Family Hx Still Independent Risk Factor for RA

The familial risk of rheumatoid arthritis (RA) cannot be explained fully by established genetic and environmental RA risk factors, so family history remains an independent risk factor for RA, researchers reported online in Arthritis and Rheumatism.

The results imply that "family history of RA will remain an important clinical risk factor for RA that cannot be replaced by genotyping of known risk loci or collection of specific risk factors," wrote Xia Jiang, MD, at Karolinska Institutet in Stockholm, and colleagues. "In particular, for ACPA [anti-citrullinated protein antibody]-negative RA, it seems that we have only found factors responsible for a very minor part of the familial aggregation."

The researchers linked national Swedish population registers to the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study, a population-based, case-control study comprised of incident RA cases 18 to 70 years old and matched controls. First-degree relatives of cases and controls were identified through the Swedish Multi-Generation register.

The intent was to assess the extent to which RA familial risk could be explained by established genetic and nongenetic RA risk factors. Medical evidence has identified genetic (shared epitope [SE] and 76 single nucleotide polymorphisms [SNPs]) and several environmental risks for RA.

The 2,844 cases had serology (ACPA) measured through ELISA, using a cutoff of 25 U/mL as positive. There were 1,828 ACPA-positive cases and 1,016 ACPA-negative cases and 4,072 controls in the analysis. First-degree relatives of cases had serology (rheumatoid factor [RF]) determined based on their history of diagnoses of seropositive or seronegative RA in the Patient Register. Information on RF was also available for EIRA cases. Blood from EIRA participants was analyzed, and HLA-DRB1 was genotyped. HLA-DRB1*01, *04, and *10 were defined as SE alleles.

The authors used multiple imputation when information was missing for covariates and to accommodate the potential for selective participation among controls.

Cases were more likely to be smokers, to have one or more biological offspring, to be exposed to silica, and to carry copies of SE. Controls were more likely to be ever drinkers and were more frequent consumers of fatty fish.

Some 11.9% of ACPA-positive cases, 6.5% of ACPA-negative cases, and 3.5% of controls had at least one first-degree relative with RA. The crude familial odds ratio (OR) for RA was 3.05 (95% CI, 2.48-3.76), a ratio that did not change appreciably when adjusting for environmental risk factors individually.

The OR for familial risk declined moderately when adjusted for genetic risk factors. When adjusted for SE, the OR was 2.69 (95% CI 2.17-3.33), when adjusted for 76 SNPs, the OR was 2.55 (95% CI 2.03-3.20), and when adjusted for both, the OR was 2.44 (95% CI 1.93-3.07).

When adjusting for all genetic and nongenetic factors, the OR for familial risk was only slightly lower than ORs adjusted only for genetic factors.