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Rare copy number variations (CNVs) are a known genetic etiology in neurodevelopmental disorders (NDD). Comprehensive CNV analysis was performed in 287 Chinese children with mental retardation and/or development delay (MR/DD) and their unaffected parents. When compared with 5,866 ancestry-matched controls, 11~12% more MR/DD children carried rare and large CNVs. The increased CNV burden in MR/DD was predominantly due to de novo CNVs, the majority of which (62%) arose in the paternal germline. We observed a 2~3 fold increase of large CNV burden in the mothers of affected children. By implementing an evidence-based review approach, pathogenic structural variants were identified in 14.3% patients and 2.4% parents, respectively. Pathogenic CNVs in parents were all carried by mothers. The maternal transmission bias of deleterious CNVs was further replicated in a published dataset. Our study confirms the pathogenic role of rare CNVs in MR/DD, and provides additional evidence to evaluate the dosage sensitivity of some candidate genes. It also supports a population model of MR/DD that spontaneous mutations in males' germline are major contributor to the de novo mutational burden in offspring, with higher penetrance in male than female; unaffected carriers of causative mutations, mostly females, then contribute to the inherited mutational burden.

Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and ∼2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488-47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the KCNQ1 (rs2237892, P = 9.29 × 10(-13)), ALDH2/MYL2 (rs671, P = 3.40 × 10(-11); rs12229654, P = 4.56 × 10(-9)), ITIH4 (rs2535633, P = 1.77 × 10(-10)) and NT5C2 (rs11191580, P = 3.83 × 10(-8)) genes. The association of BMI with rs2237892, rs671 and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed eight loci at the genome-wide significance level (P < 5.0 × 10(-8)) and an additional 14 at P < 1.0 × 10(-3) with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: A majority of hypertensives require treatment with ≥2 antihypertensive therapies to achieve blood pressure (BP) goals. Single-pill combinations (SPC) may improve convenience and adherence to therapy and reduce health care resource use and costs. The antihypertensive effects of amlodipine and valsartan are well established. This study evaluated the efficacy and safety of amlodipine/valsartan 5/160 mg SPC for the treatment of hypertension in predominantly Chinese patients not adequately controlled on valsartan 160 mg alone., Methods: In this multicentre study (24 centres), adults with stage 1 or 2 hypertension not adequately controlled with valsartan monotherapy were randomised to receive double-blind amlodipine/valsartan 5/160 mg SPC or valsartan 160 mg once daily for 8 weeks., Results: The least-square mean change (standard error) from baseline to endpoint in mean sitting diastolic blood pressure (MSDBP) at trough, the primary efficacy variable, was -10.3 (0.39) mm Hg with amlodipine/valsartan and -6.6 (0.40) mm Hg with valsartan (difference: -3.7 [0.54] mm Hg, p<0.0001). The corresponding results for mean sitting systolic blood pressure (MSSBP) were -14.9 (0.61) mm Hg and -7.0 (0.61) mm Hg, respectively (difference: -7.9 [0.84] mm Hg, p<0.0001). A significantly greater proportion of patients achieved overall BP control (MSSBP/MSDBP<140/90 mm Hg) with combination therapy (61.3%) versus monotherapy (39.3%; p<0.0001). Both treatments were well tolerated., Conclusion: Amlodipine/valsartan 5/160 mg SPC is a safe and effective therapy for lowering BP in predominantly Chinese adults with stage 1 or 2 hypertension not adequately controlled with valsartan 160 mg monotherapy., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Multiple genetic loci associated with obesity or body mass index (BMI) have been identified through genome-wide association studies conducted predominantly in populations of European ancestry. We performed a meta-analysis of associations between BMI and approximately 2.4 million SNPs in 27,715 east Asians, which was followed by in silico and de novo replication studies in 37,691 and 17,642 additional east Asians, respectively. We identified ten BMI-associated loci at genome-wide significance (P < 5.0 × 10(-8)), including seven previously identified loci (FTO, SEC16B, MC4R, GIPR-QPCTL, ADCY3-DNAJC27, BDNF and MAP2K5) and three novel loci in or near the CDKAL1, PCSK1 and GP2 genes. Three additional loci nearly reached the genome-wide significance threshold, including two previously identified loci in the GNPDA2 and TFAP2B genes and a newly identified signal near PAX6, all of which were associated with BMI with P < 5.0 × 10(-7). Findings from this study may shed light on new pathways involved in obesity and demonstrate the value of conducting genetic studies in non-European populations.

