Center for Lipid Metabolomics (R.A.H, Y.L., O.V.D., S.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Division of Cardiovascular Medicine (R.A.H., P.M.R., S.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Circ Res. 2024 Mar;134(5):e3-e14. doi: 10.1161/CIRCRESAHA.123.323623. Epub 2024 Feb 13.
Posttranslational glycosylation of IgG can modulate its inflammatory capacity through structural variations. We examined the association of baseline IgG N-glycans and an IgG glycan score with incident cardiovascular disease (CVD).
IgG N-glycans were measured in 2 nested CVD case-control studies: JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; NCT00239681; primary prevention; discovery; Npairs=162); and TNT trial (Treating to New Targets; NCT00327691; secondary prevention; validation; Npairs=397). Using conditional logistic regression, we investigated the association of future CVD with baseline IgG N-glycans and a glycan score adjusting for clinical risk factors (statin treatment, age, sex, race, lipids, hypertension, and smoking) in JUPITER. Significant associations were validated in TNT, using a similar model further adjusted for diabetes. Using least absolute shrinkage and selection operator regression, an IgG glycan score was derived in JUPITER as a linear combination of selected IgG N-glycans.
Six IgG N-glycans were associated with CVD in both studies: an agalactosylated glycan (IgG-GP4) was positively associated, while 3 digalactosylated glycans (IgG glycan peaks 12, 13, 14) and 2 monosialylated glycans (IgG glycan peaks 18, 20) were negatively associated with CVD after multiple testing correction (overall false discovery rate <0.05). Four selected IgG N-glycans comprised the IgG glycan score, which was associated with CVD in JUPITER (adjusted hazard ratio per glycan score SD, 2.08 [95% CI, 1.52-2.84]) and validated in TNT (adjusted hazard ratio per SD, 1.20 [95% CI, 1.03-1.39]). The area under the curve changed from 0.693 for the model without the score to 0.728 with the score in JUPITER (PLRT=1.1×10) and from 0.635 to 0.637 in TNT (PLRT=0.017).
An IgG N-glycan profile was associated with incident CVD in 2 populations (primary and secondary prevention), involving an agalactosylated glycan associated with increased risk of CVD, while several digalactosylated and sialylated IgG glycans associated with decreased risk. An IgG glycan score was positively associated with future CVD.
IgG 的翻译后糖基化可以通过结构变化来调节其炎症能力。我们研究了基线 IgG N-聚糖和 IgG 聚糖评分与心血管疾病 (CVD) 事件的相关性。
在 2 项嵌套 CVD 病例对照研究中测量了 IgG N-聚糖：JUPITER（使用他汀类药物预防的理由：评价罗苏伐他汀的干预试验；NCT00239681；一级预防；发现；Npairs=162）和 TNT 试验（治疗新靶点；NCT00327691；二级预防；验证；Npairs=397）。使用条件逻辑回归，我们研究了在 JUPITER 中，调整临床危险因素（他汀类药物治疗、年龄、性别、种族、血脂、高血压和吸烟）后，基线 IgG N-聚糖和聚糖评分与未来 CVD 的相关性。在 TNT 中，使用类似的模型进一步调整了糖尿病，对有显著相关性的结果进行了验证。使用最小绝对收缩和选择算子回归，在 JUPITER 中，作为选定 IgG N-聚糖的线性组合，推导出了 IgG 聚糖评分。
在这两项研究中，有 6 种 IgG N-聚糖与 CVD 相关：一种去半乳糖基化聚糖（IgG-GP4）呈正相关，而 3 种双半乳糖基化聚糖（IgG 聚糖峰 12、13、14）和 2 种单唾液酸化聚糖（IgG 聚糖峰 18、20）在经过多次测试校正后与 CVD 呈负相关（总假发现率<0.05）。4 种选定的 IgG N-聚糖构成了 IgG 聚糖评分，该评分与 JUPITER 中的 CVD 相关（每个聚糖评分标准差的调整后危险比，2.08[95%CI，1.52-2.84]），并在 TNT 中得到验证（每个 SD 的调整后危险比，1.20[95%CI，1.03-1.39]）。曲线下面积从无评分模型的 0.693 变为 JUPITER 中的 0.728（PLRT=1.1×10），从 TNT 中的 0.635 变为 0.637（PLRT=0.017）。
在 2 个人群（一级和二级预防）中，IgG N-聚糖谱与 CVD 事件相关，涉及与 CVD 风险增加相关的去半乳糖基化聚糖，而几种双半乳糖基化和唾液酸化 IgG 聚糖与风险降低相关。IgG 聚糖评分与未来 CVD 呈正相关。
