The SPINK gene family and celiac disease susceptibility

Abstract

The gene family of serine protease inhibitors of the Kazal type (SPINK) are functional and positional candidate genes for celiac disease (CD). Our aim was to assess the gut mucosal gene expression and genetic association of SPINK1, -2, -4, and -5 in the Dutch CD population. Gene expression was determined for all four SPINK genes by quantitative reverse-transcription polymerase chain reaction in duodenal biopsy samples from untreated (n=15) and diet-treated patients (n=31) and controls (n=16). Genetic association of the four SPINK genes was tested within a total of 18 haplotype tagging SNPs, one coding SNP, 310 patients, and 180 controls. The SPINK4 study cohort was further expanded to include 479 CD cases and 540 controls. SPINK4 DNA sequence analysis was performed on six members of a multigeneration CD family to detect possible point mutations or deletions. SPINK4 showed differential gene expression, which was at its highest in untreated patients and dropped sharply upon commencement of a gluten-free diet. Genetic association tests for all four SPINK genes were negative, including SPINK4 in the extended case/control cohort. No SPINK4 mutations or deletions were observed in the multigeneration CD family with linkage to chromosome 9p21-13 nor was the coding SNP disease-specific. SPINK4 exhibits CD pathology-related differential gene expression, likely derived from altered goblet cell activity. All of the four SPINK genes tested do not contribute to the genetic risk for CD in the Dutch population.

A functional methylome map of ulcerative colitis

“…Among the replicated findings, several genes have been directly associated with chronic intestinal inflammation; PTN (pleiotrophin) has been shown to be functionally linked to inflammation and cancer (Kadomatsu 2005), while THY1 (Thy-1 cell surface antigen) mediates cell adhesion during inflammation ( Jurisic et al 2010). The serine protease inhibitor SPINK4 has been shown to be differentially expressed in chronic autoimmune intestinal inflammation (celiac disease), likely derived from altered goblet cell activity, while no causative genetic variant was identified (Wapenaar et al 2007). …”

Identification of cis- and trans-acting factors involved in the localization of MALAT-1 noncoding RNA to nuclear speckles

“…SPINK4 (serine peptidase inhibitor Kazal type 4), which encodes a peptide structurally related to pancreatic secretory trypsin inhibitor, was reported as a candidate gene responsible for celiac disease (Wapenaar et al 2007). IFI44 (interferon-induced protein 44), which was originally identified to be a gene induced by interferon-a, has been suggested to encode an antiproliferative protein (Hallen et al 2007).…”

Spink13, an Epididymis-specific Gene of the Kazal-type Serine Protease Inhibitor (SPINK) Family, Is Essential for the Acrosomal Integrity and Male Fertility

“…The SPINK family has a characteristic signature that contains at least one conserved Kazal domain with six consensus cysteines forming a 1-5/2-4/ 3-6 disulfide bond pattern (15). The SPINKs are members of an ancient gene family and exist in animals as diverse as insects, birds, and mammals (16 -18).…”