Targeted genotyping for the prediction of celiac disease autoimmunity development in patients with type 1 diabetes and their family members

Table 1 Demographic data: Participants with type 1 diabetes and their first-degree relatives n (%)

Demographics	T1D only (n = 280)	T1D + CD (n = 22)	FDR only (n = 689)	FDR +CDA (n = 36)
White	249 (88.9)	22 (100)	629 (91.3)	35 (97.2)
Not hispanic	188 (67.1)	15 (68.2)	451 (65.5)	27 (75.0)
Female	178 (63.6)	17 (77.3)	409 (59.4)	26 (72.2)
Age at screening (yr), median (range)	19 (2-72)	14.5 (7-43)	40 (1-74)	39.5 (3-55)
Age at diagnosis of T1D (yr), median (range)	10 (0.1-64)	6.5 (1-21)
Presence of gastrointestinal symptoms (GI sx)	113 (40.5)	6 (27.3)	216 (31.4)	13 (36.1)
Presence of extraintestinal symptoms (Ex sx)	78 (27.9)	3 (13.6)	176 (25.5)	7 (19.4)
Both GI and Ex symptoms	56 (20)	3 (13.6)	98 (14.2)	4 (11.1)
Asymptomatic	144 (51.6)	16 (72.7)	394 (57.3)	20 (55.6)
Human leukocyte antigen (HLA) genotype
DR3-DQ2	49 (18)	2 (9.1)	148 (21.8)	10 (28.6)
DR3-DQ2 homozygote	18 (6.6)	3 (13.6)	25 (3.7)	3 (8.6)
DR7-DQ2	12 (4.4)	1 (4.6)	41 (6.1)	2 (5.7)
DR7-DQ2 homozygote	2 (0.7)	0 (0)	13 (1.9)	0 (0)
DR3/DR7-DQ2 homozygote	1 (0.37)	0 (0)	20 3.0)	3 (8.6)
DR4-DQ8	83 (30.5)	5 (22.7)	205 (30.2)	10 (28.6)
DR3-DQ2/DR4-DQ8	70 (25.7)	7 (31.8)	50 (7.4)	6 (17.1)
DR7-DQ2/DR4-DQ8	6 (2.2)	4 (18.2)	33 (4.9)	0 (0)
DQ2/DQ8 negative	31 (11.4)	0 (0)	142 (20.9)	1 (2.9)
Haptoglobin genotype (HP) (Zonulin)
HP 1-1	46 (16.4)	2 (9.1)	120 (17.4)	8 (22.2)
HP 2-1	118 (42.1)	10 (45.5)	278 (40.4)	21 (58.3)
HP 2-2	116 (41.4)	10 (45.5)	290 (42.2)	7 (19.4)
Any HP2	234 (83.6)	20 (90.9)	568 (82.6)	28 (77.7)

T1D: Type 1 diabetes; CDA: Celiac disease autoimmunity; FDRs: First-degree relatives; GI sx: Gastrointestinal Symptoms; Ex sx: Extraintestinal Symptoms; HLA: Human leukocyte antigen; HP: Haptoglobin genotype.

Table 2 Cohort prevalence of celiac disease and celiac disease autoimmunity

	n	CD	CDA	CD at screening	CDA at screening	CDA prevalence estimation
Type 1 diabetes	302	8 (2.7)	3 (1.0)	8 (2.5)	3 (0.7)	22 (7.3)
First-degree relative	725	9 (1.2)	4 (0.6)	18 (2.7)	5 (1.0)	36 (5.0)

T1D: Type 1 diabetes; FDRs: First-degree relatives; CD: Celiac disease; CDA: Celiac disease autoimmunity.

