Nutrients 2013, 5(12), 5046-5064; doi:10.3390/nu5125046

Article
Candidate Genes Involved in Beneficial or Adverse Responses to Commonly Eaten Brassica Vegetables in a New Zealand Crohn’s Disease Cohort
Bobbi Laing *, Dug Yeo Han and Lynnette R. Ferguson
Discipline of Nutrition, School of Medical Sciences, Auckland University, 85 Park Road, Grafton Campus, Auckland 1142, New Zealand; E-Mails: dy.han@auckland.ac.nz (D.Y.H.); l.ferguson@auckland.ac.nz (L.R.F.)
*
Author to whom correspondence should be addressed; E-Mail: b.laing@auckland.ac.nz; Tel.: +64-9-923-1785; Fax: +64-9-923-3362.
Received: 4 September 2013; in revised form: 22 November 2013 / Accepted: 29 November 2013 /
Published: 12 December 2013

Abstract

: Crohn’s disease (CD) is one of the two manifestations of inflammatory bowel disease. Particular foods are thought with CD to exacerbate their illness. Vegetables, especially Brassicaceae, are often shunned by people with CD because of the negative effects they are alleged to have on their symptoms. Brassicaceae supply key nutrients which are necessary to meet recommended daily intakes. We sought to identify the candidate genes involved in the beneficial or adverse effects of Brassicaceae most commonly eaten, as reported by the New Zealand adults from the “Genes and Diet in Inflammatory Bowel disease Study” based in Auckland. An analysis of associations between the single nucleotide polymorphisms (SNPs) and the beneficial or adverse effects of the ten most commonly eaten Brassicaceae was carried out. A total of 37 SNPs were significantly associated with beneficial effects (p = 0.00097 to 0.0497) and 64 SNPs were identified with adverse effects (p = 0.0000751 to 0.049). After correcting for multiple testing, rs7515322 (DIO1) and rs9469220 (HLA) remained significant. Our findings show that the tolerance of some varieties of Brassicaceae may be shown by analysis of a person’s genotype.
Keywords:
Brassicaceae; tolerability; Crohn’s disease; DIO1; HLA

1. Introduction

Crohn’s disease (CD) is one of two commonly identified inflammatory bowel diseases (IBD) the other being ulcerative colitis (UC). Both disorders are inflammatory and people experience phases of remission and deterioration.

The incidence of CD seems to be increasing and it appears that New Zealand (NZ) in 2006 had the highest rate at 16.5/105 [1]. Increases are observed particularly in the western world, and research has shown that the environment plays a considerable role [2]. It has been observed that individuals from Bangladesh (where the incidence of IBD is very low) on shifting to the United Kingdom, develop a very high incidence of IBD within a generation [3]. Nutrition is thought to play a key role and is considered to be an important environmental factor influencing the development of CD and its symptoms [4], through the nutrigenomic and epigenetic modification of the susceptibility genes [5].

Vegetables, especially Brassicaceae, are often shunned by people with CD because of the negative effects they are alleged to have on their symptoms [6,7]. However, Brassicaceae supply key nutrients. Some varieties of Brassicaceae also appear to be well tolerated by people with CD [8]. Several studies show that Brassicaceae contain many significant nutrients: fibre, the antioxidants vitamin A and C, the vitamin folate and vitamin K and the minerals such as potassium, calcium, selenium and zinc as well as the numerous phytochemicals which have key roles in maintaining health [9,10,11,12]. They help improve immunity as well as contributing to anti-inflammatory and anti-cancer activities of the body [13,14,15,16,17,18,19,20,21]. The intake of sufficient amounts of these nutrients is important for people with CD. These nutrients are necessary to meet the daily intakes as recommended in the Nutrient Reference Values for Australia and New Zealand [22].

By studying the interaction of different Brassicaceae varieties with single nucleotide polymorphisms (SNPs) in people with CD, it may be possible to uncover a genetic basis for individual tolerances. This could lead to more specific nutrition advice with respect to these important vegetables, and enhance the opportunities for CD patients to avail themselves of the benefits of Brassicaceae. The aim of this study was therefore to identify the candidate genes involved in the beneficial or adverse effects of the Brassicaceae most commonly eaten as reported by NZ adults from the “Genes and Diet in IBD Study” [4], based in Auckland.

2. Materials and Methods

2.1. Brassicaceae Selection

The Brassicaceae analysed for tolerability were those reported to be consumed by the subjects in the “Genes and Diet in IBD Study” based in Auckland NZ. These Brassicaceae were: broccoli, cabbage, cauliflower, Chinese greens, rocket (arugula), watercress, horseradish, mustard sauce, mustard powder and wasabi.

