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author:("Xu, meisheng")
1.  Genome-Wide Association Study of Survival in Patients with Pancreatic Adenocarcinoma 
Gut  2012;63(1):10.1136/gutjnl-2012-303477.
Survival of patients with pancreatic adenocarcinoma is limited and few prognostic factors are known. We conducted a two-stage genome-wide association study (GWAS) to identify germline variants associated with survival in patients with pancreatic adenocarcinoma.
We analyzed overall survival in relation to single nucleotide polymorphisms (SNPs) among 1,005 patients from two large GWAS datasets, PanScan I and ChinaPC. Cox proportional hazards regression was used in an additive genetic model with adjustment for age, sex, clinical stage and the top four principal components of population stratification. The first stage included 642 cases of European ancestry (PanScan), from which the top SNPs (P≤10−5) were advanced to a joint analysis with 363 additional patients from China (ChinaPC).
In the first stage of cases of European descent, the top-ranked loci were at chromosomes 11p15.4, 18p11.21, and 1p36.13, tagged by rs12362504 (P=1.63×10−7), rs981621 (P=1.65×10−7), and rs16861827 (P=3.75×10−7), respectively. One-hundred thirty-one SNPs with P ≤ 10−5 were advanced to a joint analysis with cases from the ChinaPC study. In the joint analysis, the top-ranked SNP was rs10500715 (minor allele frequency, 0.37; P=1.72×10−7) on chromosome 11p15.4, which is intronic to the SET binding factor 2 (SBF2) gene. The hazard ratio (95% CI) for death was 0.74 (0.66–0.84) in PanScan I, 0.79 (0.65–0.97) in ChinaPC, and 0.76 (0.68–0.84) in the joint analysis.
Germline genetic variation in the SBF2 locus was associated with overall survival in patients with pancreatic adenocarcinoma of European and Asian ancestry. This association should be investigated in additional large patient cohorts.
PMCID: PMC3816124  PMID: 23180869
Pancreatic cancer; GWAS; single nucleotide polymorphism; SET binding factor 2
2.  ABO blood group and breast cancer incidence and survival 
ABO blood type has been associated with risk and survival for several malignancies; however, data for an association with breast cancer are inconsistent. Our study population consisted of Nurses’ Health Study participants with self-reported serologic blood type and/or ABO genotype. Using Cox proportional hazards regression, we examined the association between serologic blood type and incident breast cancer among 67,697 women, including 3,107 cases. In addition, we examined the association with ABO genotype in a nested case-control study of 1,138 invasive breast cancer cases and 1,090 matched controls. Finally, we evaluated the association between serologic blood type and survival among 2,036 participants with breast cancer. No clear association was seen between serologic blood type or ABO genotype and risk of total breast cancer, invasive breast cancer, or breast cancer subtypes. Compared to women with blood type O, the age-adjusted incidence rate ratios for serologic blood type and total breast cancer were 1.06 (95% CI, 0.98–1.15) for type A, 1.06 (95% CI, 0.93–1.22) for AB, and 1.08 (95% CI, 0.96–1.20) for B. In genetic analyses, odds ratios for invasive breast cancer were 1.05 (95% CI, 0.87–1.27) for A/O, 1.21 (95% CI, 0.86–1.69) for A/A, 0.84 (95% CI, 0.56–1.26) for A/B, 0.84 (95% CI, 0.63–1.13) for B/O, and 1.17 (95% CI, 0.35–3.86) for B/B, compared to O/O. No significant association was noted between blood type and overall or breast cancer-specific mortality. Our results suggest no association between ABO blood group and breast cancer risk or survival.
PMCID: PMC3655700  PMID: 21633955
ABO blood group; ABO genotype; blood type; breast cancer; survival
3.  Genome-wide association study identifies novel alleles associated with risk of cutaneous basal cell carcinoma and squamous cell carcinoma 
Human Molecular Genetics  2011;20(18):3718-3724.
