Association of rare gene variants associated with low bone mass and dyslipidemia with the combination of atherosclerosis and osteopenic syndrome in women

Aim. To study the associations of rare gene variants involved in monogenic diseases presenting with low bone mineral density (BMD) and dyslipidemia, with combined vascular wall and bone tissue changes in women.

Material and methods. The study included 308 peri- and postmenopausal women aged 45 to 82 years, examined on an outpatient basis as part of cross-sectional (2018-2020) and prospective (baseline visit – 2012-2014, repeat – after 10 years) studies. Cardiovascular risk (SCORE) and fracture risk (FRAX) assessment, carotid ultrasound with atherosclerotic plaques (ASP) registration, multispiral computed tomography of the coronary arteries to assess the Agatston calcium index (ACI), measurement of BMD by dual-energy X-ray absorptiometry, molecular genetic examination using targeted sequencing were performed. Rare gene variants associated with monogenic diseases with low BMD (BMP1, COL1A1, COL1A2, ALPL, ENPP1, SLC34A1, LRP5, WNT1, FBN1, TGFBR2, LMNA, NOTCH2, PLS3) and with monogenic dyslipidemia and atherosclerosis (AS) (LDLR, APOE), were selected, which are combined and summarized according to the principle of entry into the gene’s networks (Е-ECM, Е-MIN, Е-WNT, Е-TGFB, Е-OTHER, Е-ALL, Е-ATHER).

Results. Low bone mass was detected in 70.4% of women, and its combinations with signs of subclinical AS – the presence of ASP and/or ACI ≥1 unit – were noted in 60.8% of patients. Among the studied genetic factors, variants of the genes SLC34A1 (6.5%), LDLR (3.3%), COL1A2 (2.3%), LRP5 (2.3%) and the sum of variants from the groups of genes E-ALL (23.7%) and E-MIN (8.4%) were more common. In the group of women with a combination of signs of subclinical AS and osteopenic syndrome (presence of ASP and/or ACI ≥1 unit and low BMD) variants of the SLC34A1 gene (0% vs 7.2%, p=0.008) and variants from three groups of genes E-ALL (9.7% vs 24.8%, p=0.047), E-MIN (0% vs 9.2%, p=0.003), E-TGFB (0% vs 4.6%, p=0.033) were significantly more frequent compared to the group without this combination of signs. The total burden of rare variants in all genes associated with monogenic diseases with low BMD (E-ALL) increased the chance of detecting a combined pathology by 3.2 times (95%CI [1.04-9.07], p=0.047). In multivariate regression analysis (adjusted for age ≥55 years, body mass index <20 kg/m², intima-media complex thickness ≥0.9 mm, total cholesterol ≥5.0 mmol/L, bone resorption marker CTx >1,008 ng/ml, SCORE ≥1%, FRAX ≥7% for the main fractures and FRAX ≥0.3% for hip fracture), the independent role of none of the studied genetic integral factors in the development of combined pathology has not been confirmed.

Conclusion. A clear trend towards an increased frequency of integral genetic factors, representing the sum of rare gene variants associated with monogenic diseases with low BMD was observed in patients with a combination of AS and osteopenic syndrome. This trend did not reach statistical significance, likely due to insufficient sample size or the predominance of clinical risk factors.

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