Coro Sánchez-Quintana

Age-dependent association of KIBRA genetic variation and Alzheimer's disease risk.

An association between memory performance in healthy young, middle aged an elderly subjects and variability in the KIBRA gene (rs17070145) has been recently described. We analyzed this polymorphism in 391 sporadic Alzheimers disease (AD) patients and 428 cognitively normal control subjects. The current study reveals that KIBRA (rs17070145) T allele (CT and TT genotypes) is associated with an increased risk (OR 2.89; p=0.03) for very-late-onset (after the age of 86 years) AD.

Interaction between poly(ADP-ribose) polymerase 1 and interleukin 1A genes is associated with Alzheimer's disease risk.

Excessive release of proinflammatory cytokines by activated microglia surrounding senile plaques might contribute to the neurodegeneration associated with Alzheimer’s disease (AD). Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear protein recently implicated in the initial inflammatory response by modulating expression of inflammation-related genes, like interleukin 1 (IL-1). As PARP-1 overactivity has been shown in the AD brain, we tested the hypothesis that the PARP-1 –410 and –1672 polymorphisms would predispose people to AD due to overexpression of the PARP-1 gene, independently or in concert with the proinflammatory IL-1A –889 polymorphism. So, we performed a case-control study in 263 Spanish AD patients and 293 healthy controls. PARP-1 –410 and PARP-1 –1672 haplotypes were associated with an increased risk for AD (global haplotype association p value = 0.019), and, in addition, PARP-1 haplotypes increased the risk of AD by interaction with the IL-1A –889 allele 2.

Association of genetic variants of ABCA1 with Alzheimer's disease risk.

ABCA1 plays key roles in cholesterol transport and apolipoprotein E (APOE) metabolism in the brain. To evaluate the relationship between ABCA1 genetic variants and Alzheimers disease (AD), independently or in concert with the APOE ε4 allele, we examined three ABCA1 polymorphisms located in the coding region (R219K, I883M, and R1587K) and two ABCA1 polymorphisms in the promoter region (C−14T and C−477T) in a group of 372 Spanish AD patients and 440 controls. The ABCA1 219K, 883I, 1587R haplotype was significantly associated with AD, conferring a risk of 1.78 (P = 0.007). The ABCA1 C−14T polymorphism modified the risk of AD in an APOE ε4 allele‐dependent fashion: in APOE ε4 carriers, homozygous for the ABCA1 −14T allele had 3.7 times higher risk of developing AD (OR = 13.99) than carriers of the ABCA1 −14CC and CT genotypes (OR = 3.79). These data suggest that the development of AD might be influenced by either a qualitative change of the ABCA1 protein caused by coding region variants (219K, 883I, and 1587R), or by a quantitative change in ABCA1 expression caused by promoter region variant (−14T) in concert with the APOE ε4 allele.

Poly (ADP-ribose) polymerase-1 (PARP-1) genetic variants are protective against Parkinson's disease

Poly (ADP-ribose) polymerase-1 (PARP-1) is involved in crucial pathogenic events in Parkinsons disease (PD). We studied the effect of promoter variations of PARP-1 gene on the risk for PD in a case-control association study comprising 146 PD patients and 161 controls from Northern Spain. Three polymorphisms from the promoter region of PARP-1 gene were analyzed: -410C/T, -1672G/A, and a (CA)n microsatellite. A protective effect against PD was found for heterozygosity at (-410) (OR 0.44) and (CA)n microsatellite (OR 0.53) polymorphisms, and heterozygosity at (-1672) polymorphism delayed by 4 years on the onset age of PD. Variations in the regulatory region of PARP-1 gene might modify the risk for PD.

Inflammation‐related genes and the risk of Parkinson’s disease: a multilocus approach

For the first time, the multilocus approach by the set‐association method has been applied for the analysis of a cluster of five genes [tumor necrosis factor α (TNF‐α), interleukin 6 (IL‐6), IL‐8, IL‐1α and IL‐10] involved in the brain neuroinflammatory pathway in Parkinson’s disease (PD), in a well‐defined group of 197 PD patients and 173 control subjects from Spain. Set‐association analysis did not reveal an independent or an interactive effect of these inflammatory genes on the PD risk.

High frequency and reduced penetrance of LRRK2 G2019S mutation among Parkinson's disease patients in Cantabria (Spain).

The frequency and penetrance of the LRRK2 G2019S mutation varies considerably in different Parkinson disease (PD) populations. This information is essential both for clinical purposes and genetic counseling. The objective of this study was to estimate the prevalence and penetrance of the G2019S mutation of the LRRK2 gene in a small region in northern Spain (Cantabria). The G2019S mutation was tested in 367 consecutive patients with PD attended as outpatients in a tertiary Hospital in Northern Spain, and 126 at‐risk family members of probands were also investigated for G2019S mutation and disease status. The gene penetrance was estimated in terms of cumulative age‐specific incidence of PD by the Kaplan‐Meier method. Thirty‐two PD patients (8.7%) carried the G2019S mutation. Penetrance estimation of the G2019S mutation was 2% at 50 years, 12% at 60 years, 26% at 70 years, and 47% at 80 years. The frequency of the G2019S mutation of the LRRK2 gene in PD patients from Cantabria is among the highest reported so far after North African Arabs and Ashkenazi Jews. At the age of 80 years only one‐half of G2019S mutation carriers manifest motor symptoms of PD.

