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


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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    • "Although this can work better than using a single variable on its own, strategies of this kind usually fall well short of the outcomes that can be achieved using approaches based on combinatorial optimization of particular sets of entities or features, which also take into account interrelationships between different entities. Such non-statistical approaches are already proving useful in related areas, such as investigations of interactions between multiple genetic risk factors for AD, depression, and other conditions [16] [17] [18]. One of the reasons for this is already well recognized in the AD field, namely that single variate measures are generally outperformed by multimodal approaches that combine genomics, proteomics, metabolomics, or other molecular investigations with information from different sources, for example cognitive test scores, imaging, or demographic factors such as gender, age, and education level [9] [13] [15]. "
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    ABSTRACT: Interventions to delay or slow Alzheimer's disease (AD) progression are most effective when implemented at pre-clinical disease stages, making early diagnosis essential. For this reason, there is an increasing focus on discovery of predictive biomarkers for AD. Currently, the most reliable predictive biomarkers require either expensive (brain imaging) or invasive (cerebrospinal fluid collection) procedures, leading researchers to strive toward identifying robust biomarkers in blood. Yet promising early results from candidate blood biomarker studies are being refuted by subsequent findings in other cohorts or using different assay technologies. Recent evidence suggests that univariate blood biomarkers are not sufficiently sensitive or specific for the diagnosis of disorders as complex, multifactorial, and heterogeneous as AD. To overcome these present limitations, more consideration must be given to the development of 'biomarker panels' assessing multiple molecular entities. The selection of such panels should draw not only on traditional statistical approaches, whether parametric or non-parametric, but also on newer non-statistical approaches that have the capacity to retain and utilize information about all individual study participants rather than collapsing individual data into group summary values (e.g., mean, variance). These new approaches, facilitated by advances in computing, have the potential to preserve the context of interrelationships between different molecular entities, making them amenable to the development of panels that, as a multivariate collective, can overcome the challenge of individual variability and disease heterogeneity to accurately predict and classify AD. We argue that the AD research community should take fuller advantage of these approaches to accelerate discovery.
    Journal of Alzheimer's disease: JAD 10/2013; 39(1). DOI:10.3233/JAD-131424 · 4.15 Impact Factor
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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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    ABSTRACT: The aim of this study was to determine the relationship between a purported luteinizing hormone/chorionic gonadotropin (LHCGR) high function polymorphism (rs4539842/insLQ) and outcome to controlled ovarian hyperstimulation (COH). This was a prospective study of 172 patients undergoing COH at the Fertility and IVF Center at GWU. DNA was isolated from blood samples and a region encompassing the insLQ polymorphism was sequenced. We also investigated a polymorphism (rs4073366 G > C) that was 142 bp from insLQ. The association of the insLQ and rs4073366 alleles and outcome to COH (number of mature follicles, estradiol level on day of human chorionic gonadotropin (hCG) administration, the number of eggs retrieved and ovarian hyperstimulation syndrome (OHSS)) was determined. Increasing age and higher day 3 (basal) FSH levels were significantly associated with poorer response to COH. We found that both insLQ and rs4073366 were in linkage disequilibrium (LD) and no patients were homozygous for both recessive alleles (insLQ/insLQ; C/C). The insLQ variant was not significantly associated with any of the main outcomes to COH. Carrier status for the rs4073366 C variant was associated (P = 0.033) with an increased risk (OR 2.95, 95% CI = 1.09-7.96) of developing OHSS. While age and day 3 FSH levels were predictive of outcome, we found no association between insLQ and patient response to COH. Interestingly, rs4073366 C variant carrier status was associated with OHSS risk. To the best of our knowledge, this is the first report suggesting that LHCGR genetic variation might function in patient risk for OHSS.
    Reproductive Biology and Endocrinology 07/2013; 11(1):71. DOI:10.1186/1477-7827-11-71 · 2.23 Impact Factor
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    • "An interesting hypothesis is that LH can increase the susceptibility to Alzheimer disease (AD) [69]. Circumstantial evidence includes the presence of LHCGR in several brain regions [70, 71], the ability of LH and hCG to cross the blood-brain barrier [71], elevated LH concentrations in AD sufferers [72, 73], the linkage of certain LHCGR variants with reduced risk of AD [74], and the ability of LH to alter amyloid precursor processing toward the amyloidogenic pathway in vitro [75]. The cross-breedings of Lhcgr knockout mice and APPsw+ Alzheimer model mice expressing human amyloid precursor, convincingly support this hypothesis; in the absence of LH action, accumulation of amyloid-β peptide (Aβ) is reduced, astrogliosis eases, and the production of several neuroproteins is corrected [76]. "
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    ABSTRACT: During the last two decades a large number of genetically modified mouse lines with altered gonadotropin action have been generated. These mouse lines fall into three categories: the lack-of-function mice, gain-of-function mice, and the mice generated by breeding the abovementioned lines with other disease model lines. The mouse strains lacking gonadotropin action have elucidated the necessity of the pituitary hormones in pubertal development and function of gonads, and revealed the processes from the original genetic defect to the pathological phenotype such as hypo- or hypergonadotropic hypogonadism. Conversely, the strains of the second group depict consequences of chronic gonadotropin action. The lines vary from those expressing constitutively active receptors and those secreting follicle-stimulating hormone (FSH) with slowly increasing amounts to those producing human choriogonadotropin (hCG), amount of which corresponds to 2000-fold luteinizing hormone (LH)/hCG biological activity. Accordingly, the phenotypes diverge from mild anomalies and enhanced fertility to disrupted gametogenesis, but eventually chronic, enhanced and non-pulsatile action of both FSH and LH leads to female and male infertility and/or hyper- and neoplasias in most of the gonadotropin gain-of-function mice. Elevated gonadotropin levels also alter the function of several extra-gonadal tissues either directly or indirectly via increased sex steroid production. These effects include promotion of tumorigenesis in tissues such as the pituitary, mammary and adrenal glands. Finally, the crossbreedings of the current mouse strains with other disease models are likely to uncover the contribution of gonadotropins in novel biological systems, as exemplified by the recent crossbreed of LHCG receptor deficient mice with Alzheimer disease mice.
    Reviews in Endocrine and Metabolic Disorders 04/2011; 12(4):245-58. DOI:10.1007/s11154-011-9174-4 · 4.89 Impact Factor
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