group with AD (p < 0.001), (OR=2.76; 95%: 1.42–5.36). The frequency of ɛ4 allele carriers was significantly overrepresented in AD group compared with VD (χ²=5.94; p=0.0148). Differences between AD and MD or VD and MD were not confirmed.     

Polymorphism of the apolipoprotein E gene and the risk of myocardial infarction

The apolipoprotein E (ApoE) gene polymorphism resulting from nucleotide substitutions in exon 4 was analyzed in Russian and Tatar patients with myocardial infarction (MI) from Bashkortostan. Alleles epsilon 2, epsilon 3, and epsilon 4 were identified by PCR. The genotype frequency distribution proved to be age-dependent in healthy Russians, genotype E2/3 increasing in frequency in subjects beyond 45. Russians who suffered MI under 45 had lower frequencies of genotype E3/3 (50.00% vs. 75.47% in controls of the same age, P = 0.013, OR = 0.33) and allele epsilon 3 (72.12% vs. 85.85%, P = 0.020, OR = 0.43) and a higher frequency of allele epsilon 4 (22.12% vs. 10.38%, P = 0.030, OR = 2.45). Russians who suffered MI complicated by cardiogenic shock (CS) had a significantly higher frequency of genotype E3/4 and lower frequencies of genotype E3/3 and allele epsilon 3 as compared with MI patients without CS. In Tatars, genotype E4/4 occurred at a frequency of 14.29% in patients who suffered MI under 45, and was not detected in healthy subjects of the same age (P = 0.024, OR = 17.85). Thus, the ApoE polymorphism was associated with higher risk of MI in Russians and Tatars under 45.     

老年痴呆关联基因的研究进展

阿尔茨海默类痴呆（AD）是老年痴呆中最常见的一种,它以渐进性的神经功能退化并伴随着整体认知能力的下降为特征。早发性AD主要是由β-淀粉样前体蛋白（APP）基因和早老素基因突变引起,而与晚发性AD发病明显相关的只有载脂蛋白E-ε4 ( APOE-ε4)等位基因。但是APOE-ε4等位基因对AD发病既非充分又非必要,而且只能解释少于50%的AD的遗传变异。所以有必要进一步寻找与AD的关联基因。 Abstract:Dementia of the Alzheimer type (AD) is the leading cause of dementias for the elders.It is a progressively neurodegenerative disorder characterized by global cognitive decline.While most of the rare early-onset AD can be explained by mutations in APP gene and presenilin genes,the genetic etiology of the more common late-onset AD is only partly explained by the APOE-ε4 genotype.But the APOE-ε4 allele is neither necessary nor sufficient to cause disease and it can only account for less than one-half of the genetic variance of AD.Thus,more genes involved in AD are our special attention.     

Oxidative damage and protection by antioxidants in the frontal cortex of Alzheimer's disease is related to the apolipoprotein E genotype.

A great number of epidemiological studies have demonstrated that the frequency of the epsilon4 allele of the apolipoprotein E gene (APOE) is markedly higher in sporadic and in familial late onset Alzheimer disease (AD). In the frontal cortex of AD patients, oxidative damage is elevated. We address the hypothesis that the APOE genotype and reactive oxygen-mediated damage are linked in the frontal cortex of AD patients. We have related the APOE genotype to the levels of lipid oxidation (LPO) and to the antioxidant status, in frontal cortex tissues from age-matched control and AD cases with different APOE genotypes. LPO levels were significantly elevated in tissues from Alzheimer's cases which are homozygous for the epsilon4 allele of APOE, compared to AD epsilon3/epsilon3 cases and controls. Activities of enzymatic antioxidants, such as catalase and glutathione peroxidase (GSH-PX), were also higher in AD cases with at least one epsilon4 allele of APOE, while superoxide dismutase (SOD) activity was unchanged. In the frontal cortex, the concentration of apoE protein was not different between controls and AD cases, and was genotype independent. The Ginkgo biloba extract (EGb 761), the neurosteroid dehydroepiandrosterone (DHEA) and human recombinant apoE3 (hapoE3rec) were able to protect control, AD epsilon3/epsilon3 and epsilon3/epsilon4 cases against hydrogen peroxide/iron-induced LPO, while hapoE4rec was completely ineffective. Moreover, EGb 761 and DHEA had no effect in homozygous epsilon4 cases. These results demonstrate that oxidative stress-induced injury and protection by antioxidants in the frontal cortex of AD cases are related to the APOE genotype.     

