Zengnan Mo

Meta-analysis identifies common variants associated with body mass index in east Asians.

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.

Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus–related hepatocellular carcinoma

To identify genetic susceptibility loci for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in the Chinese population, we carried out a genome-wide association study (GWAS) in 2,514 chronic HBV carriers (1,161 HCC cases and 1,353 controls) followed by a 2-stage validation among 6 independent populations of chronic HBV carriers (4,319 cases and 4,966 controls). The joint analyses showed that HCC risk was significantly associated with two independent loci: rs7574865 at STAT4, Pmeta = 2.48 × 10−10, odds ratio (OR) = 1.21; and rs9275319 at HLA-DQ, Pmeta = 2.72 × 10−17, OR = 1.49. The risk allele G at rs7574865 was significantly associated with lower mRNA levels of STAT4 in both the HCC tissues and nontumor tissues of 155 individuals with HBV-related HCC (Ptrend = 0.0008 and 0.0002, respectively). We also found significantly lower mRNA expression of STAT4 in HCC tumor tissues compared with paired adjacent nontumor tissues (P = 2.33 × 10−14).

Genome-wide association study in Chinese men identifies two new prostate cancer risk loci at 9q31.2 and 19q13.4

Prostate cancer risk–associated variants have been reported in populations of European descent, African-Americans and Japanese using genome-wide association studies (GWAS). To systematically investigate prostate cancer risk–associated variants in Chinese men, we performed the first GWAS in Han Chinese. In addition to confirming several associations reported in other ancestry groups, this study identified two new risk-associated loci for prostate cancer on chromosomes 9q31.2 (rs817826, P = 5.45 × 10−14) and 19q13.4 (rs103294, P = 5.34 × 10−16) in 4,484 prostate cancer cases and 8,934 controls. The rs103294 marker at 19q13.4 is in strong linkage equilibrium with a 6.7-kb germline deletion that removes the first six of seven exons in LILRA3, a gene regulating inflammatory response, and was significantly associated with the mRNA expression of LILRA3 in T cells (P < 1 × 10−4). These findings may advance the understanding of genetic susceptibility to prostate cancer.

An updating meta-analysis of the GSTM1, GSTT1, and GSTP1 polymorphisms and prostate cancer: a HuGE Review.

It has been postulated that individuals with GSTM1, GSTT1 deficiency and, GSTP1 (105Ile/Val transition) have increased susceptibility to carcinogens and are more likely to develop prostate cancer. In recent years, GST status has been extensively studied as a prostate cancer risk factor; however, the results are inconsistent. To re‐examine this controversy, we have undertaken an updating meta‐analysis of 29 studies with GSTM1 genotyping (4,564 prostate cancer cases and 5,464 controls), 22 studies with GSTT1 genotyping (3,837 cases and 4,552 controls), and 24 studies with GSTP1 genotyping (5,301 cases and 5,621 controls). The random effects odds ratio was 1.33 [95% confidence interval (95% CI): 1.15, 1.55; I2 = 68.9%, P for heterogeneity = 0.00] for the GSTM1 null versus present genotype and 1.05 (95% CI: 0.86, 1.27; I2 = 68.2%, P for heterogeneity = 0.00) for the GSTT1 null versus present genotype, and 1.06 (95% CI: 0.91, 1.24; I2 = 71.5%, P for heterogeneity = 0.00) for the GSTP1‐Val versus GSTP1‐Ile allele. For GSTM1 polymorphism, similar results reached in Caucasians and Asians, with exception for Africans. No association between GSTT1 or GSTP1 polymorphisms and prostate cancer risk was detected in different racial. In conclusion, the major finding of our study suggested that GSTM1 polymorphism conferred an increasing risk of prostate cancer on a wide population basis, however, no relationship was found between GSTT1 and GSTP1 status and the risk of prostate cancer. Prostate 69:662–688, 2009.

Low serum osteocalcin level is a potential marker for metabolic syndrome: results from a Chinese male population survey

