Participant profiles

The profiles of the 1,201 participants are listed in Table 1. Their mean age was 62 ± 11 years, 46.5% were male, and their mean BMI was 23.3 ± 3.3 kg/m2. These participants had a mean systolic BP of 138 ± 19 mmHg, a mean diastolic BP of 80 ± 12 mmHg, a mean total-C concentration of 214 ± 36 mg/dL, a mean LDL-C of 130 ± 35 mg/dL, a mean HDL-C of 65 ± 17 mg/dL, a mean TG of 117 ± 81 mg/dL, a mean HbA1c of 5.9 ± 0.6%, and a mean uric acid concentration of 5.1 ± 1.4 mg/dL. Evaluation of renal function showed a mean serum creatinine level of 0.79 ± 0.46 mg/dL, a mean eGFR-creatinine of 71.2 ± 14.2 mL/min/1.73m2, a mean serum cystatin-C level of 0.91 ± 0.41 mg/dL, and a mean eGFR-cystatin-C of 83.1 ± 19.4 mL/min/1.73m2. Their mean serum IgG4 level was 44 ± 36 mg/dL, with 42 (3.5%) of the 1,201 participants having serum IgG4 levels > 135 mg/dL (Fig. 1). Their mean serum IgG, IgE, and CH50 levels were 1,319 ± 273 mg/dL, 225 ± 593 IU/mL, and 38 ± 9 U/mL, respectively, with 7.4% and 8.6% being positive for ANA and RF, respectively. Mean intake of proteins, lipids, carbohydrates, polyunsaturated fatty acids, and saturated fatty acids was 15.2 ± 3.2%, 24.7 ± 6.1%, 54.0 ± 8.7%, 6.1 ± 1.5%, and 6.5 ± 2.0%, respectively.

Table 1 Baseline clinical characteristics of 1,201 participants with/without elevated serum IgG4 levelFig. 1

Histogram of serum IgG4 levels in health examination participants. Elevated serum IgG4 levels were observed in 42 patients (3.5%)

Characteristics of the participants with elevated serum IgG4 levels

Compared with the participants having normal serum IgG4 levels, those with elevated serum IgG4 levels were significantly older (65.8 ± 10.5 vs. 61.9 ± 11.2 years, P = 0.026), had a greater male predominance (69% vs. 46%, P = 0.004), and had significantly lower serum HDL-C levels (58.7 ± 12.7 vs. 65.6 ± 17.3 mg/dL, P = 0.018), and significantly higher serum IgG (1,564 ± 349 vs. 1,310 ± 266 mg/dL, P < 0.001), IgE (366 ± 439 vs. 219 ± 598 IU/mL, P < 0.001), and cystatin-C (0.99 ± 0.24 vs. 0.91 ± 0.41 mg/dL, P = 0.015) concentrations. Participants with elevated IgG4 also had significantly lower eGFR-cystatin-C levels (75.6 ± 20.1 vs. 83.3 ± 19.3 mL/min/1.73m2, P = 0.045) and lower intake of lipids (21.8 ± 5.9% vs. 24.9 ± 6.1%, P = 0.007), polyunsaturated fatty acids (5.4 ± 1.4% vs. 6.2 ± 1.5%, P = 0.011), and saturated fatty acids (5.8 ± 2.0% vs. 6.6 ± 2.0%, P = 0.044). The prevalence of smoking history, which has been associated with IgG4-RD [29], tended to be higher in participants with elevated than with normal serum IgG4 levels (60% vs. 46%, P = 0.085). Other variables, including BMI, BP, HbA1c levels, fraction of peripheral blood eosinophils, and prevalence of cancer, allergic diseases, and atherosclerotic diseases, did not differ in participants with and without elevated serum IgG4 levels (Table 1).

Demographic, laboratory, and nutritional factors significantly associated with elevated serum IgG4 levels

Unadjusted logistic regression analyses showed that male sex [odds ratio (OR) 2.666, 95% confidence interval (CI) 1.372–5.180], older age (OR 1.032, 95% CI 1.003–1.062), lower eGFR-cystatin-C (OR 0.980, 95% CI 0.964–0.997), lower serum HDL-C levels (OR 0.973, 95% CI 0.953–0.994), and higher HbA1c levels (OR 1.513, 95% CI 1.107–2.068) were associated with elevated serum IgG4. Assessment of nutritional factors showed that greater carbohydrate intake (OR 1.044, 95% CI 1.003–1.086) and lower intake of proteins (OR 0.893, 95% CI 0.798-1.000), lipids (OR 0.919, 95% CI 0.869–0.972), polyunsaturated fatty acids (OR 0.713, 95% CI 0.564–0.901), and saturated fatty acids (OR 0.818, 95% CI 0.683–0.981) was associated with elevated serum IgG4. Following age- and sex-adjusted analyses, male sex (OR 2.683, 95% CI 1.379–5.220), older age (OR 1.033, 95% CI 1.004–1.063), greater intake of carbohydrates (OR 1.043, 95% CI 1.002–1.085), and lower intake of lipids (OR 0.937, 95% CI 0.884–0.994) and polyunsaturated fatty acids (OR 0.769, 95% CI 0.606–0.978) remained significant, whereas the other five factors did not (Table 2).