Background: Genetic studies in mouse and human suggest that kynureninase activity may influence blood pressure and renal function. The gene coding kynureninase (KYNU) is also located on chromosome band 2q14-q23, where a linkage peak for essential hypertension was previously detected in the Chinese Han population., Methods and Results: After having found no association with common polymorphisms, this study aimed to assess the role of 1 rare variant of KYNU, Arg188Gln, and kynureninase activity in relation to hypertension. Thirty-three of 1124 Chinese patients with hypertension were heterozygous for Arg188Gln, whereas only 14 of 1084 normotensive controls were heterozygous for Arg188Gln (188G1n allele frequency, 0.015 versus 0.006; P=0.0075). A genotype-discordant sibling-pair study was performed in another 924 individuals from 213 families, indicating that 188G1n carriers had higher systolic blood pressure (168.29 ± 24.67 versus 139.00 ± 12.82 mm Hg, P<0.001) and diastolic blood pressure (105.50 ± 14.08 versus 90.75 ± 11.07 mm Hg, P=0.001) than did Arg188 homozygous siblings. The Arg188Gln variant was found to be rarer in 2 other ethnic groups (3 heterozygous among 880 hypertensive French whites and 0 of 90 black Africans with hypertension). The kynureninase activity in plasma was correlated with blood pressure in subjects from hypertensive families (P<0.05). The Kinetic Michaelis constants of 188Gln carriers was lower than that of Arg188 homozygous subjects (0.05 ± 0.02 versus 0.10 ± 0.02 mmol/L, P=0.005). Arg188Gln mutation in vitro also showed less catalytic efficiency than the wild-type KYNU enzyme (maximal reaction velocity/Kinetic Michaelis constant ratio, 0.050 ± 0.012 versus 0.11 ± 0.016 mL/min per mg; P=0.029)., Conclusions: The results show that the rare KYNU variant Arg188Gln affects kynureninase activity and are consistent with the hypothesis that this mutation can predispose to essential hypertension.

We conducted a meta-analysis of genome-wide association studies of systolic (SBP) and diastolic (DBP) blood pressure in 19,608 subjects of east Asian ancestry from the AGEN-BP consortium followed up with de novo genotyping (n = 10,518) and further replication (n = 20,247) in east Asian samples. We identified genome-wide significant (P < 5 × 10(-8)) associations with SBP or DBP, which included variants at four new loci (ST7L-CAPZA1, FIGN-GRB14, ENPEP and NPR3) and a newly discovered variant near TBX3. Among the five newly discovered variants, we obtained significant replication in the independent samples for all of these loci except NPR3. We also confirmed seven loci previously identified in populations of European descent. Moreover, at 12q24.13 near ALDH2, we observed strong association signals (P = 7.9 × 10(-31) and P = 1.3 × 10(-35) for SBP and DBP, respectively) with ethnic specificity. These findings provide new insights into blood pressure regulation and potential targets for intervention.

Background and Objective: We have recently resequenced apelin and AGTRL1 genes to identify candidate polymorphisms in family-based association with hypertension and related phenotypes. In this study, we aimed to determine and replicate these polymorphisms via a larger, independent case-control study in Shanghai Han Chinese., Methods: Two polymorphisms [rs3761581 (A/C) and T-1860C] in apelin gene and two [rs7119375 (G/A), rs10501367 (G/A)] in AGTRL1 gene were genotyped using the TaqMan assay among 969 patients diagnosed with essential hypertension and 980 age and sex-matched controls. Data were analyzed using Haplo.stats program., Results: In single-locus analysis, significant differences were observed in allele distribution of rs3761581 (P = 0.0156) in men and in rs7119375 (P = 0.0488) genotype distribution in women between patients and controls. Haplotype analysis indicated that haplotypes C-C-G-G (in order of T-1860C, rs3761581, rs7119375 and rs10501367) [adjusted odds ratio (ORadjusted) = 1.67, P = 0.0061] and T-A-A-A (ORadjusted = 1.62, P = 0.0008) conferred an increased risk for hypertension after adjustment for age, onset age, body mass index (BMI) and waist-to-hip ratio, whereas haplotype C-C-A-A (ORadjusted = 0.33, P = 0.0048) conferred a protective effect. In women, increased risk for hypertension was seen for haplotypes T-A-G-G (ORadjusted = 1.30, P = 0.0051), C-C-G-G (ORadjusted = 2.86, P < 0.0001), T-A-A-A (ORadjusted = 1.66, P = 0.0003) and C-C-A-A (ORadjusted = 2.65, P < 0.0001), whereas decreased risk was seen for haplotypes C-A-G-G (ORadjusted = 0.48, P < 0.0001) and T-C-G-G (ORadjusted = 0.40, P < 0.0001). Further haplotype-phenotype analyses indicated the robustness of these associations. For example, haplotype T-A-A-A was significantly associated with obesity index (BMI and waist-to-hip ratio) in both sexes and blood pressures in men (P-sim < 0.05)., Conclusion: In this exploratory pilot case-control study, we found robust haplotype-based and haplotype-phenotype associations of four well characterized polymorphisms in apelin-AGTRL1 system with hypertension and related phenotypes.