Osteocalcin has been recognized as a bone-derived hormone to regulate energy metabolism recently. Little is known about the role of osteocalcin as regards metabolic syndrome (MetS) in a Chinese population. Components of MetS, osteocalcin, body mass index (BMI), and prevalence of MetS were assessed in 2344 men aged 20 to 69 years who participated in the population-based Fangchenggang Area Male Health and Examination Survey, which was carried out in Guangxi province of China from September 2009 to December 2009. Osteocalcin had a statistically significant positive correlation with high-density lipoprotein cholesterol and a negative relationship with blood pressure, glucose, triglycerides, waist circumference, and BMI after adjustment for age (all P < .001). The strongest correlation was observed between osteocalcin and BMI (r = -0.26). In a multivariate analysis, decreased odds ratios (ORs) for the MetS and its components as well were observed from the first to the fourth osteocalcin quartiles. After adjustment for BMI, the OR decreased substantially. Statistically significant difference still existed in MetS (OR, 1.77; 95% confidence interval [CI], 1.10-2.85), hypertriglyceridemia (OR, 1.66; 95% CI, 1.22-2.27), hyperglycemia (OR, 1.42; 95% CI, 1.05-1.92), and low high-density lipoprotein cholesterol (OR, 1.83; 95% CI, 1.03-3.24) when these risks were compared in the lowest quartile of osteocalcin levels with those in the highest quartile. In a Chinese male population, we firstly identified an inverse association of serum osteocalcin levels with MetS, independent from the well-known MetS risk factors. This may represent a further mechanism for the elevated cardiovascular disease or type 2 diabetes mellitus risk.

Genome-wide association study in Chinese identifies novel loci for blood pressure and hypertension

Hypertension is a common disorder and the leading risk factor for cardiovascular disease and premature deaths worldwide. Genome-wide association studies (GWASs) in the European population have identified multiple chromosomal regions associated with blood pressure, and the identified loci altogether explain only a small fraction of the variance for blood pressure. The differences in environmental exposures and genetic background between Chinese and European populations might suggest potential different pathways of blood pressure regulation. To identify novel genetic variants affecting blood pressure variation, we conducted a meta-analysis of GWASs of blood pressure and hypertension in 11 816 subjects followed by replication studies including 69 146 additional individuals. We identified genome-wide significant (P < 5.0 × 10(-8)) associations with blood pressure, which included variants at three new loci (CACNA1D, CYP21A2, and MED13L) and a newly discovered variant near SLC4A7. We also replicated 14 previously reported loci, 8 (CASZ1, MOV10, FGF5, CYP17A1, SOX6, ATP2B1, ALDH2, and JAG1) at genome-wide significance, and 6 (FIGN, ULK4, GUCY1A3, HFE, TBX3-TBX5, and TBX3) at a suggestive level of P = 1.81 × 10(-3) to 5.16 × 10(-8). These findings provide new mechanistic insights into the regulation of blood pressure and potential targets for treatments.

A genome-wide association and gene–environment interaction study for serum triglycerides levels in a healthy Chinese male population

Triglyceride (TG) is a complex phenotype influenced by both genetic and environmental factors. Recent genome-wide association studies (GWAS) have identified genes or loci affecting lipid levels; however, such studies in Chinese populations are limited. A two-stage GWAS were conducted to identify genetic variants that were associated with TG in a Chinese population of 3495 men. Gene-environment interactions on serum TG levels were further investigated for the seven single nucleotide polymorphisms (SNPs) that were studied in both stages. Two previously reported SNPs (rs651821 in APOA5, rs328 in LPL) were replicated in the second stage, and the combined P-values were 9.19 × 10(-26) and 1.41 × 10(-9) for rs651821 and rs328, respectively. More importantly, a significant interaction between aldehyde dehydrogenase 2 (ALDH2) rs671 and alcohol consumption on serum TG levels were observed (P = 3.34 × 10(-5)). Rs671 was significantly associated with serum TG levels in drinkers (P = 1.90 × 10(-10)), while no association was observed in non-drinkers (P > 0.05). For drinkers, men carrying the AA/AG genotype have significantly lower serum TG levels, compared with men carrying the GG genotype. For men with the GG genotype, the serum TG levels increased with the quantity of alcohol intake (P = 1.28 × 10(-8) for trend test). We identified a novel, significant interaction effect between alcohol consumption and the ALDH2 rs671 polymorphism on TG levels, which suggests that the effect of alcohol intake on TG occurs in a two-faceted manner. Just one drink can increase TG level in susceptible individuals who carry the GG genotype, while individuals carrying AA/AG genotypes may actually benefit from moderate drinking.

