Pediatric Celiac Disease More Common With HLA Haplotype

Ricki Lewis, PhD

July 03, 2014

Human leukocyte antigen (HLA) haplotype DR3-DQ2 is associated with dosage-dependent increases in risk for celiac disease autoimmunity and celiac disease in young children, according to a study published in the July 3 issue of the New England Journal of Medicine.

Although most patients with celiac disease have at least 1 copy of DR3-DQ2 or DR4-DQ8, these haplotypes are also common in the general population. DR3-DQ2 carries a higher risk than DR4-DQ8.

Edwin Liu, MD, from the Digestive Health Institute, Children’s Hospital Colorado, and the Barbara Davis Center, University of Colorado Denver, Aurora, and colleagues investigated HLA predisposition to celiac disease among children enrolled in the Environmental Determinants of Diabetes in the Young (TEDDY) multinational prospective cohort study.

The researchers followed-up 6403 children with predisposing HLA haplotypes identified at birth, considering the effects of sex, family history of celiac disease, and nation on the incidence of celiac disease autoimmunity. Participants came from Sweden, German, Finland, and the United States.

The primary endpoint was evidence of celiac disease autoimmunity (serum tissue transglutaminase [tTG] antibodies on 2 consecutive tests at least 3 months apart), and the secondary endpoint was development of celiac disease (diagnosis on biopsy or persistently elevated tTG antibodies). The researchers conducted annual antibody testing beginning at the 2-year visit. They used stored blood samples to extrapolate onset of a detectable antibody response.

Celiac disease autoimmunity developed in 786 (12%) of the 6403 children. Of the 350 children who underwent biopsy of the small intestine, celiac disease was confirmed in 291. Twenty-one other children who were not biopsied had persistent elevation of tTG antibodies, increasing the number of children with diagnosed celiac disease to 312. One quarter of these children were diagnosed before age 3 years.

Homozygosity for the haplotypes presented greater risk than heterozygosity. Risks for celiac disease autoimmunity and celiac disease by age 5 years were 11% and 3%, respectively, among DR3-DQ2 heterozygotes and 26% and 11%, respectively, among homozygotes. For DR3-DQ2, hazard ratios for celiac disease autoimmunity were 2.09 (95% confidence interval [CI], 1.70 - 2.56) among heterozygotes and 5.70 (95% CI, 4.66 - 6.97) among homozygotes compared with children who had 1 or 2 DR4-DQ8 haplotypes.

Children with first-degree relatives with celiac disease were at elevated risk for celiac disease autoimmunity. Girls were at higher risk than boys, and children living in Sweden also were at higher risk (hazard ratio, 1.90; 95% CI, 1.61 - 2.25), with a risk nearly twice that of US children. Family history of type 1 diabetes was not a significant factor.

Homozygosity for DR3-DQ2 increased adjusted risk for celiac disease autoimmunity 5-fold, and heterozygosity doubled the risk. Swedish children face both a higher risk and earlier onset of celiac disease.

The study confirms the association of DR3-DQ2 with celiac disease autoimmunity and demonstrates a gene dosage effect. Limitations of the study include the fact that not all children were biopsied and that lower levels of autoantibodies were not considered.

Differences in risk among children from the 4 nations may reflect the age at which gluten exposure begins and the duration of breast-feeding. The researchers call for further investigation of the interplay of prenatal, environmental, and inherited factors in contributing to the risk of developing celiac disease.

The researchers have disclosed no relevant financial relationships.

N Engl J Med. 2014;371:42-49. Abstract

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