Gastroenterology

Gastroenterology

Volume 125, Issue 4, October 2003, Pages 1032-1041
Gastroenterology

Clinical-alimentary tract
A major non-HLA locus in celiac disease maps to chromosome 191 ,

https://doi.org/10.1016/S0016-5085(03)01205-8Get rights and content

Abstract

Background & aims: The pathogenesis of celiac disease is still unknown despite its well-known association with human leukocyte antigen (HLA)-DQ2 and DQ8. It is clear that non-HLA genes contribute to celiac disease development as well, but none of the previous genome-wide screens in celiac disease have resulted in identification of these genes. Methods: We, therefore, performed a 2-stage, genome-wide screen in 101 affected sibpairs from 82 Dutch families who met strict diagnostic criteria. The small intestinal biopsy samples, on which the original celiac disease diagnoses had been based, showed a Marsh III lesion in all patients on reevaluation by 1 pathologist. For association analysis of markers in regions linked to celiac disease, 216 independent MIII patients and 216 age- and sex-matched controls were available. Results: As expected, highly significant linkage to the HLA-region was detected (multipoint maximum lod score [MMLS] = 8.14). More importantly, significant linkage was also present at 19p13.1 (MMLS = 4.31), with the peak at marker D19S899. Moreover, this marker was also significantly associated with celiac disease in the case-control study (corrected P = 0.016). Furthermore, we identified suggestive linkage to 6q21–22, which is ∼70 cM downstream from the HLA region (MMLS = 3.10). Conclusions: Significant linkage of celiac disease to chromosome region 19p13.1 was detected in our genome-wide screen. These results were confirmed by the association of D19S899 to celiac disease in an independent case-control cohort. Furthermore, we identified a possible second celiac disease locus on chromosome region 6q21–22.

Section snippets

Study subjects

Families with 2 or more siblings affected with celiac disease were invited to participate in our study through an advertisement in the Dutch Celiac Society’s newsletter. Several families were also referred by their medical specialists. Blood was collected from those families in which the affected siblings were diagnosed by a small-bowel biopsy. All biopsy samples on which the original celiac disease diagnosis had been established were collected and sent to an experienced pathologist (J.W.R.M.)

Initial genome-wide screen

Sixty-seven families with 84 affected sibpairs were available for the initial genome-wide screen. Power calculations were performed to estimate the chance to detect susceptibility loci with different relative risks to a sibling of a celiac disease patient (λs). It was estimated that, with this set of families, the chance to detect a locus with a λs of 1.5 was 20%, a λs of 2.0 was 72%, a λs of 2.5 was 94%, and λs of 3.0 was 99%. A whole genome screen with microsatellite markers was performed in

Discussion

Sixty-seven families with affected sibpairs of Dutch ancestry were available for the initial genome-wide screen. A total of 84 affected sibpairs were present in these families. It was shown by power calculations that this dataset had a very high chance of detecting a celiac disease susceptibility locus with a locus-specific λs ≥ 2.5 (>94%). Also, the chance to detect a locus with a λs of 2.0 is still reasonably good (72%). However, this dataset has limited power to detect loci with smaller

Acknowledgements

The authors thank the Dutch Celiac Disease Foundation for helping us contact the celiac disease families and to all the families who participated in our study; Arjenne Kors, Anath Oren, and Winny van der Hoeven for collecting the blood samples; Eric Strengman and Ruben van ‘t Slot for isolating the DNA and checking the blind control samples; Lude Franke for blasting the primer sequences; Alienke Monsuur for typing part of the chromosome 6 markers; Bobby Koeleman for statistical advice; Greetje

References (34)

  • L.M Sollid

    Molecular basis of celiac disease

    Annu Rev Immunol

    (2000)
  • L Greco et al.

    The first large population based twin study of coeliac disease

    Gut

    (2002)
  • N Woolley et al.

    A new locus for coeliac disease mapped to chromosome 15 in a population isolate

    Hum Genet

    (2002)
  • L Greco et al.

    Existence of a genetic risk factor on chromosome 5q in Italian coeliac disease families

    Ann Hum Genet

    (2001)
  • A.T Naluai et al.

    Genome-wide linkage analysis of Scandinavian affected sib-pairs supports presence of susceptibility loci for celiac disease on chromosomes 5 and 11

    Eur J Hum Genet

    (2001)
  • A.L King et al.

    CTLA-4/CD28 gene region is associated with genetic susceptibility to coeliac disease in UK families

    J Med Genet

    (2002)
  • P Holopainen et al.

    Candidate gene regions and genetic heterogeneity in gluten sensitivity

    Gut

    (2001)
  • Cited by (0)

    Supported by a grant from the Dutch Digestive Diseases Foundation (WS 97-44 to C.W. and R.H.J.H.).

    1

    This study is dedicated to the memory of Lodewijk Sandkuijl (1953–2002), who died shortly after its completion. He was an inspiration to us and was a world expert on biostatistics.

    Deceased.

    View full text