Table 3 Univariate and multiple regression models: Factors related to celiac disease autoimmunity in participants with type 1 diabetes

	Estimate	Se	Lower limit	Upper limit	Z stat	P-value
Univariate Model (exchangeable correlation)
Female	0.6562	0.5151	-0.3534	1.6659	1.27	0.2027
Age	-0.0314	0.0152	-0.0611	-0.0017	-2.07	0.0383A
Onset of T1D	-0.0658	0.0342	-0.1329	0.0013	-1.92	0.0546
Gastrointestinal (GI) symptoms	-0.5812	0.491	-1.5435	0.3811	-1.18	0.2365
Extraintestinal (EX) symptoms	-0.9204	0.6391	-2.1731	0.3323	-1.44	0.1498
Both GI and EX symptoms	-0.4724	0.6385	-1.7239	0.7791	-0.74	0.4594
No GI or EX symptoms	0.9074	0.4931	-0.059	1.8737	1.84	0.0657
Human Leukocyte Antigen (HLA) DQ2-DR3 Heterozygous	-0.7402	0.7571	-2.2241	0.7437	-0.98	0.3282
HLA DQ2-DR3 Homozygous	0.7843	0.67	-0.5332	2.1019	1.17	0.2433
HLA DQ2-DR7 Heterozygous	0.028	1.0649	-2.0592	2.1152	0.03	0.979
HLA DQ8	-0.3975	0.5234	-1.4233	0.6283	-0.76	0.4475
HLA DQ2-DR3/DQ8	0.2767	0.4814	-0.6668	1.2203	0.57	0.5654
HLA DQ2-DR7/DQ8	2.4851	0.6507	1.2098	3.7604	3.82	0.0001B
HLA DQ2 Heterozygous	-0.575	0.6367	-1.823	0.6729	-0.9	0.3665
HLA DQ2 Homozygous	0.6192	0.666	-0.6862	1.9246	0.93	0.3525
Haptoglobin genotype (HP) 1-1	-0.6932	0.7671	-2.1967	0.8104	-0.9	0.3662
HP 2-1	0.1539	0.4414	-0.7112	1.0191	0.35	0.7273
HP 2-2	0.1525	0.4422	-0.7141	1.0192	0.34	0.7301
Any HP2	0.693	0.767	-0.81	2.197	0.9	0.366
First degree relative (FDR) with celiac disease (CD)	1.4091	0.6188	0.1962	2.622	2.28	0.0228C
FDR with Type 1 diabetes (T1D)	0.0724	0.557	-1.0193	1.1641	0.13	0.8966
FDR with thyroid disease	0.7839	0.4619	-0.1215	1.6892	1.7	0.0897
FDR with other autoimmune disease	1.1634	0.4432	0.2947	2.0321	2.62	0.0087D
CD in another relative	0.4136	0.6598	-0.8796	1.7068	0.63	0.5307
Multiple Regression Model (independence working correlation)
Intercept	-3.3213	0.927	-5.1383	-1.5043	-3.58	0.0003
Age	-0.0121	0.019	-0.0494	0.0252	-0.64	0.5246
Onset of T1D	-0.0396	0.0425	-0.1229	0.0436	-0.93	0.3509
DQ2-DR7/DQ8	2.4131	0.8401	0.7666	4.0596	2.87	0.0041E
No GI or EX symptoms	1.1905	0.6566	-0.0963	2.4774	1.81	0.0698
FDR with CD	0.6927	1.3443	-1.9421	3.3274	0.52	0.6064
FDR with thyroid disease	-0.8976	1.6214	-4.0756	2.2804	-0.55	0.5799
FDR with other autoimmune disease	1.9765	1.7861	-1.5241	5.4771	1.11	0.2685

Significant findings indicated by superscripts. T1D: Type 1 diabetes; FDRs: First-degree relatives; CD: Celiac disease; CDA: Celiac disease autoimmunity; GI sx: Gastrointestinal symptoms; Ex sx: Extraintestinal symptoms; HLA: Human leukocyte antigen; HP: Haptoglobin genotype.

