Non-carriers Of Allele Research Articles

Genetic diagnostics of functional variants of the human dopamine D2 receptor gene

The importance of dopamine D2 receptors (DRD2) for central nervous dopaminergic signalling makes variants in the DRD2 gene potential modulators of the risk or course of various behavioural, psychiatric or neurologic diseases (e.g. addiction, schizophrenia, Parkinson's disease). We developed Pyrosequencing genetic screening assays for single nucleotide polymorphisms spanning the whole range of the DRD2 gene locus up to the functionally related ankyrin repeat and kinase domain containing 1 gene (ANKK1) located at approximately 10 kb downstream of DRD2. Assays for 11 genetic variants with reported functional association were developed in DNA samples from 300 unrelated healthy Caucasians and validated by independent conventional sequencing. In all DNA samples the DRD2/ANKK1 genetic variants were identified correctly as verified by the control samples. The observed frequencies of homozygous, heterozygous and noncarriers of the minor alleles were in agreement with the Hardy-Weinberg equilibrium. Observed minor allele frequencies were DRD2 rs12364283T>C: 6.5%, rs1799978A>G: 4.8%, rs1799732C del: 14.2%, rs4648317C>T: 12.8%, rs1079597G>A: 13.8%, rs1076560G>T: 14.5%, rs1800496C>T: 0.2%, rs1801028C>G: 3.0%, rs6275C>T: 32.7%, rs6277C>T: 53.0% and ANKK1 rs1800497C>T: 17.5%. The presently developed Pyrosequencing assays are provided to facilitate further research toward personalized approaches to pathophysiological conditions involving behavioural, psychiatric and neurologic disorders including addiction, schizophrenia and Parkinson's disease.

Temporal lobe functional activity and connectivity in young adult APOE ɛ4 carriers

Background We sought to determine if the APOE ε4 allele influences both the functional activation and connectivity of the medial temporal lobes (MTLs) during successful memory encoding in young adults. Methods Twenty-four healthy young adults, i.e., 12 carriers and 12 noncarriers of the APOE ε4 allele, were scanned in a subsequent-memory paradigm, using event-related functional magnetic resonance imaging. The neuroanatomic correlates of successful encoding were measured as greater neural activity for subsequently remembered versus forgotten task items, or in short, encoding success activity (ESA). Group differences in ESA within the MTLs, as well as whole-brain functional connectivity with the MTLs, were assessed. Results In the absence of demographic or performance differences, APOE ε4 allele carriers exhibited greater bilateral MTL activity relative to noncarriers while accomplishing the same encoding task. Moreover, whereas ε4 carriers demonstrated a greater functional connectivity of ESA-related MTL activity with the posterior cingulate and other peri-limbic regions, reductions in overall connectivity were found across the anterior and posterior cortices. Conclusions These results suggest that the APOE ɛ4 allele may influence not only functional activations within the MTL, but functional connectivity of the MTLs to other regions implicated in memory encoding. Enhanced functional connectivity of the MTLs with the posterior cingulate in young adult ε4 carriers suggests that APOE may be expressed early in brain regions known to be involved in Alzheimer's disease, long before late-onset dementia is a practical risk or consideration. These functional connectivity differences may also reflect pleiotropic effects of APOE during early development.

Dementia: Predicting its risk, APOE effects and disclosure of APOE genotype

All of us—even neurologists—face a considerable risk of developing dementia. Since there is no causative treatment for most forms of dementia and only limited symptomatic therapy, it is very important to identify risk factors for dementias so that possible prophylactic treatment can be given. The first article presented in this month’s Journal Club deals with the analysis of possible risk factors for the development of late-life dementia. The risk factors range from a too low body mass index to lack of alcohol consumption. This sounds like a great relief for most of us and makes reading this article even more worthwhile. The second article deals with longitudinal modelling of agerelated memory decline and the APOE effect in homozygous and heterozygous APOE e4 allele carriers versus non-carriers. In the final article, the psychological and psychiatric consequences of disclosure of the APOE genotype for risk of Alzheimer’s disease are analysed. All these articles are of clinical relevance, in particular due to the increasing age of most populations and the consequent increased risk of the development of different types of dementia.