2.2. Tolerability of Brassicaceae

The tolerability of the Brassicaceae was ascertained from secondary analysis of the information gained from the responses to the dietary questionnaire. This questionnaire was based on Joachim’s methodology [23] and feedback from a group of patients with CD [4]. Questions in the survey were asked (and scored on a five-point scale on whether the person’s IBD condition became either: definitely better, (++) probably better (+), had no effect (=), probably worse (−), and definitely worse (− − in response to the listed food. This allowed information to be collected on how food affected their disease symptoms. This takes into account that many foods are never consumed because they are not considered palatable irrespective of the effects they are perceived to have on their symptoms of CD.

Two scales were used: the percentage of beneficial effects (definitely better and probably better) and adverse effects (definitely worse and probably worse). The responses to “makes no difference” were omitted. A nutritionist or registered nurse checked out the responses with respondents when there were any queries [4]. The dietary questionnaire also included open ended questions. These were also evaluated for additional information on foods which may affect symptoms associated with CD.

2.3. Study Population

Study participants were from the main North Island centre, Auckland and other major North Island centres. They were enrolled as part of a population based study in the IBD project whose purpose was to determine the genetic and environmental factors of CD aetiology. These people were enlisted from gastroenterology clinics or by their response from advertising in the media between May 2005 and April 2009. A total of 339 Caucasian subjects gave their informed consent to take part. The nutritional questionnaire was completed by 290 and up to 323 were genotyped (Table 1). Consent was obtained before the collection of peripheral blood for DNA extraction and genotyping. The questionnaires were taken away for participants to complete and on their return scrutinised for accuracy and completion and where necessary subjects were contacted again for clarification. All of the participants were selected on the basis of self-disclosed Caucasian ancestry only [4]. Clinical data (age, IBD diagnosis and the most recent Montreal classification of CD location [24]) were extracted from the clinical questionnaire and patient medical notes, which were supplied by the diagnosing gastroenterologist in the primary “Genes and Diet in IBD Study”. Ethical approval was given by the NZ Multi-region Human Ethics Committee (MEC04/12/11).

2.4. Genotyping

SNP data with respect to the beneficial or adverse effects of selected Brassicaceae were taken from the original “Genes and Diet in IBD Study” based in Auckland, NZ. Gene polymorphisms in this study were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The SNPs identified for each Brassicaceae variety were corrected for multiple testing using a false discovery rate [25]. R was used for statistical analyses. A p-value was considered significant if it was less than 0.05 [26].

Table 1. Summary of sample sizes and clinical data for those with Crohn’s disease (CD).

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Table 1. Summary of sample sizes and clinical data for those with Crohn’s disease (CD).
Sub-phenotypesPhenotype DescriptionN (%)
Age at diagnosis<1731 (11.0)
17–40205 (72.7)
>4046 (16.3)
BehaviourInflammatory158 (56.0)
Stricturing91 (32.3)
Penetrating33 (11.7)
LocationIleal111 (39.4)
Colonic92 (32.6)
Ileocolon79 (28.0)
Bowel ResectionNo180 (63.8)
Yes102 (36.2)
Extra-intestinal manifestationsNo232 (82.3)
Yes50 (17.7)

Note: A total of 339 participants were available for genotyping and up to 323 were genotyped. Of those, clinical information was available for 282 and the nutrition questionnaire was completed by 290; N—sample size.

3. Results

Table 2 shows the candidate genes. Table 3 shows the SNPs that were significantly associated with beneficial effects while Table 4 shows the significant SNPs which were associated with adverse effects on the symptoms of people with CD. Table S1 shows the Brassicacea frequencies [n(%)] by SNPS. A total of 37 variants were identified as having beneficial effects (p values from 0.00097 to 0.0497) and 64 SNPs with adverse effects (0.0000751 to 0.049). After correcting for multiple testing, two SNPs in two genes remained significant with adverse reactions to Brassicaceae. The rs7515322 variant in DIO1 was associated with Broccoli, and the rs9469220 variant in HLA was associated with rocket. These p-values were marked with an asterisk (*) (Table 4).

Table 2. CD related single nucleotide polymorphisms (SNPs) for association with Brassicaceae.

