Expanded Somatic Mutation Spectrum of MED12 Gene in Uterine Leiomyomas of Saudi Arabian Women

MED12, a subunit of mediator complex genes is known to harbor genetic mutations, (mostly in exon 2), causal to the genesis of uterine leiomyomas among Caucasian, African American, and Asian women. However, the precise relationship between genetic mutations vs. protein or disease phenotype is not well-explained. Therefore, we sought to replicate the MED12 mutation frequency in leiomyomas of Saudi Arabian women, who represents ethnically and culturally distinct population. We performed molecular screening of MED12 gene (in 308 chromosomes belonging to 154 uterine biopsies), analyzed the genotype-disease phenotype correlations and determined the biophysical characteristics of mutated protein through diverse computational approaches. We discovered that >44% (34/77) leiomyomas of Arab women carry a spectrum of MED12 mutations (30 missense, 1 splice site, and 3 indels). In addition to known codon 44, we observed novel somatic mutations in codons 36, 38, and 55. Most genetically mutated tumors (27/30; 90%) demonstrated only one type of genetic change, highlighting that even single allele change in MED12 can have profound impact in transforming the normal uterine myometrium to leiomyomas. An interesting inverse correlation between tumor size and LH is observed when tumor is positive to MED12 mutation (p < 0.05). Our computational investigations suggest that amino acid substitution mutations in exon-2 region of MED12 might contribute to potential alterations in phenotype as well as the stability of MED12 protein. Our study, being the first one from Arab world, confirms the previous findings that somatic MED12 mutations are critical to development and progression of uterine leiomyomas irrespective of the ethnic background. We recommend that mutation screening, particularly codon 44 of MED12 can assist in molecular diagnostics of uterine leiomyomas in majority of the patients

Impact of interlukin-6 on central obesity measures in women with polycystic ovarian syndrome

Our aim was to investigate the relationship between plasma interleukin-6 (IL-6) levels with different measures of central obesity among Saudi women with and without polycystic ovarian syndrome (PCOS). One hundred and sixty-four Saudi females, between 22 and 38 years of age, with and without PCOS were enrolled in this case-control study. Physical examination and laboratory tests were completed for every subject. 2/3 of the study population were obese. Fasting serum insulin, plasma IL-6 levels and insulin resistance show significant increase among POCS than the controls (p<.05). Based on linear regression analysis, C-reactive protein (hs-CRP) was the only independent predictor of plasma IL-6 levels, accounting for 4% of the variability in plasma IL-6 (β = 0.217, p=.005, 95% CI: 0.049–0.275). Coexistence of metabolic and inflammatory factors in PCOS females is accompanied by central obesity which overpowers the effect of insulin resistance, contributing to higher plasma levels of IL-6 and CRP.Impact statement What is already known on this subject? Polycystic ovary syndrome (PCOS) is a cluster of many cardiovascular risk factors, but is also known as an inflammatory condition. Insulin resistance and abdominal obesity are classic components of PCOS. High circulatory levels of inflammatory markers in PCOS patients have been reported but it remains unclear whether their elevation is related to PCOS itself, or are a function of abdominal adiposity. What the results of this study add? The relationship between plasma interleukin-6 levels and different measures of central obesity was investigated among Saudi women with and without PCOS. Elevations of proinflammatory cytokines and inflammatory markers were reported in PCOS patients independently of insulin resistance. It remains to be established whether the proinflammatory state in PCOS is primarily due to inflamed adipose tissue. What the implications are of these findings for clinical practice and/or further research? The present study demonstrates that coexistence of metabolic and inflammatory factors in PCOS females are accompanied by central obesity which overpowers the effect of insulin resistance, contributing to higher plasma levels of IL-6 and CRP. Future studies including a larger population are needed to investigate the mechanisms by which IL-6 and hs-CRP promote cardiovascular risk in PCOS patients