APOE dependent-association of PPAR-γ genetic variants with Alzheimer's disease risk

The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a ligand-inducible transcription factor that suppresses microglial inflammatory responses and inhibits amyloid beta (Aβ) production through promoting cholesterol efflux from glial cells. PPAR-γ agonists have been advanced as a new disease altering approach to Alzheimer's disease (AD), with rosiglitazone therapy having improved cognition in those AD patients that did not possess an Apolipoprotein E (APOE) ε4 allele. The current study was designed to explore the effect of interactions between PPAR-γ and APOE gene polymorphisms on the AD risk. We examined genetic variations of PPAR-γ by genotyping 7 haplotype tagging SNPs (htSNPs) (rs10510412, rs17793951, rs1801282, rs4135263, rs1151999, rs709149, and rs709154) in a group of 352 Spanish late-onset AD cases and 438 controls. The PPAR-γ TCCA haplotype derived from SNPs in introns 4 (rs4135263), 5 (rs1151999), and 6 (rs709149 and rs709154) showed a strong protective effect against AD in APOE ε4 allele noncarriers (p=0.001, permutation p=0.006, Bonferroni corrected p=0.021), with a frequency of 39% in cases and 50% in controls. Our data suggest that PPAR-γ genetic variants may modify the risk of AD in an APOE ε4 allele-dependent fashion.

Genetic variation in apolipoprotein E alters regional gray matter volumes in remitted late-onset depression

Background The apolipoprotein E (ApoE) gene has been confirmed as the major genetic risk factor for late-onset Alzheimer's disease (AD). The effect of ApoE polymorphism on brain morphology still remains unclear in remitted late-onset depression (RLOD). Methods A total of 37 patients with remitted geriatric depression were investigated with optimized voxel-based morphometry. We tested for differences in gray matter volume between ApoE ε4 allele noncarriers ( n = 25) and ApoE ε4 allele carriers ( n = 12) in RLOD patients. Results The volumes of right medial frontal gyrus, left middle frontal gyrus and left inferior occipital gyrus were significantly smaller in RLOD patients with ApoE ε4 allele carriers as compared to ApoE ε4 allele noncarriers. There was a significant positive correlation between gray matter volume of right medial frontal gyrus and Digit Span Test score in RLOD patients with ApoE ε4 allele carriers. Limitations This study is cross-sectional, therefore it cannot determine whether abnormal gray matter volume is a state marker or trait marker of RLOD with ApoE ε4 allele carriers. Conclusion Our findings support the hypothesis that the ApoE genotype might be associated with structural changes in RLOD.

Single Nucleotide Polymorphisms and the Likelihood of Prostate Cancer at a Given Prostate Specific Antigen Level

Prostate specific antigen is used for prostate cancer screening but its specificity is limited. Specificity might be increased by considering genotype associated prostate specific antigen levels. We examined associations between single nucleotide polymorphisms on chromosomes 10 and 19 (previously shown to be associated with prostate specific antigen) with prostate specific antigen and prostate cancer in 505 men from the Baltimore Longitudinal Study of Aging. In a model with age and date the risk ratio for prostate cancer was 1.18 (95% CI 1.13-1.23) per unit increase in prostate specific antigen. Including the interaction between alleles and prostate specific antigen significantly altered the risk ratio for prostate cancer (Cox proportional hazards p <0.001). Specifically prostate cancer risk per unit increase in prostate specific antigen was significantly different in carriers than in noncarriers of a minor allele (1.28 vs 1.10, respectively, Cox proportional hazards p <0.001), whereas men with a minor allele had a significantly higher risk of prostate cancer at prostate specific antigen levels greater than 6 ng/ml. Our data suggest that genotype influences the risk of prostate cancer per unit increase in prostate specific antigen. Prostate cancer risk stratification using prostate specific antigen and genotype could improve prostate specific antigen test performance.

