Dataset Information

Suggestive synergy between genetic variants in TF and HFE as risk factors for Alzheimer's disease.

ABSTRACT: Alzheimer's disease (AD) is a complex disease that is likely influenced by many genetic and environmental factors. Citing evidence that iron may play a role in AD pathology, Robson et al. [Robson et al. (2004); J Med Genet 41:261-265] reported that epistatic interaction between rs1049296 (P589S) in the transferrin gene (TF) and rs1800562 (C282Y) in the hemochromatosis gene (HFE) results in significant association with risk for AD. In this study we attempted to replicate their findings in a total of 1,166 cases and 1,404 controls from three European and European American populations. Allele and genotype frequencies were consistent across the three populations. Using synergy factor analysis (SFA) and Logistic Regression analysis we tested each population and the combined sample for interactions between these two SNPs and risk for AD. We observed significant association between bi-carriers of the minor alleles of rs1049296 and rs1800562 in the combined sample using SFA (P = 0.0016, synergy factor = 2.71) and adjusted SFA adjusting for age and presence of the APOE epsilon 4 allele (P = 0.002, OR = 2.4). These results validate those of the previous report and support the hypothesis that iron transport and regulation play a role in AD pathology.

SUBMITTER: Kauwe JS

PROVIDER: S-EPMC2877151 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Suggestive synergy between genetic variants in TF and HFE as risk factors for Alzheimer's disease.

Kauwe J S K JS Bertelsen S S Mayo K K Cruchaga C C Abraham R R Hollingworth P P Harold D D Owen M J MJ Williams J J Lovestone S S Morris J C JC Goate A M AM

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 20100601 4

Alzheimer's disease (AD) is a complex disease that is likely influenced by many genetic and environmental factors. Citing evidence that iron may play a role in AD pathology, Robson et al. [Robson et al. (2004); J Med Genet 41:261-265] reported that epistatic interaction between rs1049296 (P589S) in the transferrin gene (TF) and rs1800562 (C282Y) in the hemochromatosis gene (HFE) results in significant association with risk for AD. In this study we attempted to replicate their findings in a total ...[more]

PMID: 20029940

Similar Datasets

Project description:Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer's disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10-9), MINK1 (chromosome 17, meta-p = 1.98 × 10-7) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 × 10-7 and closest gene = MYBPC3, meta-p = 5.62 × 10-8). In a large 'AD-by-proxy' cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within MINK1, MBLAC1, and DDB2. Expression of MBLAC1, SPI1, MINK1 and DDB2 was differentially altered within postmortem AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid-associated RFs. We pinpoint a subset of cardiovascular-associated genes that strongly increase the risk for AD. Our collective findings support a disease model in which cardiovascular biology is integral to the development of clinical AD in a subset of individuals.

Project description:BACKGROUND & AIMS:Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for esophageal adenocarcinoma (EA) and Barrett's esophagus (BE). However, variants in these loci account for a small fraction of cases of EA and BE. Genetic factors might interact with environmental factors to affect risk of EA and BE. We aimed to identify single nucleotide polymorphisms (SNPs) that may modify the associations of body mass index (BMI), smoking, and gastroesophageal reflux disease (GERD), with risks of EA and BE. METHODS:We collected data on single BMI measurements, smoking status, and symptoms of GERD from 2284 patients with EA, 3104 patients with BE, and 2182 healthy individuals (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium GWAS, the UK Barrett's Esophagus Gene Study, and the UK Stomach and Oesophageal Cancer Study. We analyzed 993,501 SNPs in DNA samples of all study subjects. We used standard case-control logistic regression to test for gene-environment interactions. RESULTS:For EA, rs13429103 at chromosome 2p25.1, near the RNF144A-LOC339788 gene, showed a borderline significant interaction with smoking status (P = 2.18×10-7). Ever smoking was associated with an almost 12-fold increase in risk of EA among individuals with rs13429103-AA genotype (odds ratio=11.82; 95% CI, 4.03-34.67). Three SNPs (rs12465911, rs2341926, rs13396805) at chromosome 2q23.3, near the RND3-RBM43 gene, interacted with GERD symptoms (P = 1.70×10-7, P = 1.83×10-7, and P = 3.58×10-7, respectively) to affect risk of EA. For BE, rs491603 at chromosome 1p34.3, near the EIF2C3 gene, and rs11631094 at chromosome 15q14, at the SLC12A6 gene, interacted with BMI (P = 4.44×10-7) and pack-years of smoking history (P = 2.82×10-7), respectively. CONCLUSION:The associations of BMI, smoking, and GERD symptoms with risks of EA and BE appear to vary with SNPs at chromosomes 1, 2, and 15. Validation of these suggestive interactions is warranted.

Dataset Information

Suggestive synergy between genetic variants in TF and HFE as risk factors for Alzheimer's disease.

Publications

Suggestive synergy between genetic variants in TF and HFE as risk factors for Alzheimer's disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets