No association between α2-macroglobulin DNA polymorphism and Italian sporadic Alzheimer's disease

Poster Presentation: Genetic Studies II

s104

NO

ASSOCIATION

BETWEEN

POLYMORPHISM

AND

a2-MACROGLOBULIN

ITALIAN

DNA

SPORADIC

ALZHEIMER

S

Paolo

Univ of Florencr.

DISEASE Benedetta Florence Bianca

Nacmias,

Andrea

Italy; Antonio Maria

Guamieri.

Univ of Flowwe,

Tedde,

Orlacchio, Cam

Florence

Elenu

Crilinr,

Univ of Pert@, di Cum

Forleo,

Peru,&

Villa Serena,

Italy; Concettu

Pescara

Italy;

Petruzzi.

Sundro

Sorbi.

Italy

In 1998

Blacker et al. reported a significant association between the u2macroglobulin gene (A2M) polymorphism corresponding to a deletion near the 5 splice site of exon 18 and Alzheimer’s disease patients. a2-macroglobulin is a serum proteinase inhibitor codified by the A2M gene on chromosome 12 that has recently been reported to be associated with late onset Alzheimer’s disease (LOAD). A2M is present in senile plaques and may play a role in metabolism of amyloid beta peptide. A 5 bp deletion/insertion polymorphism and an IlelOOOVal polymorphism at the A2M gene have been identified as potential susceptibility markers for LOAD. In order to analyse a possible correlation between two polymorphisms and Italian sporadic Alzheimer’s disease (AD) we have studied the segregation of the deletion polymorphism in 74 AD (mean age at onset 66.64 ? 8.2) sporadic subjects and 68 controls and the IlelOMlVal polymorphism in 88 AD patients (mean age at onset 66.53 i- 8.2) and 82 controls. We did not find statistically significant differences m the distribution either of the deletion/insertion polymorphism or the A2M IlelOMlVal polymorphism in the AD group respect to controls. Moreover a stratification of our data on individual ApoE ~4 dose revealed that AD patients, within the ApoE ~4 carrier group did not show statistically significant differences with respect to ~4 not carriers in relation to allele frequencies. We failed to detect an allelic association between polymorphisms in the A2M gene, such as the 5 bp deletion/insertion polymorphism and the IlelCOOVal polymorphism of the A2M gene, and sporadic Alzheimer’s disease. Our data do not support a role for the A2M gene as genetic risk factor for Alzheimer’s disease.

ETHNICITY-DEPENDENT D C224T Melissa Institute, Tampa,

.I Freeman, Tampa,

Roskamp

FL;

ASSOCIATION

POLYMORPHISM

Ranjan

Institute, Duara.

WITH Tampa.

OF THE

ALZHEIMER’S FL:

Fiona

Mike Gold. Michael

CATHEPSIN DISEASE

Crawford. Mullun,

The Roskamp

Roskarnp

Institute,

FL

We have investigated the contradictory reports of a genetic association between AlLheimer’s Disease (AD) and the alanine+valine variant in rxon 2 of the Cathepsm D gene (CATD) in a population of clinic and community-based Alrheimer’s cases and community-based controls. Cathepsin D, which is an a~partyl protease, had been suggested to be a candidate risk factor in AD because of its P-secretase-like properties. In our total dataset of 164 caba and I IS controls, we find no association of CATD allele or genotype with occurrence of AD. However, logistic regression analyses reveal a significant interaction between ethnicity and CATD genotype on AD diagnosis. We therefore Ftratified our sample into Caucasian and Hispanic subgroups (Caucasian case? n= 101, controls=75; Hispanic cases=43, controls=36). In the Caucasian population. we found association of CATD genotype with AD diagnosis (pc.005) such that the T-containing genotype frequency was increased from 9.3% in controls to 26.7% in cases. By contrast, in the Hispanic population, the observed assoaation of CATD genotype with AD (p<.O5) was due to the opposite effect of T-carrying genotype decreasing from 33.3% in controls to I I .6% in cases. Calculation of odds ratios shows that in Hispanics, the T-carrying genotype confers 3.X fold protection against AD, while in Caucasians these genotypes confer 3.5 fold increased risk for AD. These data suggest that the C224T polymorphism is in linkage dwequilibrium with another (as yet unreported) variant which confers risk for AD and arose earlier in evolution than the C224T variant.

tion that affected individuals, in part, developed disease because of identity by descent around pathogenically important loci. As many authors have pointed out. and as many companies have realized, this approach is more likely to be successful in populations derived from few founders or those in which admixture happened rencently. We have Intended to apply a linkage disequilibrtum approach to the identtfication of new loci related to Alrheimer’s disease using a population-based sample of an homogeneous ethnic group. Thia population is composed by individuals of at least 85 years of age living in 1991 in the city of Vantaa (Finland). In order to characterize the extent to which linkage disequilibrium can be detected in this population we have started by analyzing the APOE locus and microsatellite markers around this gene, D19S908, D19S918 andAPOCl/ located in the same point of the genetic map. We have not been able to detect an association between any allele of any of these markers and the disease. Only the coding polymorphism in the APOE gene shows the well known association with the disease. Furthermore, linkage disequilibrium is not present in this region of chromosome 19. indicating that linkage disequilibrium mapping of complex disorders, notably Alzheimer’s disease, ia possibly not a good strategy for the identification and isolation of new genetic risk factors for the disease.

p?iJ

ESTROGEN HEIMER

RECEPTOR TYPE

B GENE

DEMENTIA

POLYMORPHISMS

PATIENTS

IN

A

IN ALZJAPANESE

POPULATION. Yosukr

Wukutani.

