Sandrine Mace

In-Depth Haplotype Analysis of ABCA1 Gene Polymorphisms in Relation to Plasma ApoA1 Levels and Myocardial Infarction

Objective—By regulating the cellular cholesterol efflux from peripheral cells to high-density lipoprotein, the ABCA1 protein is suspected to play a key role in lipid homeostasis and atherosclerosis. Twenty-six polymorphisms of the ABCA1 gene were genotyped and tested for association with plasma levels of ApoA1 and myocardial infarction (MI) in the ECTIM study. Methods and Results—In addition to single-locus analysis, a systematic exploration of all possible haplotype effects was performed, with this exploration being performed on a minimal set of “tag” polymorphisms that define the haplotype structure of the gene. Two polymorphisms were associated with plasma levels of ApoA1, 1 in the promoter (C-564T) and 1 in the coding (R1587K) regions, whereas only 1 polymorphism (R219K) was associated with the risk of MI. However, no haplotype effect was detected on ApoA1 variability or on the risk of MI. Conclusion—ABCA1 gene polymorphisms but not haplotypes are involved in the variability of plasma ApoA1 and the susceptibility to coronary artery disease.

ABCA2 is a strong genetic risk factor for early-onset Alzheimer's disease

Recent epidemiological, biological and genetic data indicate a relationship between cholesterol and Alzheimers disease (AD) including the association of polymorphisms of ABCA1 (a gene that is known to participate in cholesterol and phospholipid transport) with AD prevalence. Based on these data, we postulated that genetic variation in the related and brain-specific ABCA2 gene leads to increase risk of AD. A large case-control study was conducted where the sample was randomly divided into a hypothesis-testing sample (230 cases/286 controls) and a validation sample (210 cases/233 controls). Among the 45 SNPs we tested, one synonymous SNP (rs908832) was found significantly associated with AD in both samples. Additional analyses performed on the whole sample showed a very strong association between this marker and early-onset AD (OR = 3.82, 95% C.I. = [2.00 - 7.30], P = 5 x 10(-5)). Further research is needed to understand the functional role of this polymorphism. However, together with the reported associations of AD with APOE, CYP46A1 and ABCA1, the present result adds a very significant support for the role of cholesterol and phospholipid homeostasis in AD and a rationale for testing novel cholesterol homeostasis-related therapeutic strategies in AD.

No replication of genetic association between candidate polymorphisms and Alzheimer's disease.

Alzheimers disease is a genetically complex disorder, for which new putative susceptibility genes are constantly proposed in the literature. We selected 16 candidate genes involved in biological pathways closely related to the pathology, and for which a genetic association with Alzheimers disease was previously detected: ACE, BACE1, BDNF, ECE1, HSPG2, IDE, IL1a, IL6, IL10, MAPT, PLAU, PrnP, PSEN1, SORL1, TFCP2 and TGFb1. The variants originally associated with the disease were genotyped in a French Caucasian sample including 428 cases and 475 controls and tested for association in order to replicate the initial results. Despite a careful replication study design, we failed to validate the initial findings for any of these variants, with the possible exception of MAPT, SORL1 and TFCP2 for which some nominal but inconsistent evidence of association was observed.

Association studies in candidate genes: Strategies to select SNPs to be tested

Objective: When numerous single nucleotide polymorphisms (SNPs) have been identified in a candidate gene, a relevant and still unanswered question is to determine how many and which of these SNPs should be optimally tested to detect an association with the disease. Testing them all is expensive and often unnecessary. Alleles at different SNPs may be associated in the population because of the existence of linkage disequilibrium, so that knowing the alleles carried at one SNP could provide exact or partial knowledge of alleles carried at a second SNP. We present here a method to select the most appropriate subset of SNPs in a candidate gene based on the pairwise linkage disequilibrium between the different SNPs. Method: The best subset is identified through power computations performed under different genetic models, assuming that one of the SNPs identified is the disease susceptibility variant. Results: We applied the method on two data sets, an empirical study of the APOE gene region and a simulated study concerning one of the major genes (MG1) from the Genetic Analysis Workshop 12. For these two genes, the sets of SNPs selected were compared to the ones obtained using two other methods that need the reconstruction of multilocus haplotypes in order to identify haplotype-tag SNPs (htSNPs). We showed that with both data sets, our method performed better than the other selection methods.

A risk for early-onset Alzheimer's disease associated with the APBB1 gene (FE65) intron 13 polymorphism.