Background: ATP1B1 encodes the beta subunits of Na/K ATPase which plays an important role in maintaining the normal gradients of Na(+) and K(+) across plasma membrane. A recent study demonstrated an association of ATP1B1 genetic variations with blood pressure (BP) in Americans. We aimed to investigate the association between ATP1B1 polymorphisms with BP and hypertension in a Chinese population., Material and Methods: Twelve tag single-nucleotide polymorphisms (SNPs) of ATP1B1 were genotyped in 906 patients with essential hypertension (EH) and 894 normotensives (NT)., Results: None of the selected SNPs was associated with hypertension. However, an overall significant association of haplotypes containing rs1200131, rs1200137, rs3766032, rs3766039 and rs2982468 with hypertension was observed (p=0.032). A common haplotype (G-T-A-C-T) was associated with an increased risk for hypertension (OR(adjusted)=1.717, p=0.033). In NT subjects, rs3766032AA carriers had lower systolic BP (SBP) and diastolic BP (DBP) than AG/GG carriers (SBP, 112.6+/-10.0 mmHg vs. 115.5+/-10.6 mmHg, p<0.05; DBP, 75.1+/-6.8 mmHg vs. 76.8+/-6.0 mmHg, p<0.05), and rs2982468 TT carriers had lower DBP than AT/AA carriers (74.8+/-6.9 mmHg vs. 76.3+/-6.2 mmHg; p<0.01) after correction. In NT subjects, BP showed an overall significant association with haplotypes (p=0.006, for SBP and p=0.036, for DBP)., Conclusion: We conclude that haplotype in ATP1B1 may confer susceptibility to BP regulation and hypertension in this Chinese population.

Objective: We investigated the ambulatory blood pressure (BP) in rural Chinese and compared its characteristics with those reported in other population-based studies., Methods: We enrolled inhabitants from six villages of the JingNing County, China. We recorded the ambulatory BP using 90207 SpaceLabs monitors. Trained physicians measured the conventional BP at the participants' homes. Hypertension was defined as a conventional BP of > or = 140/ > or = 90 mmHg or a condition requiring the intake of antihypertensive drugs. Using MEDLINE, we searched for population-based studies on ambulatory BP monitoring., Results: The 356 participants (12-86 years) included 192 (53.9%) women and 117 (32.9%) hypertensive patients. In all participants, systolic/diastolic BP averaged 129/80 mmHg at home. The ambulatory BP means were 121/77 mmHg over 24 h, 126/81 mmHg during daytime (0800 to 1800 h) and 112/70 mmHg during night-time (2200 to 0400 h). The awake and asleep BPs averaged 126/82 and 112/70 mmHg, respectively. Using previously published definitions of daytime (1000 to 2000 h) and night-time (midnight to 0600 h) instead of those given above, inflated the BP differences with the awake and asleep BPs from 0.4/0.2 to 1.2/1.0 mmHg and from 0.3/0 to 1.4/1.6 mmHg, respectively. Compared with daytime values, conventional BP was 2.7/3.1 mmHg lower in normotensive individuals, but 14.9/1.3 mmHg higher in hypertensive patients. In our normotensive individuals, the whole-day and night-time diastolic BPs were from 1 to 4 mmHg and from 3 to 7 mmHg higher than in five other population studies in Caucasians or Japanese, whereas night-time BP in our participants was 9/5 mmHg lower than in Chinese living in Taiwan., Conclusions: We demonstrated significant differences in the characteristics of the ambulatory blood pressure across Asian and Caucasian populations. To what extent different activity patterns and genetic and environmental factors explain this context-dependency remains to be clarified.

Objective: To investigate whether linkage between essential hypertension (EH) and genetic loci near renin-angiotensin system, endothelin system, nitric oxide synthase, adrenergic receptor genes in Chinese., Methods: Linkage analysis of thirteen candidate gene loci and EH was performed in 95 Chinese nuclear families including 477 subjects using a technique of fluorescence-based gene scan with DNA short tandem repeat. The markers were selected on the chromosomal regions containing candidate genes regulating vasoactivity. GENEHUNTER package were used for two-point, non-parametric linkage analysis (NPL), maximum Lod score and transmission/disequilibrium test (TDT) in this study., Results: The results of TDT indicated relatively small P values at D1S1678, D3S1744, D4S1604, D13S800, D7S483 and D8S255 (0.01 < P < 0.05). No significant linkages was found at any locus by Lod score and NPL analysis (Lod /= 0.05)., Conclusions: TDT is considered as a sensitive test for detecting linkage disequilibrium. Significant linkage was found at 6 of the 13 loci typed in Chinese nuclear families with hypertension by using TDT, but no evidence suggested linkage of any locus to EH by NPL and Lod score. It is worthwhile to pay attention to chromosomal regions near the loci with small P values.