Coronary artery disease (CAD) is a multifactorial disorder, which is partly heritable. Herein, we implemented a mapping of CAD-associated candidate genes by using genome-wide enhancer-promoter conformation (H3K27ac-HiChIP) and expression quantitative trait loci (eQTL). Enhancer-promoter anchor loops from human coronary artery smooth muscle cells (HCASMC) explained 22% of the heritability for CAD. 3D enhancer-promoter genome mapping of CAD-genes in HCASMC was enriched in vascular eQTL genes. By using colocalization and Mendelian randomization analyses, we identified 58 causal candidate vascular genes including some druggable targets (MAP3K11, CAMK1D, PDGFD, IPO9 and CETP). A network analysis of causal candidate genes was enriched in TGF beta and MAPK pathways. The pharmacologic inhibition of causal candidate gene MAP3K11 in vascular SMC reduced the expression of athero-relevant genes and lowered cell migration, a cardinal process in CAD. Genes connected to enhancers are enriched in vascular eQTL and druggable genes causally associated with CAD.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, also known as Müllerian agenesis, is characterized by uterovaginal aplasia in an otherwise phenotypically normal female with a normal 46,XX karyotype. Previous studies have associated sequence variants of PAX8, TBX6, GEN1, WNT4, WNT9B, BMP4, BMP7, HOXA10, EMX2, LHX1, GREB1L, LAMC1, and other genes with MRKH syndrome. The purpose of this study was to identify the novel genetic causes of MRKH syndrome. Ten patients with MRKH syndrome were recruited at Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China. Whole-exome sequencing was performed for each patient. Sanger sequencing confirmed the potential causative genetic variants in each patient. In silico analysis and American College of Medical Genetics and Genomics (ACMG) guidelines helped to classify the pathogenicity of each variant. The Robetta online protein structure prediction tool determined whether the variants affected protein structures. Eleven variants were identified in 90% (9/10) of the patients and were considered a molecular genetic diagnosis of MRKH syndrome. These 11 variants were related to nine genes: TBC1D1, KMT2D, HOXD3, DLG5, GLI3, HIRA, GATA3, LIFR, and CLIP1. Sequence variants of TBC1D1 were found in two unrelated patients. All variants were heterozygous. These changes included one frameshift variant, one stop-codon variant, and nine missense variants. All identified variants were absent or rare in gnomAD East Asian populations. Two of the 11 variants (18.2%) were classified as pathogenic according to the ACMG guidelines, and the remaining nine (81.8%) were classified as variants of uncertain significance. Robetta online protein structure prediction analysis suggested that missense variants in TBC1D1 (p.E357Q), HOXD3 (p.P192R), and GLI3 (p.L299V) proteins caused significant structural changes compared to those in wild-type proteins, which in turn may lead to changes in protein function. This study identified many novel genes, especially TBC1D1, related to the pathogenesis of MRKH syndrome. The identification of these variants provides new insights into the etiology of MRKH syndrome and a new molecular genetic reference for the development of the reproductive tract.

BACKGROUND: There is an increasing interest worldwide in investigating healthcare stakeholders' perceptions and intentions to adopt pharmacogenomics (PGx) into clinical practice. However, the existing inquiries based on well-established theories and models that interpret their intentions to implement PGx are scarce. This study is the first that examines the impact of selected factors on health science students' intention to adopt genetic testing applications using the technology acceptance model while it compares two different cultural groups: Greeks (Europe; Christian) and Malays (Asia; Muslim). RESULTS: Malay students were more persuaded about benefits of genomics for drug management compared to their Greek counterparts. However, participants from both countries appear to be particularly convinced about the benefits of genomics on disease management. Moreover, students from both countries considered the potential misuse of genetic information by corporate or government bodies as their most important concern; Greek students appeared to be considerably less worried than Malay about other probable hazards such as the deficient protection of privacy and confidentiality, which could be attributed to their religious background. Participants from both samples expressed very positive attitudes towards genetic research and testing and their favourable intentions to adopt genetic testing for personal use. Exploratory factors analysis and path analysis yielded quite similar results for both samples. Path analysis revealed that the factors of attitudes, concerns, drug management benefits and disease management benefits significantly influenced students' intentions to adopt genetic testing for personal use, with attitudes being the most inspirational factor with rather high impact, while training did not seem to affect participant's intentions. The squared multiple correlation of both models was quite satisfactory reaching to 0.55 for the Malaysian sample. CONCLUSION: Similarities in the results of the two groups along with the relevant validity and reliability tests indicate that the proposed model is a good fit for future studies to interpret stakeholders' intentions to adopt genetic testing. Therefore, it can provide a promising and reliable basis for future model development to explain the relationships between intentions to adopt genetic testing and its predictors.