Analysis of the influence of OCTN1/2 variants within the IBD5 locus on disease susceptibility and growth indices in early onset inflammatory bowel disease.
OBJECTIVE
The OCTN1 (SLC22A4 1672C-->T) and OCTN2 (SLC22A5 -207G-->C) variants within the IBD5 locus have been associated with susceptibility to adult onset Crohn's disease (CD), but their contribution in children has not been examined.


METHODS
These OCTN1/2 variants and IBD5 marker single nucleotide polymorphisms (SNPs) (IGR2096a_1, IGR2198a_1, and IGR2230a_1) were examined in 299 Scottish children (200 with CD, 74 with ulcerative colitis (UC), and 25 with indeterminate colitis (IC)), together with 502 parents (for transmission disequilibrium testing) and 256 controls.


RESULTS
All SNPs were in strong linkage disequilibrium (D' >0.94). TDT analysis showed association of the OCTN1 variant with inflammatory bowel disease (IBD) (p = 0.01) and CD (p = 0.04). Allele frequencies of the OCTN1/2 variants were significantly higher in IBD/CD cases (p<0.04). The homozygous mutant OCTN1/2 haplotype was increased in IBD (24.3% v 16.1%, p = 0.02) and UC (28.2% v 16.1%, p = 0.02) compared with controls. The OCTN1/2 variants were not independent of the background IBD5 risk haplotype in conferring disease susceptibility. Unifactorial analysis in CD patients showed that carriage of the TC haplotype was associated with lower weight, height, and BMI centile (<9(th) centile) at diagnosis (weight: 87.9% v 67.3% (p = 0.002), odds ratio (OR) = 3.52 (95% confidence interval, 1.51 to 8.22); height: 84.1% v 68.4% (p<0.05), OR = 2.44 (1.00 to 5.99); BMI: 79.6% v 61.1% (p = 0.02), OR = 2.49 (1.14 to 5.44)), and lower weight centile at follow up (87.5% v 64.6% (p = 0.03), OR = 3.83 (1.03 to 14.24)). Multifactorial binary logistic regression analysis confirmed association of the TC haplotype with lower weight centile at diagnosis (p = 0.02, OR = 3.41 (1.20 to 9.66)).


CONCLUSIONS
These data implicate variants within the IBD5 haplotype, as determinants of disease susceptibility and growth indices in early onset IBD. The OCTN1/2 variants remain potential positional candidate genes, but require further analysis.
Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, UK. richardkrussell71@hotmail.com
R K
RK
Russell
H E
HE
Drummond
E R
ER
Nimmo
N H
NH
Anderson
C L
CL
Noble
D C
DC
Wilson
P M
PM
Gillett
P
P
McGrogan
K
K
Hassan
L T
LT
Weaver
W M
WM
Bisset
G
G
Mahdi
J
J
Satsangi
D000293:Adolescent; D000328:Adult; D000886:Anthropometry; D016022:Case-Control Studies; D002648:Child; D003093:Colitis, Ulcerative / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D003424:Crohn Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006128:Growth; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000150:complications / Q000235:genetics; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D015810:Linkage Disequilibrium; D008297:Male; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D000074058:Solute Carrier Family 22 Member 5; D027981:Symporters
D027701:Organic Cation Transport Proteins; C109807:SLC22A4 protein, human; C492020:SLC22A5 protein, human; D000074058:Solute Carrier Family 22 Member 5; D027981:Symporters