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Table 2. CD related single nucleotide polymorphisms (SNPs) for association with Brassicaceae.
GeneNameSNPChr
DIO1deiodinase, iodothyronine, type Irs112062441
rs75153221
IL23Rinterleukin 23 receptorrs112090261
interleukin 23 receptorrs75178471
ITLN1intelectin (galactofuranose binding)rs22749101
SEP1515 kDa selenoproteinrs58451
15 kDa selenoproteinrs58591
TNFRSF1Btumor necrosis factor receptor superfamily, member 1Brs33971
TNFSF15tumor necrosis factor (ligand) superfamily, member 15rs70295541
ATG16L1ATG16 autophagy related 16-like 1rs102103022
SLC11A1solute carrier family 11 (proton-coupled divalent metal ion transporters), member 1rs37318652
AMTaminomethyltransferasers119220133
Aminomethyltransferasers14645673
BSNbassoon presynaptic cytomatrixrs21311093
bassoon presynaptic cytomatrixrs42836053
CDKAL1CDK5 regulatory subunitrs69084253
FHITfragile histidine triad geners22501143
GPX1glutathione peroxidase 1rs18006683
SLC6A6solute carrier family 6 (neurotransmitter transporter, taurine), member 6rs412840113
solute carrier family 6 (neurotransmitter transporter, taurine), member 6rs46851543
TFtransferrinrs17998993
TLR9toll-like receptor 9rs57438363
TRAIPTRAF interacting protein rs108659593
TRAF interacting proteinrs175981373
TRAF interacting proteinrs22719603
TRAF interacting proteinrs64462983
USP4ubiquitin specific peptidase 4 (proto-oncogene)rs18657413
ubiquitin specific peptidase 4 (proto-oncogene)rs98818603
CDH29cadherin-related family member 4rs76299364
ATG12ATG12 autophagy related 12 homolog (S. cerevisiae)rs265325
CSF1Rcolony stimulating factor 1 receptorrs22828045
desert_PTGER4desert Prostaglandin E receptor 4 (subtype EP4)rs172346575
desert_PTGER4desert Prostaglandin E receptor 4 (subtype EP4)rs92927775
GPX3glutathione perosidase 3 (plasma)rs20422355
glutathione perosidase 3 (plasma)rs37630135
glutathione perosidase 3 (plasma)rs37927965
glutathione perosidase 3 (plasma)rs37927975
glutathione perosidase 3 (plasma)rs38054355
glutathione perosidase 3 (plasma)rs38285995
glutathione perosidase 3 (plasma)rs81774255
glutathione perosidase 3 (plasma)rs8704075
IBD5inflammatory bowel diseasers100777855
IL12Binterleukin 12B (natural killer cell stimulatory factor 2)rs68876955
IRGMimmunity-related GTPase family, rs49588475
OCTN1/SLC22A4solute carrier family 22 (organic cation/ergothioneine transporter), member rs10501525
OCTN2/SLC22A5solute carrier family 22 (organic cation/carnitine transporter), member 5rs26313675
P4HA2prolyl 4-hydroxylase, alpha polypeptide IIrs43615095
PTGER4prostaglandin E receptor 4 (subtype EP4)rs13736925
prostaglandin E receptor 4 (subtype EP4)rs46137635
SEPP1selenoprotein P, plasma, 1rs38778995
HLAmajor histocompatibility complex, class II, DO alphars94692206
TNFALPHAtumor necrosis factorrs18006296
CLDN12claudin 12rs10171067
claudin 12rs178640067
CNTNAP2contactin associated protein-like 2 rs78072687
IL6interleukin 6 (interferon, beta 2)rs18007957
DEFA6defensin, alpha 6, Paneth cell-specificrs7122768
JAK2janus kinase 2rs107586699
TNFSF15tumor necrosis factor (ligand) superfamily, member 15rs109824129
tumor necrosis factor (ligand) superfamily, member 15rs38109369
tumor necrosis factor (ligand) superfamily, member 15rs78679189
DLG5discs, large homolog 5 (Drosophila)rs228931110
NKX2-3NK2 homeobox 3rs1088336510
JAM3junctional adhesion molecule 3rs1160445511
SLC11A2solute carrier family 11 (proton-coupled divalent metal ion transporters), member 2rs22458912
solute carrier family 11 (proton-coupled divalent metal ion transporters), member 3rs42702012
VDRvitamin D (1,25- dihydroxyvitamin D3) receptorrs797523212
LAMP1lysosomal-associated membrane protein 1rs1287164813
DIO2deiodinase, iodothyronine, type IIrs1288530014
DIO3deiodinase, iodothyronine, type IIIrs119071514
deiodinase, iodothyronine, type IIIrs119071614
deiodinase, iodothyronine, type IIIrs94500614
GPX2|CHURC1-FNTBglutathione peroxidase 2, CHURC1-FNTB readthroughrs180066914
glutathione peroxidase 2, CHURC1-FNTB readthroughrs229632714
glutathione peroxidase 2, CHURC1-FNTB readthroughrs241206514
glutathione peroxidase 2, CHURC1-FNTB readthroughrs273784414
glutathione peroxidase 2, CHURC1-FNTB readthroughrs374259914
SELSselenoprotein Srs496581415
selenoprotein Srs717823915
FAM92Bfamily with sequence similarity 92, member Brs805091016
MAP1LC3Bmicrotubule-associated protein 1 light chain 3 beta rs228848316
microtubule-associated protein 1 light chain 3 betars720472216
microtubule-associated protein 1 light chain 3 beta rs804482016
microtubule-associated protein 1 light chain 3 beta rs805121816
NOD2nucleotide-binding oligomerization domain containing 2rs206684416
STAT3signal transducer and activator of transcription 3rs74416617
TNRC6Ctrinucleotide repeat containing 6Crs436244717
PTPN2protein tyrosine phosphatase, non-receptor type 2rs254215118
ICAM1intercellular adhesion molecule 1rs179996919
TFF3trefoil factor 3 (intestinal)rs22536921
MIFmacrophage migration inhibitory factorrs75562222
CLDN2claudin 2rs12008279X
Table 3. Results of SNPs from the candidate genes associated with beneficial effects of Brassicaceae; showing p-values only; significant p values highlighted in italic and bold; n/r: no response.