Pathological Outcomes Associated With the 17q Prostate Cancer Risk Variants

Recent studies have identified 2 distinct genetic variants along chromosome 17, including allele T of single nucleotide polymorphism rs4430796 on 17q12 and allele G of single nucleotide polymorphism rs1859962 on 17q24, that have been linked to prostate cancer risk. Less is known about tumor pathological features in carriers of these variants. Genotypes for regions 17q12 and 17q24 were determined in 759 white men with prostate cancer and compared to those in 790 healthy control volunteers using logistic regression. In patients with prostate cancer the Fisher exact or Kruskal-Wallis test was used as appropriate to assess the relationship(s) between clinical and pathological characteristics with 17q carrier status. The frequency of the 17q12 and 17q24 genetic variants was significantly higher in patients with prostate cancer compared to that in controls (OR 1.32, 1.15, respectively). Of patients with prostate cancer 83% and 77% were carriers of the 17q12 and 17q24 variants as well as 75% and 75% of controls, respectively. Carriers of 17q12 risk variants were significantly more likely to have high grade disease using an additive best fit genetic model. In addition, there were trends toward adverse pathological features associated with 17q12 independent of the best fit genetic model. Sequence variants along 17q12 and 17q24 were present in a significantly higher proportion of our prostate cancer cases than in our controls. Adverse pathological features, including higher Gleason grade and pathological stage, were more frequent in 17q12 carriers. Since these alleles may act in conjunction with variants on other chromosomes to influence prostate cancer risk, additional research is required to determine the cumulative associations of genetic risk variants with prognosis.

Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease

To examine the influence of the APOE genotype on levels of beta-amyloid (Abeta) plaque load and atrophy in patients with Alzheimer disease (AD) in vivo. Thirty-two patients with moderate AD were divided into carriers and noncarriers of the epsilon4 allele. These groups were matched for age, disease duration, education, and cognitive impairment. In all subjects, [11C]PIB-PET was performed for measurement of cerebral Abeta plaque deposition and cranial MRI for the assessment of gray matter volume by voxel-based morphometry (VBM) and for correction of partial volume effects (PVE) in the PET data. Voxel-based comparisons (SPM5) were performed between patient groups and healthy control populations and completed with multiple regression analyses between imaging data and epsilon4 allele frequency. Compared to controls, AD-typical patterns of [11C]PIB retention and atrophy were detected in both epsilon4-positive and epsilon4-negative patient groups. In direct comparison, significantly stronger and more extended [11C]PIB uptake was found in epsilon4-positive patients in bilateral temporoparietal and frontal cortex, surviving PVE correction. VBM analysis demonstrated comparable levels of atrophy in both patient groups. Regression analyses revealed a linear association between higher epsilon4 allele frequency and stronger temporoparietal Abeta plaque deposition, independently of other confounds. No major correlation between epsilon4 allele frequency and gray matter decrease was observed. These results indicate that the epsilon4-positive APOE genotype not only represents a risk factor for Alzheimer disease (AD), but also results in higher levels of Abeta plaque deposition in epsilon4-positive patients with AD compared to age-matched epsilon4-negative patients with similar levels of cognitive impairment and brain atrophy. The potential role of Abeta plaque imaging for patient inclusion and follow-up in anti-amyloid therapy trials is strengthened by these findings.

