Diverticulitis and Crohn's disease have distinct but overlapping tumor necrosis superfamily 15 haplotypes

Tara M Connelly; Christine S Choi; Arthur S Berg; Leonard Harris 3rd; Joel Coble; Walter A Koltun

doi:10.1016/j.jss.2017.02.030

Diverticulitis and Crohn's disease have distinct but overlapping tumor necrosis superfamily 15 haplotypes

J Surg Res. 2017 Jun 15:214:262-269. doi: 10.1016/j.jss.2017.02.030. Epub 2017 Feb 27.

Authors

Tara M Connelly¹, Christine S Choi¹, Arthur S Berg², Leonard Harris 3rd¹, Joel Coble³, Walter A Koltun⁴

Affiliations

¹ Division of Colon and Rectal Surgery, Department of Surgery, College of Medicine, The Pennsylvania State University, Hershey, Pennsylvania.
² Department of Public Health Sciences, College of Medicine, The Pennsylvania State University, Hershey, Pennsylvania.
³ Department of Biochemistry and Molecular Biology, College of Medicine, The Pennsylvania State University, Hershey, Pennsylvania.
⁴ Division of Colon and Rectal Surgery, Department of Surgery, College of Medicine, The Pennsylvania State University, Hershey, Pennsylvania. Electronic address: wkoltun@hmc.psu.edu.

PMID: 28624054
DOI: 10.1016/j.jss.2017.02.030

Abstract

Background: Diverticulitis (DD) and Crohn's disease (CD) have overlapping features including bowel structuring, inflammation, and infection. Tumor necrosis superfamily 15 (TNFSF15) is an immunoregulatory, anti-angiogenic gene. CD has been previously associated with a haplotype of five TNFSF15 single-nucleotide polymorphism alleles: rs3810936 (G allele), rs6478108 (A), rs6478109 (G), rs7848647 (G), and rs7869487 (A). We aimed to determine the TNFSF15 risk haplotype for DD versus controls with a subgroup analysis of youthful DD patients (aged ≤55 y) versus older controls (aged ≥55 y).

Methods: A total of 148 diverticulitis patients (90 aged ≤55 y) and 200 controls (87 aged ≥55 y) were genotyped using our custom-designed Illumina Veracode microarray chip. Genotypes from rs3810936, rs6478108, rs6478109, rs7848647, rs7869487 and two additional TNFSF15 single nucleotide polymorphisms, rs3810936 and rs11554257, were analyzed. PHASE version 2.1, R with HaploStats and the Broad Institute's Haploview program were used for statistics and imputed haplotype frequency. Permutation corrected for multiple comparisons.

Results: The CD GAGGA haplotype was significantly associated with diverticulitis (P = 0.03) in the all DD versus all controls comparison. A second haplotype, rs6478108 (A), rs6478109 (G), rs7869487 (A), and rs4263839 (G), was also associated with DD in this cohort (P = 0.025). A third haplotype rs6478108 (A), rs6478109 (G), rs7848647 (G) and rs7869487 (A), rs4263839 (G) was demonstrated in the DD < 55 versus controls >55 comparison (P = 0.045).

Conclusions: Distinct but overlapping TNFSF15 haplotypes were demonstrated in diverticulitis patients versus healthy controls when compared with the known Crohn's risk haplotype suggesting similar but distinct genetic predispositions. This study strengthens the role for a genetic predisposition to diverticulitis that involves the TNFSF15 gene.

Keywords: Crohn's disease; Diverticulitis; Haplotypes; Surgical genetics; TL1A; TNFSF15.

MeSH terms

Adult
Aged
Aged, 80 and over
Case-Control Studies
Crohn Disease / genetics*
Diverticulitis, Colonic / genetics*
Female
Genetic Markers
Genetic Predisposition to Disease*
Genotyping Techniques
Haplotypes*
Humans
Male
Middle Aged
Polymorphism, Single Nucleotide*
Tumor Necrosis Factor Ligand Superfamily Member 15 / genetics*

Substances

Genetic Markers
TNFSF15 protein, human
Tumor Necrosis Factor Ligand Superfamily Member 15