Alzheimers disease (AD) is a genetically complex neurodegenerative disorder and the leading cause of dementia of the elderly. Recently, Hu et al. suggested that a trinucleotide deletion in intron 13 of the APBB1 gene was a factor protecting against late-onset AD. We report here the results of a case/control study aimed at replicating this association. Our study included 461 AD patients and 397 matched controls. We compared the allele and genotype frequencies of the polymorphism between the two groups but did not find any statistically significant difference (P=0.08 and P=0.09, respectively). By contrast, adjusting for age and sex, we found a slight risk associated with the deletion (odds ratio=1.47, 95% confidence interval=1.05-2.04). Stratification by age showed that the risk effect associated with the deletion concerned subjects aged less than 65 years.

Association study in three different populations between the GPR88 gene and major psychoses

GPR88, coding for a G protein‐coupled orphan receptor that is highly represented in the striatum, is a strong functional candidate gene for neuropsychiatric disorders and is located at 1p22‐p21, a chromosomal region that we have previously linked to bipolar disorder (BD) in the Sardinian population. In order to ascertain the relevance of GPR88 as a risk factor for psychiatric diseases, we performed a genetic association analysis between GPR88 and BD in a sample of triads (patient and both parents) recruited in the Sardinian and the Palestinian population as well as between GPR88 and schizophrenia (SZ) in triads from the Xhosa population in South Africa. We found a positive association between GPR88 and BD in the Sardinian and Palestinian triads. Moreover, we found a positive association between GPR88 and SZ in triads from the Xhosa population in South Africa. When these results were corrected for multiple testing, the association between GPR88 and BD was maintained in the Palestinian population. Thus, these results suggest that GPR88 deserves consideration as a candidate gene for psychiatric diseases and requires to be further investigated in other populations.

Association between the Thr325Ile polymorphism of the thrombin-activatable fibrinolysis inhibitor and stroke in the Ludwigshafen Risk and Cardiovascular Health Study

The thrombin-activatable fibrinolysis inhibitor (TAFI) is a key mediator in the regulation of endogenous fibrinolysis, down-regulating clot lysis by degrading the C-terminal lysine residues from fibrin, which are important for binding and activating plasminogen. Elevated TAFI antigen levels have been suggested to be associated with promoter variants and the Ala147Thr polymorphism; increased TAFI stability and antifibrinolytic potential instead have been associated with the Thr325Ile polymorphism. We investigated the influence of these two polymorphisms on cardiovascular and thrombotic events in patients of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. The LURIC study is a prospective cohort study comprising more than 3,300 patients aimed at identifying biochemical and genetic markers for metabolic and cardiovascular diseases. We demonstrate that the Ile/Ile genotype at position 325 of TAFI associates with the incidence of stroke and the age at onset of first stroke in patients of the LURIC cohort. Both the incidence of stroke and the risk of a premature event are higher in TAFI Ile325Ile patients with predisposing risk factors for thrombotic events such as diabetes mellitus, myocardial infarction or hypertension, alone or in combination. In contrast, no significant association was identified for the TAFI Ala147Thr polymorphism. The robust association of the TAFI Thr325Ile polymorphism with the incidence and the age at onset of first stroke strongly suggests a key role for TAFI in the pathogenetic mechanism of stroke.

No replication of the association between the Nicastrin gene and familial early-onset Alzheimer's disease

Polymorphisms in the Nicastrin (NCSTN) gene have recently been associated with familial early-onset Alzheimers disease (AD). The authors genotyped four NCTSN polymorphisms in a large cohort of 489 AD cases (including 158 sporadic early-onset AD cases and 95 familial early-onset AD cases) and 386 controls but failed to replicate the association between NCSTN haplotype B and AD.

A Novel Val286Ala Polymorphism in the NPXXY Motif of the Sphingosine-1-Phosphate Receptor S1PR2 Associates with the Incidence and Age of Onset of Diabetes

Aim: S1PR2 is one of five known sphingosine-1-phosphate receptors and has recently been discussed to be implicated in the development or progression of diabetes. Our aim was to identify S1PR2 polymorphisms in the coding region of the human S1PR2 gene and perform association analyses between S1PR2 polymorphisms leading to amino acid exchanges and phenotypic parameters in a clinical study cohort. Method: We screened the coding region of the S1PR2 gene for polymorphisms resulting in amino acid exchanges in the S1PR2 protein in 40 Caucasian DNA samples from a CEPH control panel. The resulting polymorphisms were then analyzed in more than 3400 patients of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study cohort. Results: In addition to the known Asn→Lys S1PR2 polymorphism at position 10 of the S1PR2 protein, we identified a novel polymorphism in the NPXXY motif of S1PR2, resulting in the amino acid exchange Val→Ala at position 286. The S1PR2 genotype Val286Ala showed strong association with the incidence and age at onset of diabetes in the studied patient cohort. Conclusion: With our analysis we substantiate previous reports on the possible implication of S1PR2 in the development of diabetes and identified the S1PR2 Val286Ala genotype to be significantly associated with incidence and age at onset of diabetes likely due to an altered function of S1PR2.