Cytochrome P-450 Polymorphisms and Response to Clopidogrel

Conclusion: Persons with a reduced function of the CYP2C19 allele have significantly lower levels of active metabolite of clopidogrel, with diminished platelet inhibition and higher rates of major cardiovascular events than noncarriers of the CYP2C19 allele. Summary: Clopidogrel is a thienopyridine inhibitor of the platelet P2Y12 adenosine diphosphate (ADP) receptor. It is a “prodrug” that requires biotransformation to an active metabolite by a cytochrome P-450 enzyme. Esterases shunt most of clopidogrel to an inactive pathway, with the remaining prodrug requiring two separate CYP-dependent oxidative steps. Genes encoding CYP enzymes are polymorphic, with some alleles conferring reduced enzymatic function. Therefore, it is possible CYP polymorphisms can effect conversion of clopidogrel to active metabolite and hence affect the degree of clopidogrel induced platelet inhibition. In this study the authors tested the association between functional variance in CYP genes, plasma concentration of active clopidogrel drug metabolite, and platelet inhibition in response to clopidogrel. There were 162 healthy subjects analyzed as well as 1477 individuals with acute coronary syndromes treated with clopidogrel in a trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition in patients with myocardial infarction (TRITON-TIMI 38). Approximately 30% of the healthy participants were carriers of at least one CYP2C19 reduced-function allele. These individuals had a reduction of 32.4% in plasma exposure to the active metabolite of clopidogrel compared with noncarriers (P < .001). Carriers also had reduced reduction in maximal platelet aggregation compared with noncarriers (P < .001). Among clopidogrel-treated patients in TRITON-TIMI 38, carriers of reduced-function alleles had a relative increase of 53% in the composite primary end point of death due to cardiovascular causes, myocardial infarction, or stroke compared with noncarriers (12.1% vs 8%; hazard ratio [HR] for carriers, 1.53; 95% confidence interval [CI] 1.07-2.19; P = .01). Carriers had an increase by a factor of three in the risk of stent thrombosis (2.6% vs 0.8%; HR, 3.09; 95% CI, 1.19-8.00; P = .02). Comment: This study, along with the similar study also appearing in the same issue of the New England Journal of Medicine (2009;360:363-75), provides strong evidence linking genetic variations in CYP genes to reduced exposure to active drug metabolite in patients treated with clopidogrel. These polymorphisms are seen in approximately 30% of white patients, 40% of African Americans, and >55% of people of East Asian origin. Of course multiple other genetic and environmental factors can also contribute to platelet aggregation. Nevertheless, the data are quite convincing that genetic variation in the genes encoding CYP enzymes can result in meaningful and profound clinical effects.

Association study of TRAF1-C5 polymorphisms with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in Japanese

Objective:The primary aim of this study was to investigate the association of polymorphisms of TRAF1-C5, a newly identified rheumatoid arthritis (RA) risk locus in Caucasians, with susceptibility to RA and...

Dopamine DRD2 Polymorphism Alters Reversal Learning and Associated Neural Activity

In humans, presence of an A1 allele of the DRD2/ANKK1-TaqIa polymorphism is associated with reduced expression of dopamine (DA) D(2) receptors in the striatum. Recently, it was observed that carriers of the A1 allele (A1+ subjects) showed impaired learning from negative feedback in a reinforcement learning task. Here, using functional MRI (fMRI), we investigated carriers and noncarriers of the A1 allele while they performed a probabilistic reversal learning task. A1+ subjects showed subtle deficits in reversal learning. In particular, these deficits consisted of an impairment in sustaining the newly rewarded response after a reversal and in a generally decreased tendency to stick with a rewarded response. Both genetic groups showed increased fMRI signal in response to negative feedback in the rostral cingulate zone (RCZ) and anterior insula. Negative feedback that incurred a change in behavior additionally engaged the ventral striatum and a region of the midbrain consistent with the location of dopaminergic cell groups. The response of the RCZ to negative feedback increased as a function of preceding negative feedback. However, this graded response was not observed in the A1+ group. Furthermore, the A1+ group also showed diminished recruitment of the right ventral striatum and the right lateral orbitofrontal cortex (lOFC) during reversals. Together, these results suggest that a genetically driven reduction in DA D(2) receptors leads to deficient feedback integration in RCZ. This, in turn, was accompanied by impaired recruitment of the ventral striatum and the right lOFC during reversals, which might explain the behavioral differences between the genetic groups.

Polyunsaturated Fatty Acids Modulate the Effect of TCF7L2 Gene Variants on Postprandial Lipemia