Table 4 Univariate and multiple regression models: Factors related to celiac disease autoimmunity in first degree relatives of participants with type 1 diabetes

	Estimate	Se	Lower limit	Upper limit	Z stat	P-value
Univariate model (exchangeable correlation)
White	1.26	0.88	-0.47	2.98	1.43	0.154
Female	0.5433	0.3674	-0.1768	1.2635	1.48	0.1392
Age	-0.0046	0.0097	-0.0236	0.0144	-0.47	0.6355
Gastrointestinal (GI) symptoms	0.2551	0.3395	-0.4103	0.9206	0.75	0.4524
Extraintestinal (EX) symptoms	-0.3748	0.4596	-1.2756	0.526	-0.82	0.4148
Both GI and EX symptoms	-0.2715	0.5305	-1.3113	0.7682	-0.51	0.6087
No GI or EX symptoms	-0.085	0.3419	-0.7551	0.5851	-0.25	0.8036
Human Leukocyte Antigen (HLA) DQ2-DR3 Heterozygous	0.4255	0.383	-0.3251	1.1761	1.11	0.2666
HLA DQ2-DR3 Homozygous	0.8042	0.7654	-0.696	2.304	1.05	0.2934
HLA DQ2-DR7 Heterozygous	-0.0376	0.6636	-1.3382	1.263	-0.06	0.9548
HLA DQ2-DR3/DR7 Homozygous	1.02	0.715	-0.381	2.42	1.43	0.153
HLA DQ8	-0.0981	0.4058	-0.8934	0.6972	-0.24	0.809
HLA DQ2-DR3/DQ8	0.9272	0.472	0.0021	1.8523	1.96	0.0495A
HLA DQ2/DQ8 Negative	-2.1836	1.0232	-4.1891	-0.1781	-2.13	0.0328B
HLA DQ2 Heterozygous	0.3561	0.388	-0.4043	1.1166	0.92	0.3586
HLA DQ2 Homozygous	0.6842	0.5435	-0.3811	1.7495	1.26	0.2081
Haptoglobin genotype (HP) 1-1	0.2901	0.4341	-0.5607	1.1409	0.67	0.5039
HP 2-1	0.6823	0.3429	0.0103	1.3544	1.99	0.0466C
HP 2-2	-1.0763	0.4252	-1.9096	-0.2429	-2.53	0.0114D
Any HP2	-0.29	0.434	-1.141	0.561	-0.67	0.503
First degree relative (FDR) with CDceliac disease (CD)	1.6768	0.3809	0.9303	2.4233	4.4	<.0001E
FDR with thyroid disease	-0.503	0.4849	-1.4533	0.4473	-1.04	0.2995
FDR with other autoimmune disease	0.6817	0.3606	-0.025	1.3884	1.89	0.0587
CD in other relative	0.5217	0.7115	-0.8728	1.9161	0.73	0.4634
Multiple regression model (independence working correlation)
Intercept	-2.8829	0.404	-3.6746	-2.0912	-7.14	< 0.0001
HLA DQ2-DR3/DQ8	0.9407	0.5381	-0.1139	1.9953	1.75	0.0804
HLA DQ2/DQ8 Negative	-1.9348	1.0275	-3.9487	0.0791	-1.88	0.0597
HP 2-1	0.0804	0.4492	-0.8001	0.9609	0.18	0.858
HP 2-2	-1.0149	0.563	-2.1185	0.0886	-1.8	0.0715
FDR with CD	2.3635	0.7576	0.8787	3.8483	3.12	0.0018F
FDR with other autoimmune disease	-0.8269	0.7245	-2.2468	0.5932	-1.14	0.2538

Significant findings indicated by superscripts. T1D: Type 1 diabetes; FDRs: First-degree relatives; CD: Celiac disease; CDA: Celiac disease autoimmunity; GI sx: Gastrointestinal symptoms; Ex sx: Extraintestinal symptoms; HLA: Human leukocyte antigen; HP: Haptoglobin genotype.