HLA Genotype as a Risk Factor for Celiac Disease Among Relatives

Presence of High-risk HLA Genotype Is the Most Important Individual Risk Factor for Coeliac Disease Among At-Risk Relatives

Saana Paavola; Katri Lindfors; Laura Kivelä; Juliana Cerqueira; Heini Huhtala; Päivi Saavalainen Riku Tauschi; Katri Kaukinen; Kalle Kurppa

Disclosures

Aliment Pharmacol Ther. 2021;54(6):805-813.

Abstract and Introduction

Abstract

Background: Family screening has been advocated as a means to reduce the major underdiagnosis of coeliac disease. However, the precise risk of the disease in relatives and the impact of patient- and relative-related individual factors remain obscure.

Aims: To investigate the individual risk of coeliac disease among patients' relatives.

Methods: Altogether 2943 relatives of 624 index patients were assessed for the presence of previous coeliac disease diagnosis, or were screened for the disease. Coeliac disease-associated human leucocyte antigen (HLA) genotype was determined from all participants. The association between individual factors and new screening positivity was assessed by logistic regression.

Results:There were 229 previously diagnosed non-index relatives with coeliac disease and 2714 non-affected (2067 first-degree, 647 more distant) relatives. Of these 2714 relatives, 129 (4.8%) were screening-positive (first-degree 5.1%, second-degree 3.6%, more distant 3.5%). The combined prevalence of the previously diagnosed and now detected cases in relatives was 12.2% (6.3% clinically detected, 5.9% screen-detected). In univariate analysis, age <18 years at diagnosis (odds ratio 1.60, 95% CI 1.04–2.45) in index, and age 41–60 years (1.73, 1.10–2.73), being a sibling (1.65, 1.06–2.59) and having the high-risk genotype (3.22, 2.01–5.15 DQ2.5/2.5 or DQ2.5/2.2 vs other risk alleles) in relatives were associated with screening positivity. Only high-risk HLA remained significant (2.94, 1.80–4.78) in multivariable analysis.

Abstract and Introduction
Methods
Results
Discussion
References

Table 1. Clinical characteristics and HLA distribution in 2714 at-risk relatives with positive ^a or negative screening outcome
	Positive screening, n = 129		Negative screening, n = 2585		P value
	n	%	n	%	P value
Age at screening, median (Q₁, Q₃), y	40 (20, 53)		36 (17, 55)		0.556
Age <18 y at screening	29	22.7	667	26.0	0.404
Women	72	55.8	1435	55.5	0.946
Member of multiple-case family^b	35	27.1	631	24.4	0.483
Degree of consanguinity with index
First-degree relatives	106	82.2	1961	75.9	0.260^c
Sibling	51	48.1	732	37.3	0.073^d
Offspring	33	31.1	783	39.9
Parent	22	20.8	446	22.7
Second-degree relatives^e	19	14.7	515	19.9
More distant relatives	4	3.1	109	4.2
HLA risk group^f					<0.001
High^g	27	26.5	156	7.0
Intermediate^h	75	73.5	1394	62.3
Lowⁱ	0	0	686	30.7

^aPositive endomysium and transglutaminase antibodies and presence of human leucocyte antigen (HLA) DQ2 and/or DQ8.
^bAt least two first- or second-degree relatives previously diagnosed with coeliac disease.
^cFirst-degree vs second-degree vs more distant.
^dAmong first-degree relatives.
^eGrandparent, grandchild, aunt, uncle, niece, nephew, half-sibling.
^fData missing from 376 screened relatives.
^gDQ2.5 homozygotes and DQ2.5/2.2.
^hDQ2.5 heterozygotes or DQ2.2 and/or DQ8 positive.
ⁱDQ2 and DQ8 negative.

Table 2. Logistic regression analysis of different index- and relative-related characteristics for positive screening outcome ^a in 2714 at-risk relatives
	Univariate	Multivariable
	Univariate	Model 1^b	Model 2^c	Model 3^d
	OR (95% CI)	OR (95% CI)	OR (95% CI)	OR (95% CI)
Index characteristics
Age <18 y at diagnosis	1.60 (1.04–2.45)		1.34 (0.80–2.23)	1.41 (0.80–2.51)
Women	0.73 (0.49–1.07)
High vs intermediate risk HLA	1.37 (0.89–2.12)
Dermatitis herpetiformis	0.91 (0.55–1.52)
Autoimmune co-morbidity	1.39 (0.86–2.23)
TVA vs PVA/SVA	1.02 (0.68–1.62)
Relative characteristics
Age <18 y at screening	0.84 (0.55–1.28)
Women	1.01 (0.71–1.45)
High^e vs intermediate^f risk HLA	3.22 (2.01–5.15)			2.94 (1.80–4.78)
Consanguinity with index
Offspring	1	1	1	1
Sibling	1.65 (1.06–2.59)	1.67 (1.00–2.79)	1.51 (0.88–2.58)	1.30 (0.71–2.35)
Parent	1.17 (0.67–2.03)	1.58 (0.82–3.05)	1.29 (0.61–2.72)	1.05 (0.45–2.44)
Second-degree relative	0.88 (0.49–1.57)	0.86 (0.48–1.55)	0.84 (0.46–1.52)	0.90 (0.46–1.76)
More distant relative	0.87 (0.30–2.51)	0.91 (0.31–2.62)	0.84 (0.29–1.27)	1.24 (0.41–3.76)
Multiple-case family	1.15 (0.77–1.72)
Age at screening, years
0–20	1	1	1	1
21–40	1.06 (0.65–1.74)	0.97 (0.58–1.61)	1.01 (0.60–1.69)	1.06 (0.59–1.91)
41–60	1.73 (1.10–2.73)	1.21 (0.71–2.07)	1.30 (0.75–2.26)	1.62 (0.88–2.97)
61-	0.70 (0.37–1.33)	0.48 (0.23–1.01)	0.57 (0.26–1.27)	0.51 (0.19–1.34)

Note: Characteristics notified in multivariable analysis were ^bconsanguinity with the index and relative's age at screening; ^cmodel 1 and age of index <18 y at diagnosis; ^dmodel 2 and high vs intermediate risk HLA of relatives.
Abbreviations: OR, odds ratio; PVA, partial villous atrophy; SVA, subtotal villous atrophy; TVA, total villous atrophy.
^aPositive endomysium and transglutaminase antibodies and presence of human leucocyte antigen (HLA) DQ2 and/or DQ8.
^eDQ2.5 homozygotes and DQ2.5/2.2.
^fDQ2.5 heterozygotes and DQ2.2 and/or DQ8 positive.