The transcription factor 7-like 2 (TCF7L2) has been recently associated with diabetes risk, and it may exert its effect through metabolic syndrome (MetS)-related traits and be subjected to modification by environmental factors. We investigated the effect of single nucleotide polymorphisms (SNP), rs7903146 and rs12255372, within the TCF7L2 locus on postprandial lipemia and other MetS-related traits and their modulation by dietary fat. Data were collected from 1083 European Americans participating in the Genetics of Lipid Lowering Drugs and Diet Network Study. Carriers of the minor T allele at the C/T rs7903146 SNP had higher fasting plasma glucose (P = 0.012), lower homeostasis model assessment of β cell function (P = 0.041), higher plasma VLDL (P = 0.035), and lower large LDL particle (P = 0.007) concentrations and higher risk of MetS (P = 0.011) than CC individuals. Moreover, we identified significant interactions between this SNP and PUFA intake modulating fasting VLDL particle concentrations (P = 0.016) and postprandial triglycerides (TG) (P = 0.028), chylomicrons (P = 0.025), total VLDL (P = 0.026), and large VLDL (P = 0.018) concentrations. Thus, only T allele carriers with a PUFA intake ≥7.36% of energy had elevated fasting plasma VLDL concentrations and postprandial TG-rich lipoproteins. These variables did not differ in T allele carriers and noncarriers in the low-PUFA intake group. Moreover, these significant interactions were due exclusively to (n-6) PUFA intake. In summary, high (n-6) PUFA intakes (≥6.62% of energy intake) were associated with atherogenic dyslipidemia in carriers of the minor T allele at the TCF7L2 rs7903146 SNP and may predispose them to MetS, diabetes, and cardiovascular disease.

Apolipoprotein E ε4 is associated with disease-specific effects on brain atrophy in Alzheimer's disease and frontotemporal dementia

Apolipoprotein epsilon4 (apoE4) has been strongly linked with Alzheimer's disease (AD) and contributes to several other neurological disorders. We investigated the influence of epsilon4 allele carrier status on the pattern of gray matter atrophy and disease severity in 51 patients with probable AD and 31 patients with behavioral variant frontotemporal dementia (bvFTD), compared with 56 healthy controls. Voxel-based morphometry was performed by using statistical parametric mapping. The epsilon4 allele frequency was higher in the AD group (P < 0.001) than the controls but not in the bvFTD group. No differences in demographic or cognitive profiles were observed between epsilon4 allele carriers and noncarriers within any of the diagnostic groups. However, epsilon4 carrier status was associated with more severe brain atrophy in disease-specific regions compared with noncarriers in both AD and bvFTD. AD epsilon4 carriers showed greater atrophy in the bilateral parietal cortex and right hippocampus, and bvFTD epsilon4 carriers demonstrated greater atrophy in the bilateral medial, dorsolateral, and orbital frontal cortex, anterior insula, and cingulate cortex with right predominance. This regional epsilon4 effect is consistent with the hypothesis that apoE may affect the morphologic expression uniquely in different neurodegenerative diseases. The atrophy patterns in epsilon4 carriers may indicate that they are at greater risk for clinical progression.

Association of CETP polymorphisms with the risk of vascular dementia and white matter lesions

Cholesteryl ester transfer protein (CETP), a component of the high density lipoprotein (HDL), plays a central role in reverse cholesterol transport. We investigated the association of two putative functional CETP polymorphisms (C-629A and I405V) with the risk of vascular dementia (VD) and tested if this association is influenced by the presence of APOE4 allele. Our study included 163 VD patients (mean age: 74.25 +/- 7.9 years) and 452 cognitively healthy probands (mean age: 70.81 +/- 7.9 years). As a biological correlate, the association of CETP gene variants with white matter lesion (WML) load was investigated. Neither the C-629A (P = 0.169) nor the I405V (P = 0.840) polymorphism was associated with VD risk in the whole sample. However, in non-carriers of the APOE4 allele, homozygote carriers of the CETP C-629A A allele presented with an increased risk of VD (P = 0.01). Whereas in APOE4 carriers, no association of CETP polymorphisms with VD risk was detected. In addition, carriers of the CETP C-629A AA genotype presented with decreased WML load in the frontal brain (P = 0.009). Our results suggest that CETP gene polymorphisms might influence WML load and the risk of VD, the latter in non-carriers of the APOE4 allele.