ApoE −491A/T Promoter Polymorphism is not an Independent Risk Factor,but Associated with the ε4 Allele in Hungarian Alzheimer’s Dementia Population

Apolipoprotein E gene (Apoε) has three common alleles (ε2, ε3, and ε4), of which ε4 has been shown to be associated with an increased risk for Alzheimer’s disease (AD). Possible additional genetic factors, like the −491A variant of ApoE promoter may modify the development of AD, independently of the ApoE allele status. The objective of this study was to investigate whether A/T allelic polymorphism at site−491 of the ApoE promoter is associated with AD in a Hungarian population. The genomic DNA isolated from peripheral blood lymphocytes of 52 late-onset AD and 53 control individuals was used as a template for the two examined polymorphisms and PCR assay was applied. The ε4 allele was significantly over-represented in the AD group (28%) as compared with the control population (7%). No significant differences have been found between the control and the AD populations regarding the occurrence of the promoter A allele frequencies (control: 77%, AD: 70%). However, the AA genotype was more frequent in the AD group (48%) than in the control (10%) when the presence of ε4 allele was also considered. It is unlikely therefore that the −491A variant of the ApoE promoter gene is an independent risk factor in the Hungarian AD population, but a linkage disequilibrium exists between the two examined mutations.     

Plasma levels of remnant particles are determined in part by variation in the APOC3 gene insulin response element and the APOCI-APOE cluster

Remnant particles of triglyceride-rich lipoproteins (RLP) are known to be a strong predictor of atherogenicity. The serum concentrations of remnant-like particle triglyceride (RLPTG) and remnant-like particle cholesterol (RLPC) have been determined in a representative sample of the Czech MONICA study (n = 285). The relationship was investigated between remnant particle triglyceride/cholesterol concentrations and polymorphisms in the genes APOC3 (-482C-->T/3238C-->G), APOE (epsilon2/epsilon3/epsilon4), APOCI (-317-321ins), APOB (signal peptide), hepatic lipase (LIPE, -480C-->T), and lipoprotein lipase (LPL, S447X). Univariate analysis showed significant effects on RLPTG associated only with the APOE genotype (P = 0.009), the APOC3 -482C-->T genotype (P = 0.018), and the APOCI -317-321ins (P = 0.014) genotype and significant effects on RLPC with APOE (P = 0.01) and APOCI -317-321ins (P = 0.021). The raising effect of the APOE genotype for both remnant cholesterol and triglyceride was confined to the epsilon2/4 (n = 6) and varepsilon4/4 (n = 3) groups, and thus when the epsilon2/4 group was omitted in order to analyze by allele (epsilon2+/epsilon3+/epsilon4+), significance was lost (P = 0.6). There was strong linkage disequilibrium between the APOE and APOCI alleles (chi(2), P < 0.001) and a multivariate ANOVA of RLPTG with all three significantly associated variants as factors demonstrated that while the APOC3 -482C-->T effect was independent of the others (P = 0.003), the APOCI -317-321ins and APOE effects were not. This was also true for the APOCI -317-321ins and APOE effects on RLPC. To assess whether APOE-CI effects on RLPC were independent of their effects on total cholesterol and triglyceride levels, multiple linear regression was used. Using multiple linear regression, it appeared that the APOE-CI effects on RLPC were independent of their effects on plasma cholesterol, but the effects of APOC3 and APOE-CI on RLPTG could not be separated from their effects on plasma Tg levels.Further characterization of this remnant particle phenotype and its genetic determinants may lead to a better understanding of its metabolism and contribution to atherosclerosis.     

新疆维吾尔族、汉族阿尔茨海默病Neprilysin基因单核苷酸多态性研究

摘要目的：探讨新疆地区维吾尔族、汉族脑啡肽酶（Neprilysin,NEP）基因单核苷酸多态性与阿尔茨海默病（Alzheimer’SdiseaseAD）的关系。方法：对新疆地区维吾尔族、汉族≥50岁8284名人群进行AD流行病学调查,参照ADRDA．NINCDS的标准,选取散发性阿尔茨海默病（sporadicAlzheimer’s disease,SAD）患者209例（AD组）与正常对照220例（对照组）,应用聚合酶链反应一限制性片段长度多态性技术（PCR）检测NEP基因多态性,采用病例一对照的关联分析方法对NEP基因rs3736187位点进行基因型和等位基因频率分析。结果：（1）新疆维吾尔族、汉族两民族AD组与对照组间NEP基因基因型频率和等位基因频率分布差异均有统计学意义（P〈0．05）。携带T等位基因个体出现AD的危险性高于携带c等位基因的个体（0R=1．981,P〈0．05）。（2）新疆维吾尔族、汉族不同民族之间比较NEP基因基因型频率和等位基因频率分布差异均无统计学意义（P〉0．05）,而在同一民族中AD组和对照组之间比较NEP基因等位基因频率分布差异均具有统计学意义（P〈0．05）。（3）两个年龄分段（〈65岁及≥65岁）之间NEP基因基因型频率和等位基因频率分布差异均无统计学意义（P〉0．05）,而在同一年龄段内部AD组与对照组间等位基因频率分布差异具有统计学意义（P〈0．05）。（4）男性、女性之间NEP基因基因型频率和等位基因频率分布差异均无统计学意义,而在女性AD组与对照组间等位基因频率分布差异有统计学意义（P〈0．05）。结论：NEP基因rs3736187位点基因型频率和等位基因频率在新疆维吾尔族、汉族两民族间的分布相似;NEP基因的T等位基因是SAD的危险因素,在新疆维吾尔族、汉族两民族及女性SAD的发病中起重要作用。     