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Table 3. Results of SNPs from the candidate genes associated with beneficial effects of Brassicaceae; showing p-values only; significant p values highlighted in italic and bold; n/r: no response.
GeneSNPCauliflowerBroccoliCabbageChinese GreensrocketWatercressMustard powderMustard SauceWasabi
AMTrs119220130.24510.75100.35060.52990.64300.04180.31770.01720.9995
ATG12rs265320.06530.38090.37240.15320.01280.97880.02370.18220.0642
CDH29rs76299360.74310.70830.04540.35850.99000.33560.15220.46270.8607
CNTNAP2rs78072680.08990.49940.27870.02260.35160.12030.35100.13900.9995
CSF1Rrs22828040.01390.34420.45890.13510.69960.54170.99990.94410.9996
DEFA6rs7122760.000970.00160.00480.00940.03020.01970.03100.79530.7298
desert_PTGER4rs9292777n/rn/rn/r0.0296n/rn/r0.97720.2711n/r
FAM92Brs80509100.99960.04100.99950.10010.26750.99960.99990.99991.0000
FHITrs22501140.73370.84030.05900.97470.05080.78760.03540.02260.0507
GPX3rs37630130.01030.01690.99960.28620.27540.28660.40110.62940.4772
GPX3rs37927960.01870.02800.85010.38270.90100.63530.92400.21300.5985
GPX3rs8704070.99960.04750.76590.93680.75420.98590.85200.99990.9996
ICAM1rs17999690.91680.90460.02700.84280.00600.01430.01380.25380.0635
IL6rs18007950.93630.52190.69160.81120.00460.42760.07440.02930.9996
IRGMrs49588470.17830.46370.28140.03780.59380.89850.84820.88030.4834
ITLN1rs22749100.37270.03740.61610.41580.56260.80390.36900.64100.7704
JAM3rs116044550.72610.03500.99960.80630.99970.97990.99990.99990.9997
MAP1LC3Brs22884830.04030.01110.05900.25110.32900.55930.18420.93730.6128
MAP1LC3Brs72047220.23860.03610.30330.35140.55580.80650.31610.70940.7709
MAP1LC3Brs80448200.58990.88220.02230.50650.86660.42330.41100.99990.9997
MIFrs7556220.01390.00470.21910.34750.36670.53910.99990.27371.0000
NKX2.3rs108833650.02690.12110.14470.01570.05520.02250.09640.11200.9195
NOD2rs20668440.89280.62650.85170.97350.41150.98200.03970.99990.9996
PTGER4rs13736920.18420.08900.97420.01120.47110.56270.95940.31130.4380
PTPN2rs25421510.01030.00190.00230.02860.10770.00900.99990.98580.9168
SEP_15rs58590.67060.19940.05350.42490.39150.70170.04970.58200.9369
SEPP1rs38778990.00450.01270.77900.11280.74540.03600.77900.66070.5572
SLC6A6rs41284011n/rn/r0.0094n/rn/rn/r0.99990.9999n/r
SLC6A6rs46851540.58970.96350.65350.11910.19270.04700.25400.85300.4554
TNFRSF1Brs33970.28350.08960.14020.11930.04930.58720.99990.99901.0000
TNFSF15rs38109360.87820.52390.51990.12910.88470.04570.89600.26500.7494
TNFSF15rs78679180.04380.08240.16520.06130.22480.07180.07290.18700.7609
TNRC6Crs43624470.06360.19060.93910.02850.85950.07950.99700.57300.4840
TRAIPrs175981370.99950.99970.99960.99960.99960.99960.99990.09510.0248
TRAIPrs22719600.32670.03540.36210.36360.42240.81820.29400.10500.9996
TRAIPrs64462980.04240.05560.60710.09890.18270.14090.98400.22700.9997
USP4rs98818600.85900.38270.32140.87270.68170.93070.80770.04490.2229
Table 4. Results of SNPs from candidate genes associated with adverse effects of Brassicaceae; showing p-values only; significant p values highlighted in italic and bold. (* Remained significant after applying multiple testing correction using false discovery rate).

