Obesity and the risk of systemic lupus erythematosus among women in the Nurses’ Health Studies

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Abstract

Background

Obesity is increasingly prevalent and related to increased risk of several autoimmune diseases, likely via generation of inflammatory adipokines. Prior studies have not evaluated obesity in relation to systemic lupus erythematosus (SLE) risk. We prospectively evaluated whether obesity was associated with increased SLE risk among women in the U.S. Nurses’ Health Study cohorts.

Methods

We conducted a prospective cohort study among 238,130 women in the Nurses’ Health Studies (NHS, 1976–2012; NHSII, 1989–2013). Incident SLE was confirmed by American College of Rheumatology 1997 criteria and validated through medical record review. Body mass index (BMI, kg/m2) was calculated at baseline and on biennial questionnaires. Cox proportional hazards models estimated HRs (95% CIs) for SLE by cumulative average BMI category {18.5 to <25 [normal (reference)], 25 to <30 (overweight), ≥30 (obese)}, adjusting for potential time-varying confounders. Models were performed separately in each cohort; results were meta-analyzed. Sensitivity analyses used simple time-varying BMI, a 4-year lag between exposure and SLE risk window to address potential reverse causation, and evaluated BMI at age 18 and weight change since age 18. A secondary analysis started follow-up in both cohorts at similar calendar years when the prevalence of obesity in the U.S. increased most dramatically [1988 (NHS)/1989 (NHSII)].

Results

We identified 153 NHS incident SLE cases and 115 incident NHSII cases during 5,602,653 person-years of follow-up. At baseline, 8.4% of women in NHS and 11.8% in NHSII were obese. Mean age at enrollment was 42.5 (SD 7.2) years in NHS and 34.4 (SD 4.7) years in NHSII. Cumulative average obesity was significantly associated with SLE risk in NHSII [HR = 1.85 (1.17–2.91)], but not in NHS [HR = 1.11 (0.65–1.87)] compared to normal BMI. In the meta-analysis of both cohorts, obesity was not significantly associated with increased risk of SLE [HR = 1.46 (0.88–2.40)]. Simple time-varying BMI and lagging the exposure window by 4 years produced similar findings to the primary analysis. In NHSII, a 4.54 kg gain between age 18 and enrollment slightly increased SLE risk [HR = 1.09 (1.02–1.18)]. In the secondary analysis starting follow-up of both cohorts at similar calendar years, the point estimate for obesity in NHS was higher than the primary analysis [HR = 1.67 (0.81–3.45)].

Conclusion

We observed an 85% significantly increased risk of SLE among obese compared to normal BMI women in the more recent NHSII cohort, but no association was observed in the earlier NHS cohort. Secular trends in obesity may account for the differences between the two birth cohorts.

Introduction

Systemic lupus erythematosus (SLE) is a heterogeneous, chronic autoimmune disease that occurs predominantly in women. SLE is thought to develop in genetically susceptible individuals after exposure to environmental risk factors. Specific or cumulative environmental exposures may contribute to the initial break in immune tolerance resulting in autoantibody formation and to the subsequent progression to clinical manifestations over time [1]. In a prospective study of U.S. Armed Forces members who were asymptomatic at the time of blood draw, the mean interval between the detection of autoantibodies and onset of SLE was 3.3 years, and was as long as 9.4 years [2]. Thus, the window during which environmental exposures may contribute to the development of SLE is wide.

Among women, a number of reproductive factors have been associated with increased SLE risk: oral contraceptive use [3], [4], age ≤10 at menarche [3]; and use of postmenopausal hormone replacement therapy [3]. Parity and breastfeeding, however, have not been associated with SLE risk [3]. Other environmental risk factors associated with increased SLE risk include current cigarette smoking [5] and crystalline silica [6]. Moderate alcohol intake (>0.5 drinks/day) has been associated with a decreased risk of incident SLE [7].

The prevalence of obesity in the U.S. has been increasing over the past 4 decades, particularly since the late 1980s [8]. In 2014, over 40% of the U.S. adult women fulfilled the World Health Organization definition of obesity [body mass index (BMI) ≥ 30 kg/m2] [9]. Obesity is a serious public health problem, associated with increased risk for many chronic diseases including hypertension [10], type 2 diabetes [11], osteoarthritis [12], coronary artery disease [13], and cancer [14]. Adipose tissue secretes inflammatory cytokines, termed adipokines, the presence of which may contribute to the development of chronic diseases in individuals with additional genetic or environmental risk factors. Adipose tissue also increases circulating estrogens via aromatase enzymes, which convert androgens to estrogens [15]. Prospective cohort studies have identified associations between obesity and increased risk of other autoimmune diseases, such as rheumatoid arthritis [16], [17], [18], psoriatic arthritis [19], [20], and type 1 diabetes [21], [22]. However, to our knowledge, no previous study has investigated an association between obesity and risk of incident SLE.

We hypothesized that chronic obesity was associated with increased risk for incident SLE among women, and tested this hypothesis in two prospective cohorts of women: the U.S. Nurses’ Health Study and Nurses’ Health Study II.

Section snippets

Study design and population

The Nurses’ Health Study (NHS) is a prospective cohort that enrolled 121,700 women living in 11 U.S. states at its start in 1976, while Nurses’ Health Study II (NHSII) is a prospective cohort that enrolled 116,430 women living in 14 states in 1989. The cohorts differ by age at enrollment, calendar years of birth, and duration of follow-up and thus comprise two distinct birth cohorts. NHS participants were enrolled at ages 30–55 in 1976, born from 1921 to 1946, and have been followed for 36

Results

We identified 153 incident SLE cases among 114,527 women in NHS, and 115 SLE cases among 109,033 women in NHSII; greater than 90% of women in both cohorts were White. At enrollment, compared to the NHS cohort, NHSII cohort participants were younger, consumed less alcohol, smoked less, were more often pre-menopausal, and had higher oral contraceptive use (Table 1). Mean BMI was also higher in NHSII than NHS participants at cohort entry, with 11.8% obese in NHSII vs. 8.4% in NHS reflecting

Discussion

In this prospective analysis of two very large cohorts of female nurses with detailed covariate data, obese women in the more recent NHSII cohort had an 85% increased risk for developing SLE compared to women with normal BMI. By contrast, we detected no significant increased SLE risk among obese women in the earlier NHS cohort in the primary analysis. In NHSII, both cumulative average obesity and simple time-varying obesity were associated with increased SLE risk, though the point estimate for

Conclusion

We identified an 85% increased risk of SLE among obese women in NHSII, which started enrollment in 1989, and a nonsignificant increase in SLE risk among obese women in NHS, which enrolled women in 1976. Overweight (BMI 25 to <30 kg/m2) compared to normal BMI (18.5 to <25 kg/m2) was not associated with increased SLE risk in either cohort, although significant linear relationships with increasing BMI were observed in NHSII. When the NHS cohort was delayed to start follow-up in the late 1980s, when

Acknowledgments

The authors would like to thank the participants of the Nurses’ Health Studies; the Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School; and the funding sources supporting this work: NIH K24 AR066109, R01 AR057327, L30 AR070514, L30 AR066953, and K23 AR069688. The NHS was supported by National Institutes of Health (NIH) grants AR049880, AR052403, AR059073, AR066109, CA186107, and CA176726. Dr. Barbhaiya and Dr. Sparks receive

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