Session Information
Session Title: Epidemiology and Health Services Research III: Healthcare Costs and Mortality in Rheumatic Disease
Session Type: Abstract Submissions (ACR)
Background/Purpose: Familial risk of RA is composed of shared genetic and environmental factors. Previous studies exploring familial risk of RA have not incorporated environmental factors or stratified RA by serologic status. We aimed to estimate the familial risk for all, seropositive, and seronegative RA adjusting for known RA environmental risk factors.
Methods: We conducted a prospective study of family history and RA among a subset of 121,700 women followed since 1976 in the Nurses’ Health Study. In 2008, 74,024 participants provided information about family history (FH) of RA or lupus by affected first-degree relative (FDR). RA cases were validated by medical record review according to the 1987 ACR criteria for RA classification. RA serologic status was defined as +RF or ACPA by chart review or laboratory measurement. Cox proportional hazards models were performed to estimate the hazard ratio (HR) and 95% confidence interval (CI) for RA phenotypes (all, seropositive, and seronegative) by affected FDR. Cox regression models were performed for any FH and environmental factors previously shown to be associated with RA (cigarette smoking pack-years, alcohol consumption, parity, breastfeeding duration, body mass index, alcohol intake, menopause, hormone use, menses regularity, and age at menarche) for each RA phenotype.
Results: In 2,082,926 person-years of follow-up in the Nurses’ Health Study, we validated 532 RA cases (311 seropositive and 221 seronegative) among 74,024 women that provided information on FH. Any FH of RA or lupus in FDRs was reported in 143 (27%) cases and 6,856 (9%) non-cases. Any FH was associated with all RA (HR 3.76, 95% CI 3.10-4.57), seropositive RA (HR 4.03, 95% CI 3.14-5.17), and seronegative RA (HR 3.98, 95% CI 2.93-5.42) (Table 1). RA risk was greatest for those with parental FH. After adjusting for environmental factors, any FH remained significantly associated with all RA (HR 3.66, 95% CI 3.01-4.45), seropositive RA (HR 3.93, 95% CI 3.06-5.06), and seronegative RA (HR 3.84, 95% CI 2.82-5.23) (Table 2). After adjusting for FH, smoking >10 pack-years, overweight body mass index, and breastfeeding duration ≥12 months all remained significantly associated with RA.
Conclusion: In this large prospective cohort, women with a first-degree relative with RA or lupus had a four-fold increase in risk of RA compared to those with no family history. This association was similar for seropositive and seronegative RA and remained significant after adjusting for RA environmental risk factors, suggesting that familial RA risk is not fully explained by known environmental factors.
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Table 1. Age-adjusted hazard ratios for family history of RA or lupus by first-degree relatives (FDR: parent, sibling, or offspring) and RA phenotypes (all, seropositive, and seronegative) in the Nurses’ Health Study (n=74,024). |
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|
All RA |
Seropositive RA |
Seronegative RA |
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|
Family history |
HR |
95% CI |
HR |
95% CI |
HR |
95% CI |
|
No FDR |
1.0 |
Ref |
1.0 |
Ref |
1.0 |
Ref |
|
Any FDR |
3.76 |
3.10-4.57 |
4.03 |
3.14-5.17 |
3.98 |
2.93-5.42 |
|
1 FDR |
3.46 |
2.81-4.25 |
3.72 |
2.85-4.85 |
3.56 |
2.56-4.96 |
|
≥2 FDRs |
7.06 |
4.59-10.87 |
7.80 |
4.38-13.88 |
8.87 |
4.61-17.06 |
|
Parent |
4.36 |
3.47-5.46 |
5.20 |
3.91-6.93 |
4.25 |
2.92-6.19 |
|
Sibling |
3.46 |
2.54-4.73 |
3.22 |
2.11-4.90 |
4.28 |
2.92-6.19 |
|