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Table 4. Results of SNPs from candidate genes associated with adverse effects of Brassicaceae; showing p-values only; significant p values highlighted in italic and bold. (* Remained significant after applying multiple testing correction using false discovery rate).
GeneSNPBroccoliCabbageCauliflowerChinese GreensRocketWatercressHorseradishMustard powderMustard SauceWasabi
AMTrs14645670.06520.93680.06670.03760.24020.21710.93540.47830.82410.5862
ATG16L1rs102103020.71400.02320.21580.05590.39500.33980.25280.45250.05370.3769
BSNrs21311090.34180.58380.03170.65930.48650.45340.52930.58100.59590.6147
BSNrs42836050.72910.10960.77570.82190.54480.62080.02350.94200.79790.4625
CDH29rs76299360.13950.70870.04940.14810.20220.22510.55190.58410.96840.0803
CDKAL1rs69084250.87500.62550.88910.82460.29990.02980.26570.70700.34700.5407
CLDN12rs10171060.86620.02910.38610.99960.99960.99000.05340.33360.08120.0527
CLDN12rs178640060.37100.19130.37230.03120.28930.88060.80010.52300.95200.8456
CLDN2rs120082790.40420.81270.88160.10020.04810.89820.32400.81700.88220.5584
desert_PTGER4rs172346570.33190.04580.65350.06720.83780.99580.09590.02440.65300.1830
DIO1rs112062440.32960.09680.49870.21540.24480.52800.01360.34600.15200.4456
DIO1rs75153220.000167 *0.10700.08640.51970.22080.05120.66580.34400.65500.3161
DIO2rs128853000.23050.71100.98090.28110.57100.55320.00830.08330.20000.1935
DIO3rs11907150.02520.89630.63160.67610.98750.55350.20950.53800.53860.0211
DIO3rs11907160.13620.11260.98060.31820.55790.03610.10600.27200.25300.0039
DIO3rs9450060.59670.27920.29230.71760.60020.92020.07910.22300.19800.0019
DLG5rs22893110.30030.08300.84460.78540.87300.04230.27110.13900.76600.5258
FHITrs22501140.37700.45060.44900.00660.86200.42850.13170.93200.51100.0191
GPX1rs18006680.57730.75000.73130.60760.28720.26120.04180.16770.42770.1434
GPX2rs18006690.35620.03740.26520.32660.92010.99970.30970.11100.08300.7837
GPX2rs22963270.62880.87220.63160.47660.12520.87740.37340.80500.84500.0392
GPX2rs24120650.67470.89850.68860.79370.97860.73600.08070.03770.01010.0164
GPX2rs27378440.57890.66130.21040.21190.28710.47910.28380.06370.15430.0230
GPX2rs37425990.52810.77620.83610.53210.79830.74950.11210.13260.06730.0276
GPX3rs20422350.38410.55880.07190.33110.00190.09580.48100.28500.50600.1288
GPX3rs37927960.60280.56770.72840.73360.18330.47950.85150.02020.39040.7421
GPX3rs37927970.85690.65720.94860.49270.01350.05460.80750.32640.94580.2587
GPX3rs38054350.03550.39070.23921.00000.02510.09960.17620.57500.83800.1363
GPX3rs38285990.64410.18370.65080.70010.03680.17430.71330.06740.70720.3305
GPX3rs81774250.03000.64360.00400.10060.24890.47420.81500.99990.99990.3026
HLArs94692200.50980.37600.41800.29100.0000751 *0.22410.21650.63600.56560.4644
IBD5rs100777850.60670.69850.34010.92510.21850.04470.74560.77400.91200.8265
IL12Brs68876950.74050.03990.58530.01590.47120.51170.08070.24170.03090.0131
IL23Rrs112090260.02390.15840.50100.34940.48150.86820.53040.44500.80000.7140
IL23Rrs75178470.10360.01940.08450.00400.87930.02530.27310.30320.68690.9516
JAK2rs107586690.61940.58040.01120.59260.68080.18910.47300.39000.98340.4026
JAM3rs116044550.29930.76120.33130.76780.01720.99970.27340.85700.27000.9695
LAMP1rs128716480.13600.86430.01540.42940.80061.00000.53180.43500.28800.2019
MAP1LC3Brs80512180.80730.04730.45870.42530.99960.07090.06870.49400.44800.3652
NOD2rs20668440.12700.86700.04840.41700.97600.19400.70670.04630.16700.7287
OCTN1rs10501520.00280.06300.01670.11740.26920.96000.04220.07140.12300.0691
OCTN2rs26313670.00260.12220.00710.08620.40660.79190.02730.03220.16650.0317
P4HA2rs43615090.16830.29700.25690.07960.03670.23320.55640.18050.24970.0298
PTGER4rs46137630.27210.07520.66810.03640.59220.52150.12370.02100.62500.4243
SELSrs49658140.03480.03260.86010.64100.15830.30800.06460.67770.76200.8457
SELSrs71782390.03290.02190.54080.95850.29710.19620.11680.59000.86800.9406
SEP_15rs58450.45630.02320.90030.29000.60730.04750.57420.34180.06920.8078
SEP_15rs58590.40500.01490.80410.28950.53950.02870.29790.39800.05110.4922
SLC11A1rs37318650.77900.74990.03020.55380.90350.86470.61700.71680.48850.5708
SLC11A2rs2245890.13520.27710.32330.59820.04330.01840.28810.14400.55500.4478
SLC11A2rs4270200.69980.75630.04940.82530.00980.07720.24220.64770.86840.0282
SLC6A6rs46851540.94130.33520.77190.03590.40940.62880.98410.52600.94910.3369
STAT3rs7441660.52400.03270.22390.29320.92020.47680.56760.65100.22560.6283
TFrs17998990.02690.42950.62920.74910.82850.67870.60080.70400.52700.5817
TFF3rs2253690.16070.34940.01710.95420.82370.84190.83380.19280.77040.3020
TLR9rs57438360.55910.04950.65910.33290.30570.42650.53400.90000.63700.2379
TNF.ALPHArs18006290.03910.84130.35260.39250.39410.23030.93870.20800.37900.1965
TNFSF15rs109824120.87580.62160.78210.74700.61710.02880.98200.75280.21330.7304
TNFSF15rs70295540.60690.71340.79870.87990.50540.02720.59180.57700.04820.4466
TRAIPrs108659590.01940.35720.05800.36370.08230.40260.58070.94870.96800.0578
TRAIPrs175981370.01940.37660.01520.78120.66670.20560.30280.57900.60200.4352
USP4rs18657410.17370.23350.06630.03370.32550.65250.18600.63600.82080.6487
USP4rs98818600.02320.12750.04740.06570.98790.83380.06350.76690.87240.4960
VDRrs79752320.85570.55180.63550.67890.14310.48630.04880.69400.37800.4483

