Additional AID in Multiplex T1D Families (fig. )
Additional autoimmunity was significantly higher among the sib-pairs than among the parent-offspring families (55.6 vs. 37.9%, respectively; p = 0.05). In 22.2% of the sib-pairs and in 8.6% of the parent-offspring families, coexistent AID was found in both the first-affected family member (in the parent-offspring family: the parent) and the second-affected family member (p = 0.03).
Additional AID in multiplex T1D families.
Associated Autoimmunity in Familial and Sporadic Patients (table )
Demographic Data. The mean duration of follow-up was comparable in the familial subgroups as well as in the sporadic group. Within the familial group, mean age at diagnosis was similar in the parent-offspring and the sib-pairs. Gender distribution revealed a male preponderance (60.2%) in the parent-offspring group and a slight female predominance (53.1%) in the sib-pairs (p = 0.047). These two parameters were not analyzed in the sporadic group as the patients were age- and gender-matched.
Additional AID. The overall frequency of additional AID as well as the percentage of patients with two or more coexistent autoimmunities were similar in the familial and sporadic patients. Among the familial T1D patients, the frequency of additional AID tended to be more prevalent in the sib-pairs than in the parent-offspring sub-group. The percentage of patients with two or more coexistent autoimmunities was significantly higher in the sib-pairs than in the parent-offspring group (11.7 vs. 4.1%, p = 0.04).
Type of AID. AIT was the most common co-morbidity in both familial subgroups and the sporadic group. The prevalence of AIT, CD, PA and ‘other’ coexistent autoimmunities was comparable in familial and sporadic groups. Within the familial group, each autoimmune co-morbidity tended to be higher in the sib-pair group; this difference reached statistical significance (p = 0.006) only for PA.
The most frequent combinations of additional AID were AIT with CD (10 patients, 5 familial and 5 sporadic) and AIT with PA (7 patients, 5 familial and 2 sporadic). Other combinations were: CD with PA, and CD or PA with ‘other’ autoimmunities.
Timing to Detection of AID Relative to T1D Diagnosis. Associated AID were detected before diagnosis, simultaneously with diagnosis, and after diagnosis of T1D in 8.1, 19.2, and 72.7%, respectively, of the familial cases and in 6.5, 17.2, and 76.3%, respectively, of the sporadic cases with a similar distribution in the familial subgroups. Although statistically not significant, the median time elapsed between diagnosis of T1D and co-occurrence of other autoimmunity tended to be shorter in the familial than in the sporadic patients, particularly in the sib-pair subgroup. In both familial and sporadic groups, the sequence of occurrence of the various AID was similar, with CD appearing first, thyroid disease second and PA last. In the familial group, CD was detected significantly earlier and PA significantly later than the remaining AID (p = 0.02 and p = 0.049, respectively).
Autoimmunity in T1D patients – comparison between familial and sporadic cases and between familial subgroups (parent-offspring and sib-pairs)
Autoimmunity in Nuclear Family Members (table )
The number of families positive for AID and frequency of diseases in each family were significantly higher in the familial group (p < 0.001 and p = 0.001, respectively). The prevalence and the frequency of AID per family tended to be higher in the sib-pair subgroup.
Positive autoimmunity in nuclear families was clustered into three categories: AIT, CD, and ‘other’ AID. While thyroid autoimmunity was the most common disease among both familial and sporadic nuclear families, thyroid and ‘other’ autoimmunities were significantly more prevalent in the nuclear families of the familial cases (p = 0.014 and p < 0.001, respectively). The rate of two or three types of autoimmunity per family was significantly higher among familial than sporadic nuclear families (15.7 vs. 5.3%, p < 0.001).
Autoimmunity in nuclear family members – comparison between familial and sporadic cases and between familial subgroups (parent-offspring and sib-pairs)
Predictors of Autoimmune Co-Occurrence
Logistic regression analysis of additional AID clustered together showed that female gender was associated with coexistent AID in both familial and sporadic groups (OR = 2.28, CI [1.07, 4.85], p = 0.03 and OR = 2.26, CI [1.06, 4.85], p = 0.04, respectively). Presence of autoimmunity in the nuclear family was associated with coexistent AID only in the familial cases (OR = 2.11, CI [1.0, 4.49], p = 0.05). Age at diagnosis of T1D and duration of diabetes was not associated with co-occurrence of autoimmunity in either the familial or sporadic cases.
HLA Class II Typing
Among the 64 sib-pair T1D patients who underwent HLA typing, 28 patients had co-existent AID. The percentage of susceptibility alleles in the HLA class II DR3 region was more frequent among patients with associated AIT than those without AIT (82.4 vs. 56.5%, respectively; p = 0.05). The percentage of susceptibility alleles in the HLA class II DR3-DQ2 region was more frequent among patients with associated CD than those without CD (87.5 vs. 60%; the difference did not reach statistical significance, probably due to the small number of subjects tested). The frequency of DR3-DQ2 was higher in patients with a greater number of coexistent AID: with none, 57.1%, with one, 71.4%, and with two or more, 87.5%. The distribution of nucleotide polymorphisms in CTLA-4 was similar in patients with and without AIT.