Offspring |
4.27 |
2.89-6.34 |
3.83 |
2.22-6.62 |
5.23 |
2.93-9.32 |
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Table 2. Multivariable analyses of family history of RA or lupus in any first-degree relative (FDR) and environmental factors estimating hazard ratios for RA phenotypes (all, seropositive, and seronegative) in the Nurses’ Health Study (n=74,024). |
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All RA |
Seropositive RA |
Seronegative RA |
|
Multivariable models |
HR (95% CI) |
HR (95% CI) |
HR (95% CI) |
|
Family history1 |
|
|
|
|
No FDR |
1.0 (Ref) |
1.0 (Ref) |
1.0 (Ref) |
|
Any FDR |
3.66 (3.01-4.45) |
3.93 (3.06-5.06) |
3.84 (2.82-5.23) |
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Cigarette smoking pack-years2 |
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|
Never to ≤10 |
1.0 (Ref) |
1.0 (Ref) |
1.0 (Ref) |
|
10 to 20 |
1.50 (1.15-1.94) |
1.75 (1.27-2.41) |
1.15 (0.73-1.81) |
|
≥20 |
1.57 (1.29-1.92) |
1.69 (1.31-2.18) |
1.41 (1.03-1.94) |
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WHO body mass index category2 |
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Normal or underweight |
1.0 (Ref) |
1.0 (Ref) |
1.0 (Ref) |
|
Overweight |
1.26 (1.04-1.53) |
1.27 (0.99-1.62) |
1.29 (0.94-1.75) |
|
Obese |
1.07 (0.83-1.37) |
0.99 (0.71-1.38) |
1.26 (0.86-1.85) |
|
Alcohol intake (g/day)2 |
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|
Never to ≤5 |
1.0 (Ref) |
1.0 (Ref) |
1.0 (Ref) |
|
5 to <10 |
0.76 (0.57-1.02) |
0.72 (0.49-1.05) |
0.82 (0.52-1.31) |
|
≥10 |
0.99 (0.79-1.25) |
0.97 (0.72-1.30) |
1.02 (0.71-1.48) |
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Parity and breastfeeding duration2 |
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Parous, no breastfeeding |
1.0 (Ref) |
1.0 (Ref) |
1.0 (Ref) |
|
Parous, 1-11 months |
0.92 (0.75-1.13) |
1.03 (0.79-1.34) |
0.78 (0.56-1.09) |
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Parous, ≥12 months |
0.69 (0.52-0.91) |
0.77 (0.54-1.10) |
0.58 (0.37-0.90) |
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Nulliparous |
1.32 (0.93-1.86) |
1.54 (1.00-2.38) |
1.02 (0.57-1.84) |
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Menopausal status and hormone use2 |
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Post-menopausal, no hormone use |
1.0 (Ref) |
1.0 (Ref) |
1.0 (Ref) |
|
Pre-menopausal |
0.69 (0.50-0.95) |
0.71 (0.48-1.06) |
0.65 (0.39-1.09) |
|
Post-menopausal, hormone use |
1.01 (0.81-1.25) |
1.02 (0.77-1.35) |
1.02 (0.73-1.44) |
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Age at menarche2 |
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≥12 years old |
1.0 (Ref) |
1.0 (Ref) |
1.0 (Ref) |
|
<12 years old |
0.98 (0.79-1.20) |
1.07 (0.83-1.39) |
0.85 (0.60-1.21) |
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Menses regularity2 |
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Regular |
1.0 (Ref) |
1.0 (Ref) |
1.0 (Ref) |
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Irregular |
1.13 (0.88-1.45) |
1.21 (0.88-1.66) |
1.04 (0.69-1.56) |
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1Adjusted for age, cigarette smoking pack-years, WHO body mass index category, alcohol intake, parity, breastfeeding duration, menopausal status, hormone use, age at menarche, and menses regularity. |
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2Adjusted for age and any family history of RA of lupus in first-degree relatives. |
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Disclosure:
J. A. Sparks,
None;
C. Y. Chen,
None;
L. T. Hiraki,
None;
S. Malspeis,
None;
K. H. Costenbader,
None;
E. W. Karlson,
None.
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