To identify genetic contributions to type 2 diabetes (T2D) and related glycemic traits (fasting glucose, fasting insulin, and HbA1c), we conducted genome-wide association analyses (GWAS) in up to ...7,178 Chinese subjects from nine provinces in the China Health and Nutrition Survey (CHNS). We examined patterns of population structure within CHNS and found that allele frequencies differed across provinces, consistent with genetic drift and population substructure. We further validated 32 previously described T2D- and glycemic trait-loci, including G6PC2 and SIX3-SIX2 associated with fasting glucose. At G6PC2, we replicated a known fasting glucose-associated variant (rs34177044) and identified a second signal (rs2232326), a low-frequency (4%), probably damaging missense variant (S324P). A variant within the lead fasting glucose-associated signal at SIX3-SIX2 co-localized with pancreatic islet expression quantitative trait loci (eQTL) for SIX3, SIX2, and three noncoding transcripts. To identify variants functionally responsible for the fasting glucose association at SIX3-SIX2, we tested five candidate variants for allelic differences in regulatory function. The rs12712928-C allele, associated with higher fasting glucose and lower transcript expression level, showed lower transcriptional activity in reporter assays and increased binding to GABP compared to the rs12712928-G, suggesting that rs12712928-C contributes to elevated fasting glucose levels by disrupting an islet enhancer, resulting in reduced gene expression. Taken together, these analyses identified multiple loci associated with glycemic traits across China, and suggest a regulatory mechanism at the SIX3-SIX2 fasting glucose GWAS locus.
Dwarfism is a common severe growth disorder, but the etiology is unclear in the majority of cases. Recombinant human growth hormone may be a treatment option, but it has limited efficacy. The ...currently known laboratory assays do not meet the precision requirements for clinical diagnosis. Here, we have constructed a targeted next-generation sequencing (NGS) panel of selected genes that are suspected to be associated with dwarfism for genetic screening.
Genetic screening of 91 children with short stature of unknown etiology was performed with the help of the NGS panel. All the coding regions and exon-intron boundaries of 166 genes were included in the panel. To clarify the pathogenicity of these mutations, their clinical data were reviewed and analyzed.
The assay identified p.A72G, p.I282V, and p.P491S variants of the PTPN11 gene and a p.I437T variant of the SOS1 gene in 4 cases with Noonan syndrome. A frameshift mutation (p.D2407fs) of the ACAN gene was identified in a case of idiopathic short stature with moderately advanced bone age. A p.R904C variant of the COL2A1 gene was found in a patient, who was accordingly diagnosed with Stickler syndrome. Severe short stature without limb deformity was associated with a p.G11A variant of HOXD13. In addition, we evaluated evidence that a p.D401N variant of the COMP gene may cause multiple epiphyseal dysplasia.
Our findings suggest that syndromes, particularly Noonan syndrome, may be overlooked due to atypical clinical features. This gene panel has been verified to be effective for the rapid screening of genetic etiologies associated with short stature and for guiding precision medicine-based clinical management.
Siraitia grosvenorii
seeds are rich in abundant active compounds beneficial to human health. To clarify the digestion characteristics of
Siraitia grosvenorii
seed flour (SSF) and promote the use of ...SSF in the processing of functional staple foods, SSF was prepared, its composition and physicochemical properties were studied, and the processing characteristics of SSF-wheat flour were systematically investigated. The results showed that the torque curve and other parameters of the dough were significantly affected by the amount of SSF added. With the increase of SSF proportion, the water absorption showed an increasing trend, while the degree of protein weakening first weakened and then enhanced. At 20% SSF, the dough was more resistant to kneading. In response to an increase in SSF, the L* value decreased significantly, and the a* and b* values increased gradually, while the specific volume decreased gradually. Additionally, the hardness, adhesiveness, and chewiness of the bread enhanced gradually, while its elasticity, cohesiveness, and resilience decreased gradually. After the addition of 30% SSF, the inner tissue of steamed bread was more delicate. With an increase in SSF proportion, the predicted glycemic index (pGI) of steamed bread weakened markedly. Overall, these results showed that SSF, as a kind of food ingredient with hypoglycemic activity, can be used in the production of new functional steamed bread products. This study provides basic research data for the development of products containing
S. grosvenorii
seed.
