Background

Breast cancer (BC) is the most common and fatal cancer among women, yet the causal relationship between circulating lipids, lipid-lowering drugs, and BC remains unclear.

Methods

Mendelian randomization (MR) and summary data-based MR (SMR) analysis are used to explore the causal relationship between plasma lipids, lipid-lowering drug targets, and BC.

Results

The result of MR suggested that per mg/dL higher levels of LDL-C (OR = 1.045, FDR = 0.023), HDL-C (OR = 1.079, FDR = 0.003), TC (OR = 1.043, FDR = 0.026), and APOA-I (OR = 1.085, FDR = 2.64E-04) were associated with increased BC risk, while TG was associated with reduced BC risk (OR = 0.926, FDR = 0.003). Per mg/dL higher levels of HDL-C (OR = 1.080, FDR = 0.011) and APOA-I (OR = 1.083, FDR = 0.002) were associated with increased ER+BC risk, while TG was associated with reduced ER+BC risk (OR = 0.909, FDR = 0.002). For every per 1 mg/dL decrease in LDL, HMGCR (OR: 0.839; FDR = 0.016), NPC1L1 (OR: 0.702; FDR = 0.004), and PCSK9 (OR: 0.916; FDR = 0.026) inhibition were associated with reduced BC risk, whereas CETP inhibition (OR: 1.194; FDR = 0.026) was associated with increased BC risk. For every per 1 mg/dL decrease in LDL, HMGCR (OR: 0.822; FDR = 0.023), NPC1L1 (OR: 0.633; FDR = 2.37E-03), and APOB inhibition (OR: 0.816; FDR = 1.98E-03) were associated with decreased ER−BC risk, while CETP inhibition (OR: 1.465; FDR = 0.011) was associated with increased ER−BC risk. SMR analysis indicated that HMGCR was associated with increased BC risk (OR: 1.112; p = 0.044).

Conclusion

Lipids are associated with the BC risk, and lipid-lowering drugs targets HMGCR, NPC1L1, PCSK9, and APOB may be effective strategies for preventing BC. However, lipid-lowering drugs target CETP may potentially increase BC risk.

中文翻译：

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循环脂质、降脂药物靶点和乳腺癌风险：孟德尔随机化和基于汇总数据的孟德尔随机化的综合证据

背景

乳腺癌（BC）是女性中最常见和致命的癌症，但循环脂质、降脂药物和 BC 之间的因果关系仍不清楚。

方法

采用孟德尔随机化 (MR) 和基于汇总数据的 MR (SMR) 分析来探讨血脂、降脂药物靶点和 BC 之间的因果关系。

结果

MR 结果表明，每 mg/dL LDL-C（OR = 1.045，FDR = 0.023）、HDL-C（OR = 1.079，FDR = 0.003）、TC（OR = 1.043，FDR = 0.026）、 APOA-I（OR = 1.085，FDR = 2.64E-04）与 BC 风险增加相关，而 TG 与 BC 风险降低相关（OR = 0.926，FDR = 0.003）。每 mg/dL 较高水平的 HDL-C（OR = 1.080，FDR = 0.011）和 APOA-I（OR = 1.083，FDR = 0.002）与 ER+BC 风险增加相关，而 TG 与 ER+BC 降低相关风险（OR = 0.909，FDR = 0.002）。LDL 每降低 1 mg/dL，HMGCR（OR：0.839；FDR = 0.016）、NPC1L1（OR：0.702；FDR = 0.004）和 PCSK9（OR：0.916；FDR = 0.026）抑制与 BC 降低相关风险，而 CETP 抑制（OR：1.194；FDR = 0.026）与 BC 风险增加相关。LDL 每减少 1 mg/dL，HMGCR（OR：0.822；FDR = 0.023）、NPC1L1（OR：0.633；FDR = 2.37E-03）和 APOB 抑制（OR：0.816；FDR = 1.98E-03） ）与 ER-BC 风险降低相关，而 CETP 抑制（OR：1.465；FDR = 0.011）与 ER-BC 风险增加相关。SMR 分析表明，HMGCR 与 BC 风险增加相关（OR：1.112；p  = 0.044）。

结论

血脂与 BC 风险相关，针对 HMGCR、NPC1L1、PCSK9 和 APOB 的降脂药物可能是预防 BC 的有效策略。然而，针对 CETP 的降脂药物可能会增加 BC 风险。