Mapping the effect of APOE ε4 on gray matter loss in Alzheimer's disease in vivo

Previous studies suggest that in Alzheimer's disease (AD) the Apolipoprotein E ( APOE) ε4 allele is associated with greater vulnerability of medial temporal lobe structures. However, less is known about its effect on the whole cortical mantle. Here we aimed to identify APOE-related patterns of cortical atrophy in AD using an advanced computational anatomy technique. We studied 15 AD patients carriers (ε4+, age: 72 ± 10 SD years, MMSE: 20 ± 3 SD) and 14 non-carriers (ε4−, age: 69 ± 9, MMSE: 20 ± 5) of the ε4 allele and compared them to 29 age-and-sex matched controls (age: 70 ± 9, MMSE: 28 ± 1). Each subject underwent a clinical evaluation, a neuropsychological battery, and high-resolution MRI. UCLA's cortical pattern matching technique was used to identify regions of local cortical atrophy. ε4+ and ε4− patients showed similar performance on neuropsychological tests ( p > .05, t-test). Diffuse cortical atrophy was detected for both ε4+ ( p = .0001, permutation test) and ε4− patients ( p = .0001, permutation test) relative to controls, and overall gray matter loss was about 15% in each patients group. Differences in gray matter loss between carriers and non-carriers mapped to the temporal cortex and right occipital pole (20% greater loss in carriers) and to the posterior cingulate, left orbitofrontal and dorsal fronto-parietal cortex (5–15% greater loss in non-carriers). APOE effect in AD was not significant ( p > .74, ANOVA), but a significant APOE by region (temporal vs fronto-parietal cortex) interaction was detected ( p = .002, ANOVA), in both early and late-onset patients ( p < .05, ANOVA). We conclude that the ε4 allele modulates disease phenotype in AD, being associated with a pattern of differential temporal and fronto-parietal vulnerability.

Association study of the IL18RAP locus in three European populations with coeliac disease

Coeliac disease is caused by dietary gluten, triggering a chronic inflammation of the small intestine in genetically predisposed individuals. Recently, a risk locus on chromosome 2q11-q12, harbouring interleukin 18 receptor accessory protein (IL18RAP) and three other genes, was suggested for coeliac disease. IL18 has been shown to play an important role in T helper type 1 activity in coeliac disease, making this locus a highly interesting candidate. In this study, two previously indicated risk variants at the IL18RAP locus (rs13015714 and rs917997) were tested for genetic association in 1638 cases with coeliac disease and 1385 control individuals from the Finnish, Hungarian and Italian populations. The protein expression level of IL18RAP was also compared between risk allele carriers and non-carriers by Western blotting. Furthermore, immunohistochemical analysis was performed to study IL18RAP protein expression in small intestinal biopsies of untreated and treated coeliac patients and controls. We confirmed genetic association and dose effects of variants at the 2q12.1 locus with coeliac disease in the Hungarian population. The GA haplotype of the markers rs13015714 and rs917997 showed the strongest association (P = 0.0001, odds ratio = 1.475, 95% confidence interval 1.21-1.80). Two putative isoforms of IL18RAP were detected and the ratios and total levels of these isoforms may contribute to the aetiology of coeliac disease. Our study supports IL18RAP as a novel predisposing gene for coeliac disease and highlights the need for further functional studies on this relatively unknown gene in coeliac disease pathogenesis.

The polymorphism Arg585Gln in the gene of the sterol regulatory element binding protein-1 (SREBP-1) is not a determinant of ketosis prone type 2 diabetes (KPD) in Africans

Aim Ketosis prone type 2 diabetes (KPD) is an atypical form of diabetes described mainly in people of sub-Saharan African origin. Its pathogenesis is unknown, although we have previously described a high prevalence of glucose-6-phosphate-dehydrogenase (G6PD) deficiency in patients with KPD. However, 50% of these deficient patients lacked the G6PD gene mutation. The isoforms of the transcription factor sterol regulatory element binding protein 1 (SREBP-1) are known to stimulate G6PD gene expression, and some polymorphisms in the SREBP-1 gene ( SREBF-1) have been described only in Africans. We investigated one of these, the Arg585Gln polymorphism, in a candidate gene approach for KPD. Methods We examined the presence of the Arg585Gln polymorphism in SREBF-1 in 217 consecutive unrelated Africans [73 patients with KPD, 80 with classical type 2 diabetes (T2D) and 64 nondiabetic subjects]. Patients underwent clinical and biochemical evaluations, and were assessed for G6PD activity and insulin secretion (glucagon test). Results There were no differences in frequency of the Arg585Gln polymorphism and the 585Gln allele among the three groups (allele frequency: KPD: 0.089, T2D: 0.031, nondiabetic group: 0.070; P = 0.1). When the 585Gln allele frequency was compared separately between patients with KPD and those with T2D, it was significantly higher in the former ( P = 0.032). There was no difference between carriers and noncarriers of the 585Gln allele regarding G6PD activity and insulin secretion. Conclusion The results of this exploratory study show that the polymorphism Arg585Gln in SREBF-1 is not associated with the KPD phenotype. Further studies in larger populations are needed to confirm our findings.