Effects of apolipoprotein E genotype on blood lipid composition and membrane platelet fluidity in Alzheimer's disease.

The blood lipid composition (plasma, platelets and leukocytes), platelet membrane fluidity, apolipoproteins A and B in the plasma of AD patients and control subjects with distinct Apo E genotypes were investigated. No significant differences were found between the Apo E genotype and the cholesterol, phospholipids, triglycerides and Apo B levels in the plasma; cholesterol and phospholipids levels in platelet and leukocyte membranes; and platelet membrane fluidity of AD and control groups. However, the phospholipid levels in the leukocyte membranes of the control subgroup with the genotypes epsilon3/epsilon3 and epsilon3/epsilon4 and the AD subgroups with the genotypes epsilon2/epsilon3 and epsilon3/epsilon3, epsilon3/epsilon4 and epsilon4/epsilon4 were significantly lower than those observed in the control subgroup with the genotype epsilon2/epsilon3. Moreover, the cholesterol and phospholipid levels in the platelet membranes of the AD subgroup with the epsilon2 allele were significantly higher than those in the AD subgroup without the epsilon2 allele and the control subgroups with and without the epsilon2 allele. A strong correlation was found between cholesterol and phospholipids levels in the platelet membranes of the AD and control subgroups without the epsilon2 allele, but the residual cholesterol level in the platelet membranes of the AD subgroup was twice that observed in the control subgroup. Furthermore, the Apo A levels in the plasma of the AD subgroup with the epsilon3 allele were significantly lower than those observed in the AD subgroup without the epsilon3 allele and the control subgroup with the epsilon3 allele. The results are discussed in terms of involvement of lipid metabolism in the etiopathogenesis of AD.     

The association of a cystatin C gene polymorphism with late-onset Alzheimer's disease and vascular dementia

A polymorphism in the cystatin C (CST3) gene was suggested to associate with Alzheimer's disease (AD). In the present study we attempted to determine the association between CST3 polymorphism and AD or vascular dementia (VD), and whether such effects are dependent of the APOE4 allele. The polymorphisms of CST3 genotype were determined using polymerase chain reactions (PCR) followed by gel electrophoresis in 124 AD, 70 VD, and 115 control individuals. No statistical difference in CST3B allele frequencies was observed among all three groups. Associations between CST3B/B genotype and AD patients older than 75-year-old, or VD patients younger than 75-year-old were evident. The APOE4 allele alone significantly increased the odds for the developing AD, but not VD. A logistic regression analysis revealed that either CST3 or its interaction with APOE4 were not significant predictors of AD. However, a synergistic association of CST3 and APOE4 alleles was observed in predicting VD patients. These results suggest that CST3 might interact with APOE4 on conferring vascular pathologies.     

CYP17, SRD5A2, CYP1B1, and CYP2D6 gene polymorphisms with prostate cancer risk in North Indian population

To investigate the involvement of the CYP17, SRD5A2, CYP1B1, and CYP2D6 variants with prostate cancer, a case-control study of 100 patients and an equal number of age-matched control men was conducted. There appears to be a nonsignificant increase with risk of prostate cancer for individuals carrying one copy of the CYP17 A2 allele (OR, 1.80; 95% CI, 0.99-3.29, P=0.05). The risk was increased in individuals having two A2 alleles (OR; 2.81, 95% CI, 1.06-7.40, P=0.03). Compared with men having the VV genotype of SRD5A2 gene, there was no significant association between the VL genotype and the risk of prostate cancer (OR; 0.54, 95% CI; 0.29-1.03, P=0.06). There was no difference in the occurrence of the genotype LL between controls and prostate cancer patients (OR; 0.90, 95% CI; 0.43-1.89, P=0.79). There was a nonsignificant increased risk of prostate cancer for individuals carrying the CYP1B1Leu/Val genotype (OR, 1.70, 95% CI, 0.91-3.17, P =0.09), which was increased in those having the Val/Val allele (OR, 3.38; 95% CI, 1.13-10.07, P=0.02). Relative to men homozygous for the wild-type allele in CYP2D6 gene, those heterozygous for the B allele had an odds ratio of 1.78 (95% CI, 0.76-4.17, P=0.18) for patients, and for homozygous individuals, it was 1.95 (0.55-6.93, P=0.30). These observations have suggested that the CYP17 A2/A2, CYP1B1 Val/Val, and CYP2D6 genotypes may be associated with an altered risk of prostate cancer, while the CYP2D6 and SRD5A2 V89L polymorphism have no association with its risk in the North Indian population.     

