Statistical Genetics Research Group, Institute of Medical Biometry, Heidelberg University, Heidelberg, Germany.
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
Breast Cancer Res. 2023 Oct 2;25(1):111. doi: 10.1186/s13058-023-01713-5.
Latin American and Hispanic women are less likely to develop breast cancer (BC) than women of European descent. Observational studies have found an inverse relationship between the individual proportion of Native American ancestry and BC risk. Here, we use ancestry-informative markers to rule out potential confounding of this relationship, estimating the confounder-free effect of Native American ancestry on BC risk.
We used the informativeness for assignment measure to select robust instrumental variables for the individual proportion of Native American ancestry. We then conducted separate Mendelian randomization (MR) analyses based on 1401 Colombian women, most of them from the central Andean regions of Cundinamarca and Huila, and 1366 Mexican women from Mexico City, Monterrey and Veracruz, supplemented by sensitivity and stratified analyses.
The proportion of Colombian Native American ancestry showed a putatively causal protective effect on BC risk (inverse variance-weighted odds ratio [OR] = 0.974 per 1% increase in ancestry proportion, 95% confidence interval [CI] 0.970-0.978, p = 3.1 × 10). The corresponding OR for Mexican Native American ancestry was 0.988 (95% CI 0.987-0.990, p = 1.4 × 10). Stratified analyses revealed a stronger association between Native American ancestry and familial BC (Colombian women: OR = 0.958, 95% CI 0.952-0.964; Mexican women: OR = 0.973, 95% CI 0.969-0.978), and stronger protective effects on oestrogen receptor (ER)-positive BC than on ER-negative and triple-negative BC.
The present results point to an unconfounded protective effect of Native American ancestry on BC risk in both Colombian and Mexican women which appears to be stronger for familial and ER-positive BC. These findings provide a rationale for personalised prevention programmes that take genetic ancestry into account, as well as for future admixture mapping studies.
与欧洲血统的女性相比，拉丁美洲和西班牙裔女性罹患乳腺癌（BC）的可能性较低。观察性研究发现，个体美洲原住民血统比例与 BC 风险之间呈反比关系。在这里，我们使用种系信息标记物排除这种关系的潜在混杂因素，估计美洲原住民血统对 BC 风险的无混杂作用。
我们使用分配信息量测量值为个体美洲原住民血统比例选择稳健的工具变量。然后，我们根据 1401 名哥伦比亚女性（其中大多数来自昆迪纳马卡和胡拉的安第斯中部地区）和 1366 名来自墨西哥城、蒙特雷和韦拉克鲁斯的墨西哥女性进行了单独的孟德尔随机分析，并进行了敏感性和分层分析。
哥伦比亚美洲原住民血统比例的增加与 BC 风险呈负相关（按 ancestry proportion 每增加 1%，反向方差加权比值比 [OR] 为 0.974，95%置信区间 [CI] 为 0.970-0.978，p=3.1×10）。墨西哥美洲原住民血统的相应 OR 为 0.988（95%CI 0.987-0.990，p=1.4×10）。分层分析显示，美洲原住民血统与家族性 BC 之间的关联更强（哥伦比亚女性：OR=0.958，95%CI 0.952-0.964；墨西哥女性：OR=0.973，95%CI 0.969-0.978），对雌激素受体（ER）阳性 BC 的保护作用强于 ER 阴性和三阴性 BC。
本研究结果表明，在哥伦比亚和墨西哥女性中，美洲原住民血统与 BC 风险之间存在无混杂的保护作用，对于家族性和 ER 阳性 BC 作用更强。这些发现为考虑遗传血统的个体化预防计划以及未来的混合映射研究提供了依据。
