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Background <p>Estrogens exert a beneficial effect on metabolism. Women carrying <i>BRCA</i> likely pathogenic/pathogenic variants (LP/PV) are at increased risk of premature menopause and may therefore be at higher risk of developing metabolic disorders later in life. In this single-center prospective cohort study, we investigated whether the specific <i>BRCA</i> mutation (<i>BRCA</i>1 vs. <i>BRCA</i>2) has a differential impact on metabolism in women.</p> Methods <p>Eligible participants were <i>BRCA</i> LP/PV carriers who were premenopausal or underwent menopause –either natural or iatrogenic– within the 5 years prior to enrollment. Blood samples for lipid and glucose panels were obtained every 6 months, for a total of four time points. Body composition variables were evaluated at baseline and at the final follow-up using bioimpedance analysis. Glucose tolerance was assessed using the homeostatic model assessment for insulin resistance (HOMA-IR). Associations between lipid and glucose profile and patient characteristics were evaluated using univariable and multivariable linear regression models.</p> Results <p>Fifty-seven BRCA1 and 58 BRCA2 LP/PV carriers were included in the final analysis. At baseline, <i>BRCA1</i> LP/PV carriers had a higher body mass index (BMI) (27.3 vs. 24.6&#xa0;kg/m<sup>2</sup>, <i>p</i> = 0.01) and higher fat mass (27.3 vs. 21.9&#xa0;kg, <i>p</i> = 0.013) than <i>BRCA2</i> LP/PV carriers. Insulin levels and HOMA-IR were consistently higher in <i>BRCA1</i> than in <i>BRCA2</i> LP/PV carriers at all time points, and this difference was not attributable to age, BMI, menopausal status, risk-reducing salpingo-oophorectomy, previous chemotherapy or use of cholesterol-lowering agents. The lipid profile was similar between the groups, although <i>BRCA1</i> LP/PV carriers showed a tendency toward a less favorable profile (higher LDL and lower HDL).</p> Conclusions <p>These prospective results suggest that <i>BRCA1</i> LP/PV carriers might have impaired glucose tolerance and a greater tendency toward insulin resistance compared with <i>BRCA2</i> LP/PV carriers: this first report needs further independent confirmations from other cohorts.</p>

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Impaired glucose tolerance in women with BRCA1 versus BRCA2 pathogenic or likely pathogenic variants: Results from a prospective cohort study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月14日

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  • Giovanni Grandi,
  • Claudia Piombino,
  • Giovanna Sighinolfi,
  • Elena Barbieri,
  • Marta Venturelli,
  • Chiara Melotti,
  • Rebecca Lippi Bruni,
  • Valentina Grisendi,
  • Riccardo Cuoghi Costantini ,
  • Mina Grippa,
  • Emma Zattarin,
  • Elena Tenedini,
  • Elisabetta Razzaboni,
  • Giulia Brigante,
  • Roberto D’Amico,
  • Benedetta Nanni,
  • Renata Menozzi,
  • Laura Cortesi,
  • Massimo Dominici,
  • Antonio La Marca,
  • Angela Toss

摘要

Background

Estrogens exert a beneficial effect on metabolism. Women carrying BRCA likely pathogenic/pathogenic variants (LP/PV) are at increased risk of premature menopause and may therefore be at higher risk of developing metabolic disorders later in life. In this single-center prospective cohort study, we investigated whether the specific BRCA mutation (BRCA1 vs. BRCA2) has a differential impact on metabolism in women.

Methods

Eligible participants were BRCA LP/PV carriers who were premenopausal or underwent menopause –either natural or iatrogenic– within the 5 years prior to enrollment. Blood samples for lipid and glucose panels were obtained every 6 months, for a total of four time points. Body composition variables were evaluated at baseline and at the final follow-up using bioimpedance analysis. Glucose tolerance was assessed using the homeostatic model assessment for insulin resistance (HOMA-IR). Associations between lipid and glucose profile and patient characteristics were evaluated using univariable and multivariable linear regression models.

Results

Fifty-seven BRCA1 and 58 BRCA2 LP/PV carriers were included in the final analysis. At baseline, BRCA1 LP/PV carriers had a higher body mass index (BMI) (27.3 vs. 24.6 kg/m2, p = 0.01) and higher fat mass (27.3 vs. 21.9 kg, p = 0.013) than BRCA2 LP/PV carriers. Insulin levels and HOMA-IR were consistently higher in BRCA1 than in BRCA2 LP/PV carriers at all time points, and this difference was not attributable to age, BMI, menopausal status, risk-reducing salpingo-oophorectomy, previous chemotherapy or use of cholesterol-lowering agents. The lipid profile was similar between the groups, although BRCA1 LP/PV carriers showed a tendency toward a less favorable profile (higher LDL and lower HDL).

Conclusions

These prospective results suggest that BRCA1 LP/PV carriers might have impaired glucose tolerance and a greater tendency toward insulin resistance compared with BRCA2 LP/PV carriers: this first report needs further independent confirmations from other cohorts.