Psoriasis-2 (PSORS2) is caused by the heterozygous mutation of the caspase recruitment domain 14 (
CARD14
) gene on chromosome 17q25. To evaluate the contribution of
CARD14
variants in psoriasis of ...the Chinese Han population, we performed deep sequencing of the
CARD14
gene in 372 Chinese Han patients with psoriasis. The exonic nucleotide variants were confirmed by Sanger sequencing in the affected individuals and 1114 controls. In 27 patients with psoriasis, we identified 15 variations, including three novel variants: c.381C>G (p.Cys127Trp), c.712A>G (p.Met238Val) and c.2260_2261delinsGG (p.Gln754Gly). These findings could enrich and update the Human Gene Mutation Database of
CARD14
variants for psoriasis.
Tacrolimus is a widely used immunosuppressant after organ transplantation. The narrow therapeutic window and individual variability in tacrolimus pharmacokinetics make management of this agent a ...great challenge. This study was undertaken to determine the association of clinical markers, cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5) and nuclear receptor subfamily 1, group I, member 3 (NR1I3) gene polymorphisms with tacrolimus pharmacokinetics. A total of 96 liver transplant patients were enrolled in the study. Tacrolimus dose-adjusted trough concentration (C/D ratio) and clinical markers were recorded for one month after transplantation. CYP3A5 and NR1I3 gene polymorphisms for both donor and recipient were genotyped. In single variable analysis, hemoglobin (Hb), hematocrit (Hct), donor CYP3A5, NR1I3 gene polymorphisms and recipient CYP3A5 gene polymorphisms were associated with log-transformed tacrolimus C/D ratios. Hb, donor CYP3A5, NR1I3 gene polymorphisms and recipient CYP3A5 gene polymorphisms showed association with log-transformed tacrolimus C/D ratios in the final multiple linear regression model. Donor CYP3A5 polymorphisms were the most important variant, accounting for 14.3% of total variation involved in tacrolimus pharmacokinetics. This information could be useful in developing individualized tacrolimus treatment after liver transplantation.
In order to comprehensively screen genetic variants leading to differential expression of the important human ABCB1 gene in the primary drug-metabolizing organ, ABCB1 mRNA expression levels were ...measured in 73 normal liver tissue samples from Chinese subjects. A set of Tag SNPs. were genotyped. In addition, imputation was performed within a 500 kb region around the ABCB1 gene using the reference panels of 1,000 Genome project and HapMap III. Bayesian regression was used to assess the strength of associations by compute Bayes Factors for imputed SNPs. Through imputation and linkage disequilibrium analysis, the imputed loci rs28373093, rs1002205, rs1029421, rs2285647, and rs10235835, may represent independent and strong association signals. rs28373093, a polymorphism 1.5 kb upstream from the ABCB1 transcription start site, has the strongest association. 2677 G>A/T and 3435C>T confer a clear gene-dosage effect on ABCB1 mRNA expression. The systematic characterization of gene-wide common quantitative trait loci associated with ABCB1 mRNA expression in normal liver tissues would provide the candidate markers to ABCB1-relevant clinical phenotypes in Chinese population.
Coronary atherosclerosis, the main cause of cardiovascular disease, is a progressive disease. Recent Genome Wide Association Studies (GWASs) discovered several novel loci associated with coronary ...artery disease (CAD) or its main complication myocardial infarction (MI). In this study, we investigated the associations between previously reported CAD- and MI-associated variants and coronary atherosclerosis in Chinese Han population.