4. Discussion

On looking more closely at the candidate SNPs associated with CD that were tested for beneficial or adverse effects with the ingestion of selected Brassicaceae, we noted, as one would expect with an inflammatory disorder like Crohn’s disease that several of the genes associated with these SNPs were involved in functions relating to immunity. AGT12 (rs26532) and AGT16L1 (rs10210302) are necessary for autophagy; CSFIR (rs2282804), governs macrophages, DEFA6 (rs712276) relates to the Paneth cells and its role in defence and HLA (rs9469220) a major histocompatibility complex, also involves the immune system. The ICAM1gene, (rs1799969) is expressed on the cells of the immune system and the endothelium [27]. IL12B, (rs6887695), has also been associated with another immune disorder, asthma [28]. IRGM, (rs4958847) is a gene associated with the autophagy pathway in CD [29]. IL23R, (rs11209026 and rs7517847) is another gene recognised as being involved in the adaptive immunity pathway as is JAK2 (rs10758669) which is also essential for signalling events in innate immunity [28]. PTPN2 (rs2542151) controls a range of cellular processes e.g., cell growth and TLR9 (rs5743836) has a major role in both innate and adaptive immunity [28].

A number of SNPs are also associated with genes involved in cell transport, rs1050152 (SLC22A4/OCTN1) and rs2631367 (SLC22A5/OCTN2) linked to carnitine [30,31,32]; rs224589 and rs427020 (SLC11A2) linked to iron. ITLN1 (rs2274910) and TF (rs1799899) are other genes associated with iron metabolism [28]. The SNPs rs41284011 and rs4685154 (SLC6A6) are linked with taurine which is linked to muscle function and having CD has been linked to diminished muscle strength [33,34,35]. Another gene of interest is the VDR gene (rs7975232) which facilitates the action of vitamin D3, as well as having a role in the homeostasis of calcium [36]. CDH29 (rs7629936) is also a gene, with a SNP identified in this analysis, linked to calcium via calcium-reliant cell adhesion proteins [28]. Other genes of note are associated with responses of people with CD eating Brassicaceae are the DIO1 (rs11206244 and rs75153322) and DIO3 (rs1190715, rs1190716, and rs945006) genes which are important for the proper functioning of the thyroid gland. DIO1, also encodes selenoproteins [37,38] as does GPX3, (rs2042235, rs3763013, rs3792796, rs3792797, rs3805435, rs3828599, rs8177425, and rs870407, GPX1 (rs1800668) and GPX2 (rs1800669, rs2296327, rs2412065, rs2737844, rs37425990).