Yurnagata,

Kenji

Kursuyu

Urakami.

Nakashirna,

Tottori

Kenji Univ,

Wada-lsoe,

Yona~o

Ymhikl

Aduchi.

Kuwu

Jupun

The pathogenesis of Alzheimer type dementia (ATD) is thought to be multifactorial. Recent studies have revealed that the estrogen replacement therapy have beneficial effects for prevention and cognitive improvement of ATD. Our group previously estimated that the intronic polymorphisms (P and X alleles) of the estrogen receptor 01 (ERu) gene are significantly higher in ATD than those in the control group in a Japanese polulation. Estrogen receptor p (ERP), a newly cloned estrogen receptor. have been reported that it distributea over brain, and might have critical effects with estrogen, ERa and other estrogen related molecules on neuronal activity. In this report, we investigated the association between polymorphisms within the exon4 and exon5 in the ERP gene and ATD in a Japanese population. Polymerase chain reaction (PCR) followed by restriction fragment length polymorphisms (RFLPs) of the ERP gene were determined in I50 patients with ATD and I40 control subjects (CTL). In all examined subjects a missense polymorphism and a 21 bp deletion polymorphism in exonl of the ERP gene were not detected. An exon5 silent polymorphism of the ERP gene was classified by RsaI-RFLP. Although we found a significant racial defference m higher incidence rate of the exon5 silent polymorphism (892G->A) compared with previous report, there is no association m distribution of the ERP gene aon5 polymorphism between ATD and CTL. Single strand conformational polymorphism analysis of the PCR products of exon4 and exon5 did not show other extraconformers. The examinations for identification of the polymorphisms within other ERP exons and the pathogenic ERP gene mtronic polymorphisms such ab the ERa gene intronic polymorphisms and for participation of ERP in the pathogen&s of ATD need to be executed in the future.

p%J Andrras Ku-z.

AN EXONIC A MAJOR

POLYMORPHISM RISK

Pupusrotiropoulos. Tech

Goettinjien, Grrmuny;

Univ

Main

of Munich,

Gottingen Michael

FACTOR

Ludwig,

Bagli,

Munich

Germany;

ALZHEIMER’S

Unrv of Bonn, Germany;

Hans

Wolfgang

OF THE CATHEPSIN

FOR

Fowl,

M&r,

Bonn

Reinhard

IS

Grrmunp;

Alrxundw

Komhuber,

Univ

Univ

qf

Muni1.h

Hun,

Univ of Bonn,

Johanna Tech

D GENE

DISEASE

Munich,

oj

Bonn

Grrtnum LINKAGE

DISEQUILIBRIUM

HEIMER’S Jordi

Perez-Tur,

Helsinki

Verkoniemi,

Tuomo

Finland;

Finland;

Raimo

Polvikoski,

John

A Ha&,

AS A TOOL

FOR

MAPPING

ALZ-

GENES

Inst de Biomedicina-CSIC,


DISEASE

V&win

Sulkava,

Kimmo Mayo

Spain;

Liisa M~llykan@s,

Univ of Kuopio,

Kontula.

Mutti

Clin, Ja~~ksonville,

Kuopio

Haltia,

Univ

Fmlnnd;

Unit, Auli

of Helsinki.

FL

Molecular genetic approaches have proved an exceptionally effective approach to the study of monogenic disorders, to the extent that most major diaxses with clearly defined modes of inheritance have been solved with respect to their pathogenic loci over the last 15 years. In contra& the genetic contribution to common diseases with complex modes of inheritance has largely remained obscure. The development of high throughput sequencing, coupled with the identification of large numbers of polymorphisms at high density throughout the genome, has led to optimism, tempered most recently, that this technology might allow the mapping of complex traits in ewe&ally unrelated mdiwduals. through disequilibrium mapping: i.e., by making the assump-

Background: Cathepsin D (catD) is an tntracellular acid proteaae possibly involved m Alaheimer’s disease (AD)-related neurodegeneration through cleavage of the amyloid precursor protein (APP) into amyloidogenic components. An exonic polymorphism of the c&D gene (C-T (ala-ml) transition at position 224) was associated with altered pro-catD secretion and intracellular maturation of the enzyme. Objective: We studied whether the exonic polymorphism of the c&D gene influences the risk for the development of AD. The study was performed in 127 demented patients and I84 controls. Results: The catD*T allele was significantly over-represented in demented patients (I 1.8%) compared to non-demented controls (4.96, p = 0.001). Carriers of the catD*T allele had a 3.1.fold increased risk for developing AD than non-carrier\. The odds ratio for subjects with the apolipopmtein E (APOE) ~4 allele (APOE*4) and the cntD*T allele was 19.0 compared to subjects with neither of these two alleles. Conclusion: Our data confirm the results of a recently performed pilot study in an independent sample and wggest that the c&D genotype ia strongly associated with the risk for Alzheimer’a diaeae.