Apolipoprotein E Polymorphism and Brain Morphology in Mild Cognitive Impairment

Background: The apolipoprotein E (ApoE) genotype has been confirmed as the major genetic risk factor for late-onset Alzheimer’s disease (AD). How the ApoE genotype and brain morphology relate to each other is only partly understood, particularly in mild cognitive impairment, the assumed prestage of AD. Methods: A total of 83 subjects with mild cognitive impairment (aging-associated cognitive decline criteria) were investigated with optimized voxel-based morphometry (VBM). We tested for differences in gray and white matter densities between groups according to their ApoE status, i.e. Ε4 allele noncarriers (n = 42), subjects with one Ε4 allele (n = 27) and subjects with two Ε4 alleles (n = 14). Results: In individuals carrying two Ε4 alleles, VBM revealed a decline in gray matter density predominantly in the medial temporal lobe region. Subjects with a single copy of the Ε4 allele exhibited gray matter atrophy in the right inferior frontal gyrus. With respect to white matter changes, atrophy was only found in subjects homozygous for Ε4 and confined to the right superior and middle temporal gyrus. Conclusion: Our findings support the hypothesis that the ApoE genotype in mild cognitive impairment might be associated with structural changes typically found in the early stages of AD.

Better Memory Functioning Associated With Higher Total and Low-Density Lipoprotein Cholesterol Levels in Very Elderly Subjects Without the Apolipoprotein e4 Allele

To examine the association of cholesterol with cognitive functioning in oldest old community dwelling individuals with and without the apolipoprotein e4 (APOE4) allele. One hundred eighty-five nondemented, community dwelling individuals (>or=85) were assessed with a broad neuropsychological battery. Bloods were drawn to assess total, low-density lipoprotein (LDL), and high-density lipoprotein cholesterol, as well as for APOE genotyping. In contrast to our expectations, high total cholesterol and high LDL cholesterol were associated with higher memory scores for noncarriers of the APOE4 allele. No significant associations between cognitive performance and lipid profile were found for carriers of the APOE4 allele. In oldest old nondemented noncarriers of the APOE4 allele, high cholesterol is associated with better memory function. Further examination of the role of APOE genotype on the association between cholesterol and cognitive performance, especially in the oldest old is warranted.

MHC loci affecting cervical cancer risk: distinguishing the effects of HLA-DQB1 and non-HLA genes TNF, LTA, TAP1 and TAP2

Cervical cancer has been associated with specific human leukocyte antigen (HLA) haplotypes/alleles and with polymorphisms at the nearby non-HLA loci TNF, LTA, TAP1 and TAP2. Distinguishing effects of individual loci in the major histocompatibility complex (MHC) region are difficult due to the complex linkage disequilibrium (LD) pattern characterized by high LD, punctuated by recombination hot spots. We have evaluated the association of polymorphism at HLA class II DQB1 and the TNF, LTA, TAP1 and TAP2 genes with cervical cancer risk, using 1306 familial cases and 288 controls. DQB1 was strongly associated; alleles *0301, *0402 and (*)0602 increased cancer susceptibility, whereas *0501 and *0603 decreased susceptibility. Among the non-HLA loci, association was only detected for the TAP2 665 polymorphism, and interallelic disequilibrium analysis indicated that this could be due to LD with DQB1. As the TAP2 665 association was seen predominantly in non-carriers of DQB1 susceptibility alleles, we hypothesized that TAP2 665 may have an effect not attributable to LD with DQB1. However, a logistic regression analysis suggested that TAP2 665 was strongly influenced by LD with DQB1. Our results emphasize the importance of large sample sizes and underscore the necessity of examining both HLA and non-HLA loci in the MHC to assign association to the correct locus.