Cardiology Division (M.C.H., J.P.P., P.N.), Massachusetts General Hospital, Harvard Medical School, Boston.
Department of Medicine (M.C.H., J.P.P., P.N.), Massachusetts General Hospital, Harvard Medical School, Boston.
Circulation. 2021 Feb 2;143(5):410-423. doi: 10.1161/CIRCULATIONAHA.120.051775. Epub 2020 Nov 9.
Premature menopause is an independent risk factor for cardiovascular disease in women, but mechanisms underlying this association remain unclear. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy, is associated with accelerated atherosclerosis. Whether premature menopause is associated with CHIP is unknown.
We included postmenopausal women from the UK Biobank (n=11 495) aged 40 to 70 years with whole exome sequences and from the Women's Health Initiative (n=8111) aged 50 to 79 years with whole genome sequences. Premature menopause was defined as natural or surgical menopause occurring before age 40 years. Co-primary outcomes were the presence of any CHIP and CHIP with variant allele frequency >0.1. Logistic regression tested the association of premature menopause with CHIP, adjusted for age, race, the first 10 principal components of ancestry, smoking, diabetes, and hormone therapy use. Secondary analyses considered natural versus surgical premature menopause and gene-specific CHIP subtypes. Multivariable-adjusted Cox models tested the association between CHIP and incident coronary artery disease.
The sample included 19 606 women, including 418 (2.1%) with natural premature menopause and 887 (4.5%) with surgical premature menopause. Across cohorts, CHIP prevalence in postmenopausal women with versus without a history of premature menopause was 8.8% versus 5.5% (<0.001), respectively. After multivariable adjustment, premature menopause was independently associated with CHIP (all CHIP: odds ratio, 1.36 [95% 1.10-1.68]; =0.004; CHIP with variant allele frequency >0.1: odds ratio, 1.40 [95% CI, 1.10-1.79]; =0.007). Associations were larger for natural premature menopause (all CHIP: odds ratio, 1.73 [95% CI, 1.23-2.44]; =0.001; CHIP with variant allele frequency >0.1: odds ratio, 1.91 [95% CI, 1.30-2.80]; <0.001) but smaller and nonsignificant for surgical premature menopause. In gene-specific analyses, only CHIP was significantly associated with premature menopause. Among postmenopausal middle-aged women, CHIP was independently associated with incident coronary artery disease (hazard ratio associated with all CHIP: 1.36 [95% CI, 1.07-1.73]; =0.012; hazard ratio associated with CHIP with variant allele frequency >0.1: 1.48 [95% CI, 1.13-1.94]; =0.005).
Premature menopause, especially natural premature menopause, is independently associated with CHIP among postmenopausal women. Natural premature menopause may serve as a risk signal for predilection to develop CHIP and CHIP-associated cardiovascular disease.
绝经前是女性心血管疾病的独立危险因素，但这种关联的机制尚不清楚。不确定潜能的克隆性造血（CHIP）是指与年龄相关的造血细胞的扩增，这些细胞具有白血病突变但没有可检测到的恶性肿瘤，与动脉粥样硬化的加速有关。绝经前是否与 CHIP 相关尚不清楚。
我们纳入了英国生物库（n=11495）中年龄在 40 至 70 岁的绝经后妇女的全外显子序列，以及妇女健康倡议（n=8111）中年龄在 50 至 79 岁的具有全基因组序列的妇女。绝经前被定义为自然或手术绝经发生在 40 岁之前。主要复合结局是存在任何 CHIP 和 CHIP 变体等位基因频率>0.1。逻辑回归测试了绝经前与 CHIP 的关联，调整了年龄、种族、祖先的前 10 个主成分、吸烟、糖尿病和激素治疗的使用。次要分析考虑了自然与手术性绝经前和特定基因的 CHIP 亚型。多变量调整的 Cox 模型测试了 CHIP 与新发冠状动脉疾病之间的关联。
该样本包括 19606 名女性，其中 418 名（2.1%）有自然性绝经前，887 名（4.5%）有手术性绝经前。在两个队列中，有和没有绝经前史的绝经后女性中 CHIP 的患病率分别为 8.8%和 5.5%（<0.001）。在多变量调整后，绝经前与 CHIP 独立相关（所有 CHIP：比值比，1.36[95%置信区间，1.10-1.68]；=0.004；CHIP 变体等位基因频率>0.1：比值比，1.40[95%置信区间，1.10-1.79]；=0.007）。自然性绝经前的相关性更大（所有 CHIP：比值比，1.73[95%置信区间，1.23-2.44]；=0.001；CHIP 变体等位基因频率>0.1：比值比，1.91[95%置信区间，1.30-2.80]；<0.001），而手术性绝经前的相关性较小且无统计学意义。在特定基因的分析中，只有 CHIP 与绝经前显著相关。在绝经后中年女性中，CHIP 与新发冠状动脉疾病独立相关（与所有 CHIP 相关的风险比：1.36[95%置信区间，1.07-1.73]；=0.012；与 CHIP 变体等位基因频率>0.1 相关的风险比：1.48[95%置信区间，1.13-1.94]；=0.005）。
绝经前，尤其是自然性绝经前，与绝经后女性的 CHIP 独立相关。自然性绝经前可能是易患 CHIP 和 CHIP 相关心血管疾病的风险信号。
