Angiotensin-converting enzyme (ACE) has been implicated in multiple biological system, particularly cardiovascular diseases. However, findings associating ACE insertion/deletion polymorphism with hypertension or other related traits are inconsistent. Therefore, in a two-stage approach, we aimed to fine-map ACE in order to narrow-down the function-specific locations. We genotyped 31 single nucleotide polymorphisms (SNPs) of ACE from 1168 individuals from 305 young-onset (age ≤40) hypertension pedigrees, and found four linkage disequilibrium (LD) blocks. A tag-SNP, rs1800764 on LD block 2, upstream of and near the ACE promoter, was significantly associated with young-onset hypertension (p = 0.04). Tag-SNPs on all LD blocks were significantly associated with ACE activity (p-value: 10–16 to <10–33). The two regions most associated with ACE activity were found between exon13 and intron18 and between intron 20 and 3′UTR, as revealed by measured haplotype analysis. These two major QTLs of ACE activity and the moderate effect variant upstream of ACE promoter for young-onset hypertension were replicated by another independent association study with 842 subjects.

Methadone maintenance treatment (MMT) is the major tapering therapy for morphine addictive patients. There have gender differences reported in response to MMT. This study discovered that the estrogen‐response element single nucleotide polymorphism (ERE‐SNP; rs16974799, C/T) of cytochrome 2B6 gene (cyp2b6; methadone catabolic enzyme) responded differently to MMT dosing. Oestradiol was associated with high MMT dosing, high enantiomer (R‐ or S‐) of 2‐ethylidene‐1,5‐dimethyl‐3,3‐dipheny‐pyrrolidine (EDDP; methadone metabolite) to methadone ratio and increased drug‐seeking behaviour, implicating oestradiol‐CYP‐EDDP/methadone axis decreasing MMT efficacy. In mouse model, oestrogen mitigates methadone antinociceptive response, facilitates methadone catabolism and up‐regulates methadone‐associated metabolizing enzymes. Oestrogen also ablates chronic methadone administration‐induced rewarding response. Mechanism dissection revealed the CC genotype of CYP2B6‐ERE‐SNP exerts higher ERE sequence alignment score, higher estrogenic response as compared to TT genotype. At last, preclinical study via targeting estrogen signal that tamoxifen (TMX; selective estrogen receptor modulator, SERM) could facilitate the tolerance phase rewarding response of methadone. Strikingly, TMX also reduces tapering/abstinence phases methadone liability in mice. In conclusion, this study demonstrates altering methadone metabolism through targeting estrogen signals might be able to free morphine addictive patients from the addiction of opioid replacement therapy. Therefore, the add‐on therapy clinical trial introducing SERM in MMT regimen is suggested.

Objective. To explore the relationship between body constitution (BC) types and weight change in patients with schizophrenia and who underwent second-generation antipsychotics (SGAs) treatment. Method. Body weight and waist circumference of eighty-five participants were measured for 6 consecutive weeks. Constitutions of Yin-Xu, Yang-Xu, and Stasis were assessed using the Body Constitution Questionnaire (BCQ). Results. Participants with body constitutions Yin-Xu (50.6%), Yang-Xu (49.4%), or Stasis (38.8%) exhibited worse physical condition and unhealthy daily habits, particularly in Stasis constitution. Moreover, Stasis constitution was significantly associated with several factors, including BMI, body weight, waist circumference, perception of stress, perception of health, staying up late, and less physical exercise. However, perception of stress showed significant difference in Yin-Xu, Yang-Xu, and Stasis. Generalized estimating equation (GEE) analysis revealed that significant time effects in body weight increase in the imbalanced BC types and gentleness BC type. SGAs induced weight gain in imbalanced BC type as well as gentleness BC type, especially treated with olanzapine. Conclusions. This is the first study to explore the longitudinal relationship between BC and weight gain in schizophrenia patients undergoing SGAs treatment. Health care providers should focus on weight gain problems in schizophrenia patients who underwent SGAs treatment.

Objectives: Angiotensin converting enzyme (ACE) plays major roles in the pathogenesis of cardiovascular diseases (CVD). However, findings on the relations between ACEvariants and CVD have not been consistent. The purpose of this study was to map quantitative trait loci (QTL) for serum ACE activity, a heritable endophenotype of cardiovascular diseases (estimated heritability = 0.58). Methods: With 1,271 individuals from 373 young-onset (age ≤40) hypertension pedigrees, 479 deCODE microsatellite markers were genotyped. Results: We identified a previously unknown loci on chromosomes 9 at 149.4 cM (LOD = 3.00) in addition to a strong linkage peak near the ACE structural locus on chromosome 17 at 89.6 cM (LOD = 4.60). Conclusions: These results not only indicate that the ACE gene or nearby loci on 17q was among the strongest QTL influencing ACE activity, but also reveal a potential ACE QTL in human genome, pointing to the complexity of ACE regulation.

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