Table 2 Odds ratios for elevated serum IgG4 levels in the 1,201 participants

Subgroup analyses in men showed that older age (OR 1.046, 95% CI 1.009–1.084), lower eGFR-cystatin-C levels (OR 0.981, 95% CI 0.963-1.000), and higher HbA1c levels (OR 1.519, 95% CI 1.077–2.143) were significantly associated with elevated serum IgG4. In contrast, analyses in women found that only nutritional factors, including greater carbohydrate intake (OR 1.116, 95% CI 1.040–1.197) and lower intake of lipids (OR 0.876, 95% CI 0.794–0.966), polyunsaturated fatty acids (OR 0.639, 95% CI 0.419–0.973), and saturated fatty acids (OR 0.718, 95% CI 0.521–0.989), were significantly associated with elevated IgG4 (Table 3).

Table 3 Odds ratios for elevated serum IgG4 levels in the male and female participants

In addition, we conducted a sub-analysis excluding one case of IgG4-RD. Unadjusted logistic regression analyses showed that male sex (OR 2.574, 95% CI 1.320–5.020), older age (OR 1.030, 95% CI 1.001–1.060), lower eGFR-cystatin-C (OR 0.980, 95% CI 0.964–0.997), lower serum HDL-C levels (OR 0.975, 95% CI 0.955–0.996), and higher HbA1c levels (OR 1.526, 95% CI 1.116–2.086) were associated with elevated serum IgG4. Assessment of nutritional factors showed that lower intake of lipids (OR 0.924, 95% CI 0.874–0.978), polyunsaturated fatty acids (OR 0.731, 95% CI 0.577–0.926), and saturated fatty acids (OR 0.833, 95% CI 0.693-1.000) was associated with elevated serum IgG4. Following age- and sex-adjusted analyses, male sex (OR 2.590, 95% CI 1.326–5.056), older age (OR 1.031, 95% CI 1.001–1.061), and lower intake of lipids (OR 0.942, 95% CI 0.888–0.999) remained significant, whereas the other five factors did not (Table S1). Subgroup analyses in men showed that older age (OR 1.043, 95% CI 1.006–1.081), lower eGFR-cystatin-C levels (OR 0.981, 95% CI 0.963-1.000), and higher HbA1c levels (OR 1.540, 95% CI 1.090–2.174) were significantly associated with elevated serum IgG4. Analyses in women was the same as those in Table 3 (Table S2).

Diagnosis of IgG4-RD in participants with elevated serum IgG4 levels

Fifteen participants with elevated serum IgG4 agreed to undergo secondary examinations for IgG4-RD (Table 4). Their mean age was 67.9 ± 9.0 years (range 56–93 years). One subject had chronic kidney disease with hydronephrosis and a retroperitoneal lesion (periaortitis/periarteritis) and was diagnosed with possible IgG4-RD based on the 2020 revised Japanese comprehensive diagnostic criteria. According to the 2019 ACR/EULAR classification criteria for IgG4-RD, this participant had an inclusion score of 8 points, but did not meet the threshold for inclusion due to involvement of a single organ and lack of biopsy of the affected organ. This subject was a male in his 70s with a serum IgG4 concentration of 254 mg/dL. His previous medical history included hypertension, renal insufficiency, and right hydronephrosis. Laboratory findings included serum creatinine 2.04 mg/dL; eGFR-creatinine 25.7 mL/min/1.73m2; serum IgG 2,419 mg/dL, serum IgE 464 IU/mL, serum CH50 43 U/mL, and urinary β2-microglobulin 1033 µg/L. Contrast-enhanced computed tomography (CT) showed periaortic/periarterial wall thickening of the abdominal aorta and its major branch and right hydroureteronephrosis (Fig. 2) but involvement of no other organs, such as the salivary and lacrimal glands, pancreas, bile duct, and kidneys.

. Characteristics and results of secondary examination in the 15 participants with elevated serum IgG4 levelsFig. 2

Hydronephrosis and periaortic/periarterial lesion in one participant with elevated serum IgG4 level. Contrast-enhanced computed tomography (CT) imaging showed right hydroureteronephrosis (A, arrow) and periaortic/periarterial wall thickening of the abdominal aorta and its major branch (B)