It is curious to note that six of the candidate genes identified have SNPS that are linked with both adverse and beneficial effects. The SNP rs7629936 (CDH29) is associated with adverse effects for cauliflower and beneficial effects for cabbage. The SNP rs2250114 (FHIT) is associated with adverse effects to Chinese greens and wasabi but beneficial effects for mustard powder and mustard sauce. The SNP rs3792796 (GPX3) is associated with adverse effects to mustard powder with beneficial effects to cauliflower and broccoli. The SNP rs2066844 (NOD2) is associated with adverse effects to cauliflower and mustard sauce and beneficial effects to mustard powder. The SNP rs5859 (SEP15) is associated with adverse effects to cabbage and watercress but beneficial effects to mustard powder. The SNP rs9881860 (USP4) is associated with adverse effects to broccoli and Chinese greens and beneficial effects to mustard sauce.

These differences in tolerance may relate to the different composition of each Brassicaceae. Brassicaceae differ in their nutritional components especially with respect to their phytochemical composition [8]. They are also unique in that they contain the phytochemicals known as glucosinolates. Up to two hundred different glucosinolates have been recorded [39]. These have been intensely researched because of their links with cancer reduction and properties associated with destroying or inhibiting the growth of bacteria, fungi and nematodes [40]. Each plant species of the Brassicaceae family may also contain up to four different classes of glucosinolates. The most common glucosinolates in cabbage are for example glucobrassicin, glucoraphanin, glucotropaeolin and sinigrin whereas in broccoli the abundant glucosinolates are glucoraphanin, glucobrassicin, gluconapin, and progoitrin [41]. Rocket’s predominate glucosinolates are glucoraphanin, DMB-GLS and glucoerucin [42].

When the vegetables are cooked, the glucosinolates reach the large intestine intact and the microbiota release the isothiocyanates and other metabolites with diverse outcomes [43]. The different combinations of glucosinolates in combination with particular SNPs may contribute to dissimilar outcomes produced by the microbiota. People with Crohn’s disease also have a microbiota community that differs from those with a normal gut [44]. So these differences too in the microbiota communities will also play a part in the difference in response. Escherichia coli are bacteria which have been identified as having increased numbers in those with Crohn’s disease [45,46,47,48]. They have also been associated with formation of granuloma (a common feature of Crohn’s disease) when internalised by macrophages in vitro [49]. Escherichia coli movement across Membranous cells (M-cells) has been shown in vitro to be reduced by soluble plant fibres such as broccoli [50]. [M-cells are part of the epithelium on the lymphoid follicles of the large intestine and act as a portal by which microorganisms can gain entry] [51].The ingestion of broccoli has also been shown in the IBD mouse model mdr1a(−/−) to lower inflammation in the large bowel through changes in the microbiota metabolism [52]. However, from the analysis provided in this paper, this response maybe modulated in a different way in humans depending on the particular SNP they have. For example the SNP rs9469220 variant in HLA and the SNP rs7515322 in DIO1 which remained significant after correcting for multiple testing.

The rs9469220 variant in HLA was associated with an adverse reaction to the Brassicaceae rocket. HLA (human leucocyte antigen) genes are located in the region of MHCII in chromosome 6. This is very close to the HLA complexP5 (HCP5) which is associated with susceptibility to autoimmune diseases [53]. Variations in the HLA region have been associated with an inflammatory colonic phenotype [54,55,56]. HLA contains 4 classes and this SNP is with the class II MHC subgroup DO alpha. Both Class I and II HLA genes are necessary for normal lymphocyte performance [56]. This subgroup is associated with extracellular proteins that regulate peptide loading with antigens [57,58]. Class II molecules engage with CD4 T cells. These activate an immune response which may involve inflammation with the enlisting of phagocytes or activate B cells engaging antibodies in the immune response [59,60]. The polymorphism rs9469220 (identified in this study with an adverse response to rocket) has been linked to total IgE levels [61,62]. IgE has a pivotal role in type I sensitivity associated with allergic forms of asthma, rhinitis, urticaria and dermatitis [63]. IgE is also recognized as providing immunity to parasites [64]. The fact that the SNP rs9469220, in people with CD in this study is significantly associated with an adverse reaction to the Brassicaceae rocket would suggest that ingestion of this food engages the immune response in a type I sensitivity reaction. Hence an exacerbation of symptoms of CD occurs.

