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A luteinizing hormone receptor intronic variant is significantly associated with decreased risk of Alzheimer's disease in males carrying an apolipoprotein E ε4 allele

Section of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
BMC Medical Genetics (Impact Factor: 2.08). 02/2008; 9(1):37. DOI: 10.1186/1471-2350-9-37
Source: DOAJ

ABSTRACT

Genetic and biochemical studies support the apolipoprotein E (APOE) epsilon4 allele as a major risk factor for late-onset Alzheimer's disease (AD), though ~50% of AD patients do not carry the allele. APOE transports cholesterol for luteinizing hormone (LH)-regulated steroidogenesis, and both LH and neurosteroids have been implicated in the etiology of AD. Since polymorphisms of LH beta-subunit (LHB) and its receptor (LHCGR) have not been tested for their association with AD, we scored AD and age-matched control samples for APOE genotype and 14 polymorphisms of LHB and LHCGR. Thirteen gene-gene interactions between the loci of LHB, LHCGR, and APOE were associated with AD. The most strongly supported of these interactions was between an LHCGR intronic polymorphism (rs4073366; lhcgr2) and APOE in males, which was detected using all three interaction analyses: linkage disequilibrium, multi-dimensionality reduction, and logistic regression. While the APOE epsilon4 allele carried significant risk of AD in males [p = 0.007, odds ratio (OR) = 3.08(95%confidence interval: 1.37, 6.91)], epsilon4-positive males carrying 1 or 2 C-alleles at lhcgr2 exhibited significantly decreased risk of AD [OR = 0.06(0.01, 0.38); p = 0.003]. This suggests that the lhcgr2 C-allele or a closely linked locus greatly reduces the risk of AD in males carrying an APOE epsilon4 allele. The reversal of risk embodied in this interaction powerfully supports the importance of considering the role gene-gene interactions play in the etiology of complex biological diseases and demonstrates the importance of using multiple analytic methods to detect well-supported gene-gene interactions.

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    • "Genomewide association studies (GWAS) suggested that SNPs within the FSHR and LHCGR genes may contribute to the pathogenesis of the disease (). Especially, the polymorphism rs4073366 (c.161C 28GOC) located within the first intron of the LHGCR gene was associated with a protective effect from the disease risk in males (Haasl et al. 2008). "
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    • "While rs4073366 is a potential predictor of OHSS risk, the functional consequences of this polymorphism on LHR function are yet to be elucidated. rs4073366 has a major allele of “C” on the “+” strand (“G” on the “-“strand in this study) and resides in a cryptic 3’ splice acceptor site (data not shown) which could potentially impact LHCGR mRNA processing yielding a splice variant with altered activity [67]. In addition, the intronic region surrounding rs4073366 is complementary to APOE mRNA and has been associated with decreased risk of Alzheimer’s disease (AD) in males carrying the APOE ϵ4 allele [67]. "
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