We performed a case-control association study with 2,335 coronary atherosclerosis patients and 1,078 controls undergoing coronary angiography of Chinese Han from China. Fourteen single nucleotide polymorphisms (SNPs), located at 1p13.3, 1q41, 2q36.3, 6q25.1, 9p21.3, 10q11.21 and 15q22.33, were genotyped in our sample collection. Six SNPs at 9p21 were associated with coronary atherosclerosis susceptibility (P(trend)<0.05) and rs10757274 showed the most significant association (P = 2.38×10(-08), OR = 1.34). These associations remained significant after adjustment for multiple comparisons. Rs17465637 at 1q41 (P(trend) = 6.83×10(-03), OR = 0.86) also showed significant association with coronary atherosclerosis, but the association was not significant after multiple comparisons. Additionally, rs501120 (P = 8.36×10(-03), OR = 0.80) at 10q11.21 was associated with coronary atherosclerosis in females, but did not show association in males and all participants. Variants at 1p13.3, 2q36.3, 6q25.1 and 15q22.33 showed no associations with coronary atherosclerosis and main cardiovascular risk factors in our data.
Our findings indicated variants at 9p21 were significantly associated with coronary atherosclerosis in Han Chinese. Variants at 1q41 showed suggestive evidence of association and variants at 10q11.21 showed suggestive evidence of association in females, which warrant further study in a larger sample.
Variations in the activities of Cytochrome P450s are one of the major factors responsible for inter-individual differences in drug clearance rates, which may cause serious toxicity or inefficacy of ...therapeutic drugs. Various mRNA level is one of the key factors for different activity of the major P450 genes. Although both genetic and environmental regulators of P450 gene expression have been widely investigated, few studies have evaluated the functional importance of cis- and trans-regulatory factors and environmental factors in the modulation of inter-individual expression variations of the P450 genes. In this study, we measured the mRNA levels of seven major P450 genes (CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5) in 96 liver biopsy samples from Chinese population. Both trans-acting (mRNA levels and non-synonymous SNPs of putative regulator genes) and cis-acting (gene copy number and functional SNPs) factors were investigated to identify the determinants of the expression variations of these seven P450 genes. We found that expression variations of most P450 genes, regulator genes and housekeeping genes were positively correlated at the mRNA level. After partial correlation analysis using ACTB and GAPDH expression to eliminate the effect of global regulators, a UPGMA (Unweighted Pair Group Method with Arithmetic Mean) tree was constructed to reveal the effects of specific regulation networks potentially masked by global regulators. Combined with the functional analysis of regulators, our results suggested that expression variation at the mRNA level was mediated by several factors in a gene-specific manner. Cis-acting genetic variants might play key roles in the expression variation of CYP2D6 and CYP3A5, environmental inducers might play key roles in CYP1A1 and CYP1A2 variation and global regulators might play key roles in CYP2C9 variation. In addition, the functions of regulators that play less important roles in controlling expression variation for each P450 gene were determined.
Background
Hypospadias is a common congenital malformation of male external genitalia, which mainly manifests as an abnormal urethral opening on the ventral side of the penis. The etiology and ...clinical phenotype of hypospadias is highly heterogeneous, and its clinical diagnosis is challenging. Currently, over 70% of patients have an unknown etiology. Here, we performed a targeted analysis of gene mutations in 130 patients with hypospadias of unknown etiology to find the precise genetic cause.
Methods
We developed a targeted next‐generation sequencing (NGS) panel, encompassing the exon coding regions of 105 genes involved in external genitalia and urogenital tract development and performed sequencing analysis on 130 children with hypospadias of unknown etiology.
Results
In total, 25 patients with hypospadias (19.2%) were found to have 20 mutations among the nine genes involved in external genitalia and urogenital tract development, including 16 reported and four novel mutation sites. Twenty‐two patients (16.9%) had diagnostic variants. Multiple genetic mutations were identified in three of the 25 patients. Hypospadias combined with micropenis was the most common phenotype (68%) in 25 patients.
Conclusions
Higher frequency mutations were identified in SRD5A2 (52%) and AR (24%) in our patient cohort. Middle or posterior hypospadias with micropenis may be significant indicators of genetic variations. Polygenic inheritance may be a rare genetic cause of hypospadias.
In this study, we performed targeted next‐generation sequencing of 105 genes associated with molecular regulation of external genitalia and urogenital tract development in 130 patients with hypospadias of unknown etiology. A total of 25 patients (19.2%) were found to carry genetic variants in one or more of the nine targeted genes. We also found that middle or posterior hypospadias with micropenis may represent significant signs for genetic variations.
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