The other SNP which remained significant after correcting for multiple testing, was SNP (rs7515322) in DIO1. DIO1 is part of the family of selenoenzymes which are important signalling molecules which activate or deactivate thyroid hormones, so play a key role in thyroid metabolism. As thyroid hormones are key to the development and metabolism of most tissues, these selenoproteins have a significant contribution to make. The DIO1 gene is located in chromosome 1p33-p32 [28]. It is described as a thioredoxin fold integral membrane protein found in the plasma membrane. Transcripts of it have been identified in the intestines, thyroid, gonads, pituitary gland and placenta [65]. DIO1 has a number of roles. It supplies a large portion of circulating plasma T3, it also acts as a scavenging enzyme removing inactive iodothyronines and recycling iodine, as well as playing a part in thyronamine biosynthesis [66,67,68]. Studies have also shown DIO activity associated with local inflammation and tumoural tissues [69,70]. DIO1 as a selenoprotein has also been discovered to be protective against iodine deficiency when its activity is reduced with selenium deficiency. This was observed in regions of endemic goitre, when selenium was given to people with iodine deficiency with a consequent lowering of thyroid function [71]. Selenium levels have been reported as being significantly lower in New Zealand people with Crohn’s disease [72]. People in New Zealand with Crohn’s disease and low selenium levels and with this SNP rs7515322 may have also a heightened adverse response to Broccoli.

However, another mechanism may be involved. Critically ill people have been shown to have lower DIO1 hepatic activity, and this has been thought to be modulated through Cytokines e.g., IL1, IL6 and TNFα [73]. Cytokines may also decrease the function of DIO1 and IL-1β has been shown to inhibit DIO1 activities in hepatocarcinoma cell lines [74]. IL-1β is one of the cytokines increased in patients with Crohn’s disease [75] and associated with inflammation in this disorder. This SNP rs9469220 could link to an adverse response through progoitrin one of the most abundant glucosinolates in broccoli [41]. Progoitrin after ingestion is converted to goitrin by the activity in bacteria [76] and goitrin is known to decrease thyroid hormone production [77].

In addition, many adults in NZ are in a state of mild iodine deficiency with the adult population having a medium iodine concentration of 53 µg/L [78]. Schneider et al. in their murine study showed that DIO1 may enable the major thyroid hormone T3 to be released into the circulatory system when an animal was iodine deficient [66]. Thyrocytes also react quickly to iodine deficiency by increasing the release of angiogenic signals. This is a VEGF-A dependent process [79]. VEGF production has been shown to be significantly increased with active Crohn’s disease [80].

Those people with CD having this SNP rs7515322 may with the ingestion of broccoli experience a greater degree of deficiency in iodine. This combined with a decrease in DIO1 activity from the influence of IL-1beta activity associated with CD (DIO1 normally increases with iodine deficiency) as well as an increased VEGF levels with the release of angiogenic signals with thyrocyte production, may exacerbate their symptoms of CD.

When investigating individual SNPs from this analysis of a New Zealand population with CD, it is interesting to note the two SNPs which are significantly associated with adverse effects (after correcting for multiple testing) to the two Brassicaceae—broccoli and rocket. Studying a wider range of Brassicaceae would increase the possibility of the identification of more significant SNPs and improve the range of Brassicaceae that would be available to choose from. If people want to avoid the long and tedious trial and error approach to working out what they can eat, or be more discerning about advice given to avoid many of the Brassicaceae as in the FODMAP diet [81] knowledge of their SNP profile and how it interacts with Brassicaceae would be helpful. It would enable people to select Brassicaceae more appropriately and maximise on their nutritional benefits.

5. Conclusions

It is now possible to identify two specific SNPs rs7515322 (DIO1), and rs9469220 (HLA) associated with the two forms of Brassicaceae broccoli and rocket respectively, with regard to having an adverse effect on the symptoms of people with CD. Further research is required to substantiate our findings and to conclusively determine the nature of the observed association of an adverse effect with the two forms of Brassicaceae broccoli and rocket and the two SNPs rs7515322 (DIO1), and rs9469220 (HLA) respectively, with CD. This study indicates that the tolerance of some varieties of Brassicaceae may be predicted by analysis of a person’s genotype. This information is a step towards enabling those with CD to select appropriate Brassicaceae and be exposed to key nutrients. This raises the possibility that with suitable nutrition, there is a real prospect of a significant improvement in symptoms associated with this disorder.

Abbreviations

CDCrohn’s Disease
IBDinflammatory bowel disease
NZNew Zealand
SNPSingle nucleotide polymorphism
UCUlcerative Colitis

Acknowledgements

This analysis was based on the secondary analysis of data from the “Genes and Diet in IBD Study”. The authors of this original data set were Angharad R Morgan, Wen Jiun Lam, Christopher M Triggs and Alan G Fraser. Nutrigenomics New Zealand is a collaboration between AgResearch Ltd., Plant and Food Research and The University of Auckland, with funding through the Ministry of Business, Innovation and Employment (MBIE). This particular study was possible through the financial support from the Valrae Collins’ scholarship for research on CD.

Conflicts of Interest

The authors declare no conflicts of interest.

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