The Association of Smoking and Erectile Dysfunction: Results From the Fangchenggang Area Male Health and Examination Survey (FAMHES)

To describe the prevalence of erectile dysfunction (ED) and its association with smoking and other risk factors among a large male population. Data were collected from 2686 men attending the Fangchenggang Area Male Health and Examination Survey from September 2009 to December 2009. ED was assessed using the 5-item International Index of Erectile Function. Self-reported smoking history was obtained from the questionnaire. Prevalence of ED was 49.5% among 2686 Chinese men in Fangchenggang aged 20-79 years. After adjusting for age, alcohol drinking, physical activity, hypertension, diabetes, dyslipidemia, and obesity, smokers who smoked ≥20 cigarettes daily had a significantly increased risk of ED than never smokers (odds ratio [OR], 1.23; 95% confidence interval [CI], 1.03-1.49; P = .02). After further adjustment for education, the risk of ED was still significantly higher in men smoking more than 23 years than never smokers (OR, 1.60; 95% CI, 1.22-2.09; P = .001). Association of age and education with ED was statistically significant after adjusting for the other variables. A history of diabetes and hypertension all increased the risk of ED, but statistically significant differences did not exist after adjustment for other variables. The association between smoking and ED risk in men was higher with a habit of drinking alcohol (OR, 1.32; 95% CI, 1.01-1.74) or physical inactivity (OR, 1.33; 95% CI, 1.05-1.67), or with a with a history of hypertension (OR, 1.71; 95% CI, 1.11-2.62), dyslipidemia (OR, 1.39; 95% CI, 1.06-1.81), and diabetes (OR, 2.69; 95% CI, 1.4-6.98). Our results show that heavy smoking might cause ED and that the duration of the habit increases the risk of ED. Furthermore, it highlights the potential interaction of smoking with other life habits or medical history on ED risk.

Genetic Variations Affecting Serum Carcinoembryonic Antigen Levels and Status of Regional Lymph Nodes in Patients with Sporadic Colorectal Cancer from Southern China

Background Serum carcinoembryonic antigen (sCEA) level might be an indicator of disease. Indeed, an elevated sCEA level is a prognostic factor in colorectal cancer (CRC) patients. However, the genetic determinants of sCEA level in healthy and CRC population remains unclear. Thus we investigated the genetic markers associated with elevated serum sCEA level in these two populations and its clinical implications. Methods and Findings Genome-wide association study (GWAS) was conducted in a cohort study with 4,346 healthy male adults using the Illumina Omni 1 M chip. Candidate SNPs associated with elevated sCEA levels were validated in 194 CRC patients on ABI Taqman platform. Eight candidate SNPs were validated in CRC patients. The rs1047781 (chr19- FUT2) (A/T) was associated with elevated sCEA levels, and rs8176746 (chr9- ABO) was associated with the regional lymph metastasis in the CRC patients. The preoperative sCEA level was a risk factor for tumor recurrence in 5 years after operation (OR = 1.427, 95% CI: 1.005∼1.843, P = 0.006). It was also one of the risk factors for regional lymph node metastasis (OR = 2.266, 95% CI: 1.196∼4.293, P = 0.012). The sCEA level in rs1047781-T carriers was higher than that in the A carriers in CRC patients without lymph node metastasis (P = 0.006). The regional lymph node metastasis in patients with homozygote AA of rs8176746 was more common than that in the heterozygote AG carriers (P = 0.022). In addition, rs1047781-AT and TT CRC patients exhibited a worse disease-free survival than AA genotype carriers (P = 0.023). Conclusions We found candidate SNPs associated with elevated sCEA levels in both healthy males and CRC population. Rs1047781 (chr19- FUT2) may be the susceptible locus for recurrence of CRC in a population from Southern China.

Oestradiol is a protective factor for non‐alcoholic fatty liver disease in healthy men

Visceral fat is a risk factor for non‐alcoholic fatty liver disease (NAFLD). A reduction in sex hormones is associated with increased abdominal fat. Thus, we investigated whether reduced testosterone (T) or oestradiol (E2) levels in men are associated with NAFLD and central obesity. The study involved a survey of 1,882 men between 20 and 60 years of age. We detected hepatic fat infiltration by ultrasound. Early morning serum was analyzed for total testosterone (TT), E2, sex hormone‐binding globulin (SHBG), follicle‐stimulating hormone (FSH) and luteinizing hormone (LH). Free testosterone (FT) was calculated using the Vermeulen method. In the studied population, the prevalence of NAFLD, FSH, LH and SHBG increased with age, TT and FT declined with age, and E2 remained stable. However, in the NAFLD group, TT remained stable, FT and E2 declined, and hepatic fat infiltration increased (P < 0.001 for both). Using multivariate analysis, a correlation was found between E2 and NAFLD, with an odds ratio of 0.954 (95% confidence interval: 0.946–0.967). E2 is one of the protective factors against NAFLD in healthy men. T has no significant correlation with NAFLD. Further investigation would be required to assess the clinical consequences of reduced E2 in men with NAFLD, particularly for men whose TT remained stable.