Mannose-binding lectin 2 gene and risk of adult glioma.

Dominique S Michaud,David G Cox,Afshan Siddiq,Shelley S Tworoger,Federico C F Calboli,Michael E Sughrue,J Michael Gaziano,Carlos A Camargo,Andrew T Parsa,David J Hunter,Danielle M Backes,Meir Stampfer,Jing Ma,Dana C Crawford

doi:10.1371/journal.pone.0061117

Abstract

Background and AimsThe immune system is likely to play a key role in the etiology of gliomas. Genetic polymorphisms in the mannose-binding lectin gene, a key activator in the lectin complement pathway, have been associated with risk of several cancers.MethodsTo examine the role of the lectin complement pathway, we combined data from prospectively collected cohorts with available DNA specimens. Using a nested case-control design, we genotyped 85 single nucleotide polymorphisms (SNPs) in 9 genes in the lectin complement pathway and 3 additional SNPs in MBL2 were tested post hoc). Initial SNPs were selected using tagging SNPs for haplotypes; the second group of SNPs for MBL2 was selected based on functional SNPs related to phenotype. Associations were examined using logistic regression analysis. All statistical tests were two-sided. Nominal p-values are presented and are not corrected for multiple comparisons.ResultsA total of 143 glioma cases and 419 controls were available for this analysis. Statistically significant associations were observed for two SNPs in the mannose-binding lectin 2 (ML2) gene and risk of glioma (rs1982266 and rs1800450, test for trend p = 0.003 and p = 0.04, respectively, using the additive model). One of these SNPs, rs1800450, was associated with a 58% increase in glioma risk among those carrying one or two mutated alleles (odds ratio = 1.58, 95% confidence interval = 0.99–2.54), compared to those homozygous for the wild type allele.ConclusionsOverall, our findings suggest that MBL may play a role in the etiology of glioma. Future studies are needed to confirm these findings which may be due to chance, and if reproduced, to determine mechanisms that link glioma pathogenesis with the MBL complement pathway.

Highlights

Gliomas comprise 32% of all brain tumors and 80% of all malignant brain tumors [1] and encompass a spectrum of histologies that include low grade gliomas, anaplasic astrocytomas and glioblastomas (GBM)
This is true in candidate gene analyses, where SNPs are selected in specific genes and prior probability for associations is hard to estimate, but in any event is higher than when using unselected polymorphisms
Study Populations We identified cases and controls from three large US prospective cohort studies: the Physicians’ Health Study (PHS) [19], the Nurses’ Health Study (NHS) [20], and the Health Professionals Follow-up Study (HPFS) [21]

Summary

Introduction

Gliomas comprise 32% of all brain tumors and 80% of all malignant brain tumors [1] and encompass a spectrum of histologies that include low grade gliomas, anaplasic astrocytomas and glioblastomas (GBM). Fewer than 4.5% of patients diagnosed with GBMs, the most common glioma subtype (60%), are alive five years post-diagnosis [1]. While necessary when conducting agnostic analyses, over correcting for multiple comparisons can result in missed genetic associations that are etiologically important. This is true in candidate gene analyses, where SNPs are selected in specific genes and prior probability for associations is hard to estimate, but in any event is higher than when using unselected polymorphisms. Genetic polymorphisms in the mannose-binding lectin gene, a key activator in the lectin complement pathway, have been associated with risk of several cancers

Methods

Results

Conclusion