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.2008 Apr 25:9:37.
doi: 10.1186/1471-2350-9-37.

A luteinizing hormone receptor intronic variant is significantly associated with decreased risk of Alzheimer's disease in males carrying an apolipoprotein E epsilon4 allele

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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 epsilon4 allele

Ryan J Haasl et al. BMC Med Genet..

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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Figures

Figure 1
Figure 1
Age of onset is significantly affected by lhcgr2 genotype in males. AoO in lhcgr2 heterozygous and homozygous males (n = 50, p = 0.001).
Figure 2
Figure 2
Risk associated with ε4 allele is negated in male, lhcgr2 heterozygotes. Contingency table illustrating the relative frequencies of lhcgr2/APOEgenotypes in males and females (black = AD; white = Control).
Figure 3
Figure 3
Novel missense mutation in exon 11 of LHCGR. (A) Chromatogram from one of two samples heterozygous for a novel C->T (Arg->Stop) missense mutation in codon 479 (exon 11) ofLHCGR. (B) Chromatogram from a sample homozygous for 'C' at the same site.
Figure 4
Figure 4
lhcgr2 shares similarity with consensus 3' acceptor splice sites and ApoE mRNA. (A) lhcgr2 as a potential miRNA that regulates the expression of ApoE. The reversedLHCGRsequence is complimentary to a fragment ofAPOEmRNA at 13 out of 16 sites. (B) Pairwise sequence alignment of a portion of LHR intron 1 in human and mouse (Mus musculus). The human sequence includes lhr2 (rs4073366) and bears sequence features characteristic of 3' acceptor splice sites.
Figure 5
Figure 5
Significant linkage disequilibrium between lhcgr1 and multipleLHBloci. In the schematic ofLHB, exons are represented as black boxes and the positions of the 7LHBpolymorphisms scored are indicated by vertical lines. lhb3 is composed of two SNPs, which are in complete LD with each other. For each polymorphism, genotype frequencies are represented in the form of two pie charts, where the left chart represents genotype frequencies among individuals lacking an LQ-insert allele in exon 1 ofLHCGR(lhcgr1) and the right chart represents genotype frequencies among individuals possessing 1 or 2 LQ-insert alleles. Frequencies above the graphs correspond to AD males, while frequencies below the graph correspond toallindividuals sampled in this study. * = significant difference (p < 0.05), ** = highly significant difference (p < 0.01).
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References

    1. Bertram L, Tanzi RE. The current status of Alzheimer's disease genetics: what do we tell the patients? Pharmacol Res. 2004;50:385–396. doi: 10.1016/j.phrs.2003.11.018. - DOI - PubMed
    1. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261:921–923. doi: 10.1126/science.8346443. - DOI - PubMed
    1. Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Pericak-Vance MA, Joo SH, Rosi BL, Gusella JF, Crapper-MacLachlan DR, Alberts MJ, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology. 1993;43:1467–1472. - PubMed
    1. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. Jama. 1997;278:1349–1356. doi: 10.1001/jama.278.16.1349. - DOI - PubMed
    1. Roses A, Devlin B, Conneally P, Small G, Saunders A, Pritchard M. Measuring the genetic contribution of APOE in late-onset Alzheimer disease. Am J Hum Genet. 1995;57:A202.

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