Case-control study of vascular endothelial growth factor (VEGF) genetic variability in Alzheimer's disease

Vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis and blood vessel function. Recent evidence indicates that VEGF facilitates memory and learning through stimulating angiogenesis and neurogenesis in the rat hippocampal dendate gyrus. Abnormal regulation of VEGF expression has been reported in the pathogenesis of both atherosclerosis and motoneuron degeneration in amyotrophic lateral sclerosis, with low VEGF-producing polymorphisms (-2578 allele A and -634 allele G) conferring increased susceptibility for the development of the disorders. We tested whether these polymorphisms downregulating expression of VEGF might increase the risk of developing Alzheimers disease (AD). So, we performed a case-control study in 362 Spanish AD patients and 428 healthy controls. The current study does not demonstrate an association between VEGF (-2578) and VEGF (-634) genotypes or haplotypes and AD.

Glycogen synthase kinase‐3β and tau genes interact in Parkinson's and Alzheimer's diseases

Gao and coworkers’ article linking hair color to risk for Parkinson’s disease (PD) is of great interest. I have proposed elsewhere that the role of pigmentation genes in influencing the risk for development of apparently unrelated disorders, such as melanoma and PD, merits deep investigation. For PD, where the pathology is focused on heavily pigmented neurons in substantia nigra, epidemiological evidence points to a greater occurrence of melanoma among PD patients. There is a common embryological origin of cells targeted by both diseases, the centrality of L-DOPA in melanin and dopamine synthesis, and the plausible suspicion that variations in pigmentation genes, particularly in tyrosinase, could increase the risk for both diseases. If a relation between PD and melanoma is confirmed, it may be possible to predict a greater risk for PD (and melanoma) based on pigmentationrelated characteristics. With such a risk factor in hand, interventions for PD could be targeted and applied early in life. Comparable mechanisms could act also in other neurodegenerative diseases: in amyotrophic lateral sclerosis, an increase in melanomas has already been reported; a retinal pigmentary retinopathy has long been observed in Guamanian amyotrophic lateral sclerosis/PDC (Parkinson Dementia Complex), and variants on TRPM7 (Transient Receptor Potential (Channel) Melastatin 7) and TRPM2, which intriguingly are members of the Melastatin family, have been found in a subgroup of these patients. The so-called pigmentation genes are, in fact, pleomorphic, such that neurodegeneration could be facilitated in some pigmentation variants existing in the population, presumably in individuals with greater levels of pheomelanin in pigmented cells. This line of reasoning opens the exciting possibility of investigating neurodegeneration through the study of epithelial pigmentation. Melanocytes are readily cultured, even from hair follicles, thus providing an accessible model for intense laboratory investigation.

Interaction between CD14 and LXRβ genes modulates Alzheimer's disease risk

A chronic inflammatory process with activation of microglial cells contribute to the neurodegeneration associated with Alzheimers disease (AD). CD14 and LXRbeta are receptors involved in the regulation of inflammatory responses of microglia in response to bacterial infection or lipopolysaccharide stimulation. In a case-control study in 266 AD patients and 273 healthy controls, we examined whether the combined gene effects between CD14 (-260) polymorphism and LXRbeta (intron 5) polymorphism might be responsible for susceptibility to AD. Subjects carrying both the CD14 (-260) C/C and the LXRbeta (intron 5) G/G genotypes had a six times lower risk of developing AD than subjects without these risk genotypes (OR 0.16, 95% CI 0.04-0.67, p=0.01). These data support a role for innate immune response genes in risk for AD.

No association between low density lipoprotein receptor genetic variants and Alzheimer's disease risk†

A number of studies suggest that brain cholesterol metabolism may play a role in Alzheimers disease (AD) development, probably through modulation of amyloid beta production. The discovery that apolipoprotein E (APOE) ε4 allele is a risk factor for sporadic AD raises the possibility that the receptors to which APOE binds on the surface of neurons are also involved in the neurodegenerative process. To evaluate the relationship between low density lipoprotein receptor (LDLR) genetic variant and AD, independently or in concert with the APOE ε4 allele, we examined three LDLR polymorphisms located in exons 8 (rs 11669576), 10 (rs 5930), and 13 (rs 5925), in a large group of 322 Spanish AD patients and 314 controls. The current study does not demonstrate an association between LDLR genotypes or haplotypes and AD, neither in the total sample nor when the populations were stratified for the presence or absence of the APOE ε4 allele.