ApoE genotype affects allele-specific apo[a] levels for large apo[a] sizes in African Americans: the Harlem-Basset Study

The genetic variability of apolipoprotein E (apoE) influences plasma lipoprotein levels, and allele frequencies differ between African Americans and Caucasians. As African Americans have higher lipoprotein [a] (Lp[a]) levels than Caucasians, we investigated the effects of the apoE gene on allele-specific apolipoprotein [a] (apo[a]) levels across ethnicity. We determined apo[a] sizes, allele-specific apo[a] levels (i.e., levels associated with alleles defined by size), and the apoE gene polymorphism in 231 African Americans and 336 Caucasians. African Americans, but not Caucasians, with the apo E2 genotype had lower levels of Lp[a] compared with those with the apo E4 genotype (9.6 vs. 11.2 nmol/l; P = 0.034, expressed as square root levels). Distribution of apo[a] alleles across apoE genotypes were similar between African Americans and Caucasians. Among African Americans with large apo[a], the allele-specific apo[a] level was significantly lower among epsilon2 carriers compared with epsilon3 or epsilon4 carriers (5.4 vs. 6.6 and 7.4 nmol/l, respectively; P < 0.005, expressed as square root levels). In contrast, there was no significant difference in allele-specific apo[a] levels across apoE genotypes among Caucasians. For large apo[a] sizes, apoE genotype contributed to the observed African American-Caucasian differences in allele-specific apo[a] levels.     

Influence of methylmalonyl-CoA mutase alleles on resistance to bovine tuberculosis in the European wild boar (Sus scrofa)

An association study was carried out to examine the influence of methylmalonyl-CoA mutase (MUT) polymorphisms on the susceptibility of a well-studied wild boar population from southern Spain to develop bovine tuberculosis (bTB). To this end, we examined polymorphisms at a closely linked dinucleotide microsatellite flanking exon 2 of the MUT gene in 37 wild boars with bTB and 36 non-infected individuals. The microsatellite showed low polymorphism in the studied population, with only three alleles (MUTm-A, MUTm-B and MUTm-C) found, in contrast to the 11 alleles previously reported for domestic pigs. Our case-control study showed that the MUTm-B allele was associated with disease in a dominant pattern (odds ratio = 3.36; 95% CI = 1.05-10.72; P = 0.04), while the MUTm AA genotype appeared to have a protective effect against bTB infection (odds ratio = 4.33; 95% CI = 1.20-14.96; P = 0.02). Interestingly, infected wild boars heterozygous for MUTm AB are at an advantage (11-fold) to contain the systemic spread of the disease when compared to other genotypes, implying that a balanced polymorphism may be present in the population. These results strengthen previous observations regarding the importance of the MUT gene on bTB resistance in wild boars and indicate that polymorphisms at this locus will influence the risk of acquiring and maintaining bTB in the studied population.     

Polymorphic gene markers of lipid metabolism are associated with diabetic nephropathy in patients with type 1 diabetes mellitus

In groups of type 1 diabetes mellitus patients with and without clinical signs of diabetic nephropathy (n = 62 and n = 68, respectively), a search was made for associations between diabetic nephropathy and the polymorphic marker epsilon2/epsilon3/epsilon4 of apolipoprotein E gene (APOE), I/D marker of apolipoprotein B gene (APOB), and Ser447Ter marker of lipoprotein lipase-encoding gene (LPL). The risk of diabetic nephropathy was higher in the carriers of allele epsilon3 and genotype epsilon3/epsilon3 of the polymorphic marker epsilon2/epsilon3/epsilon4 of APOE gene as well as in the carriers of allele 1 and APOB genotype/gene (OR = 2.08 and 2.16; 1.91 and 2.11, respectively). Conversely, the carriers of allele D showed a reduced risk of this complication (OR = 0.52). No significant differences in distribution of alleles and genotypes of the polymorphic marker Ser447Ter of LPL gene were found between the groups. Our results indicate that the genes encoding two major components of lipid metabolism are involved in the development of diabetic nephropathy in patients with type 1 diabetes mellitus.