Hereditary factors in primary biliary cholangitis (PBC) have been well defined in genome-wide association studies, but there are few direct data available that define the relative risk (RR) for family members with an affected proband. An increased risk in first-degree relatives has been demonstrated in a variety of studies, but data have been lacking on further detailed associations for subsequent generations. The objective of this study was to use the unique Icelandic genealogical database to study the familiality of PBC. All patients with positive antimitochondrial antibody measurements in Iceland during the period 1991-2015 who fulfilled diagnostic criteria for PBC were included. The Icelandic genealogical database was used to assess familial relations. For each case of PBC, 10,000 control subjects matched for age, sex, and number of known relatives were randomly chosen from this database to calculate the familial RR of PBC. The average kinship coefficient (KC) of the patients was calculated and compared with the average KC of controls. Overall, 222 PBC patients were identified (182 females, 40 males; median age, 62 years). First-, second- and third-degree relatives of the PBC patients had a high RR of the disease: 9.13 (P < 0.0001), 3.61 (P = 0.014) and 2.59 (P = 0.008), respectively. In fourth- and fifth-degree relatives, the RR was also increased to 1.66 (P = 0.08) and 1.42 (P = 0.08), respectively. The average KC of the patients was also higher than that of the control subjects, with 21.34 × 10-5 versus 9.56 × 10-5 (P < 0.0001). Conclusion: Relatives of PBC patients had markedly higher risk for development of the disease compared with controls and importantly our data demonstrate that the risk was significantly increased even in second- and third-degree relatives.
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