Table 1 Genes with Susceptibility/Resistance Alleles Defined with National Collaborative Toxoplasmosis Study and EMSCOT Cohorts.

From: Toxoplasma Modulates Signature Pathways of Human Epilepsy, Neurodegeneration & Cancer

Gene

SNP (Allele)

P Value

Reason Candidate Gene

Replicate/Proof of Principle/Phenotype

Reference/Supporting Data

HLA Class II

DQ3

<0.02

MD

Hydrocephalous in children (DQ3), Fewer cysts in HLA transgenic mice (DQ1)

11

DQ1

<0.0005

COL2A1

rs6823 (G)

<0.03 (brain)

ED

EMSCOT replicates, imprinted, brain and eye disease

12, 13

rs2276455 (A)

<0.03

rs2276455 (G)*

<0.0005

rs1635544 (C)

<0.03

rs2070739 (T)

<0.02

rs2276454 (A)

<0.007

rs3803183 (T)

<0.02

rs3803183 (T)*

<0.003

ABCA4

rs952499 (C)

<0.03

HC

EMSCOT replicates, imprinted, localized in human brain

12, 13, HC

rs952499 (T)*

<0.005

rs2297633 (G)*

<0.0003

rs1761375 (G)*

<0.0001

rs3112831 (C)*

<0.02

P2RX7

rs1621388(C1772T)

<0.021

OI

EMSCOT replicates for differing alleles; ATP mediated cell death, cytokine signaling, pro-inflammation

14, 15, OD

rs1718119(T1068C)

<0.015

HLA Class I

A

<0.01

MD

Genotype association and phenotypes humans and mice. PBMC from cohort. Peptides for HLA A2, A11, B7 confer protection

16,17,18,19,20,21,22, OD

B

C

ERAP1

rs149173(T/C)

<0.0077

LfL

Genotype association and phenotypes humans and mice

16, OD

rs17481856(C/T)

0.0253

IRAK4

rs1461567

<0.023

IOID

Genotype; phenotype, cell death, inflammation

23

rs4251513

<0.045

NALP1

rs8081261

<0.002

MD TRNG

Genotype (MD region; human); phenotype, cell death, inflammation; MD

24,25,26,27,28,29,30

rs11652907

<0.02

rs9902174

<0.04

ALOX12

rs6502997

<0.0003

MD TRNG

Genotype and phenotype, cell death proinflammation

31

rs312462 (C)

<0.03

 

rs6502998 (C)

<0.03

 

rs434473

<0.04

 

TLR9

rs574386 (T1905C)

<0.008

TLRs

Brazil and Poland replicates; phenotype, ligand

32

rs352140 (C)

<0.0001

AM

TIRAP

rs8177374(S180L)

<0.006

IOID

Genotype; Phenotype TLR signaling and cytokines

AM

FOXQ1

rs920209

<0.02

HC

Note NK cells mice

33, OD

TREX1

rs 2242150(A/T)

0.02

SPD

Related clinical & Type 1 IFN phenotype, LFL

34, 35, OD or AM

NFκβ1

rs997476(C/A)

<0.02

CtoPiEA

Phenotype, nuclear localization, signaling pathway

36, OD

TGFβ1

rs10417924 (G overtranscribed)

0.016

CtoPiEA, MD

Phenotype transcriptomics, GRA1

37, 38

NOD2 (Brazil)

rs3135499 (C/A)†

<0.04

LfL Brazil

Eye Disease, IL17, CD4+

39

  1. Abbreviations: Reason for selection of gene to test sequentially as single candidate gene in NCCCTS (1981–2016): MD, Murine model data; ED, Eye disease in humans caused by mutation of this gene; HC, Hydrocephalous caused in humans by gene mutation and adult macular degeneration associated with allelic variants; OI, Implicated alleles for other infections; LfL, Logical to test from literature and other findings, for example MHC Class I presentation of antigen for ERAP1; IOID, Gene in other diseases in the literature; MD TRNG, Toxo 1 region, not gene initially in humans based on rat Toxo 1 region; TLRs, Testing TLR genes now replicated by other cohorts and proven to be important in mice; SPD, similar pattern of brain disease as AG brain disease due to DNA ligase mutations; CtoPIEA, Central to genetic pathway identified with original analysis led to TDT analysis herein. Note: LfL Brazil, Minas Gerais, did not replicate in US full cohort; no *, significant in NCCCTS not EMSCOT;* significant in EMSCOT cohort not NCCCTS. P values are nominal. Supporting Data [SD]: References (#) with narrative summary of findings and gene function for published work or in preparation (AM) or original data in this manuscript (OD) in Fig. 1 or online supplement.
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