We conducted a genome-wide association study on cutaneous basal cell carcinoma (BCC) among 2045 cases and 6013 controls of European ancestry, with follow-up replication in 1426 cases and 4845 controls. A non-synonymous SNP in the MC1R gene (rs1805007 encoding Arg151Cys substitution), a previously well-documented pigmentation gene, showed the strongest association with BCC risk in the discovery set (rs1805007[T]: OR (95% CI) for combined discovery set and replication set [1.55 (1.45–1.66); P= 4.3 × 10−17]. We identified that an SNP rs12210050 at 6p25 near the EXOC2 gene was associated with an increased risk of BCC [rs12210050[T]: combined OR (95% CI), 1.24 (1.17–1.31); P= 9.9 × 10−10]. In the locus on 13q32 near the UBAC2 gene encoding ubiquitin-associated domain-containing protein 2, we also identified a variant conferring susceptibility to BCC [rs7335046 [G]; combined OR (95% CI), 1.26 (1.18–1.34); P= 2.9 × 10−8]. We further evaluated the associations of these two novel SNPs (rs12210050 and rs7335046) with squamous cell carcinoma (SCC) risk as well as melanoma risk. We found that both variants, rs12210050[T] [OR (95% CI), 1.35 (1.16–1.57); P= 7.6 × 10−5] and rs7335046 [G] [OR (95% CI), 1.21 (1.02–1.44); P= 0.03], were associated with an increased risk of SCC. These two variants were not associated with melanoma risk. We conclude that 6p25 and 13q32 are novel loci conferring susceptibility to non-melanoma skin cancer.
PMCID: PMC3159556  PMID: 21700618
4.  Preparation and optimization of matrix metalloproteinase-1-loaded poly(lactide-co-glycolide-co-caprolactone) nanoparticles with rotatable central composite design and response surface methodology 
Nanoscale Research Letters  2012;7(1):359.
Matrix metalloproteases are key regulatory molecules in the breakdown of extracellular matrix and in inflammatory processes. Matrix metalloproteinase-1 (MMP-1) can significantly enhance muscle regeneration by promoting the formation of myofibers and degenerating the fibrous tissue. Herein, we prepared novel MMP-1-loaded poly(lactide-co-glycolide-co-caprolactone) (PLGA-PCL) nanoparticles (NPs) capable of sustained release of MMP-1. We established quadratic equations as mathematical models and employed rotatable central composite design and response surface methodology to optimize the preparation procedure of the NPs. Then, characterization of the optimized NPs with respect to particle size distribution, particle morphology, drug encapsulation efficiency, MMP-1 activity assay and in vitro release of MMP-1 from NPs was carried out. The results of mathematical modeling show that the optimal conditions for the preparation of MMP-1-loaded NPs were as follows: 7 min for the duration time of homogenization, 4.5 krpm for the agitation speed of homogenization and 0.4 for the volume ratio of organic solvent phase to external aqueous phase. The entrapment efficiency and the average particle size of the NPs were 38.75 ± 4.74% and 322.7 ± 18.1 nm, respectively. Further scanning electron microscopy image shows that the NPs have a smooth and spherical surface, with mean particle size around 300 nm. The MMP-1 activity assay and in vitro drug release profile of NPs indicated that the bioactivity of the enzyme can be reserved where the encapsulation allows prolonged release of MMP-1 over 60 days. Taken together, we reported here novel PLGA-PCL NPs for sustained release of MMP-1, which may provide an ideal MMP-1 delivery approach for tissue reconstruction therapy.
PMCID: PMC3457853  PMID: 22747956
Matrix metalloproteinase-1; PLGA-PCL; Nanoparticles; Rotatable central composite design; Response surface methodology
5.  Genome-wide association study identifies nidogen 1 (NID1) as a susceptibility locus to cutaneous nevi and melanoma risk 
Human Molecular Genetics  2011;20(13):2673-2679.
We conducted a genome-wide association study on the number of melanocytic nevi reported by 9136 individuals of European ancestry, with follow-up replication in 3581 individuals. We identified the nidogen 1 (NID1) gene on 1q42 associated with nevus count (two linked single nucleotide polymorphisms with r2 > 0.9: rs3768080 A allele associated with reduced count, P = 6.5 × 10−8; and rs10754833 T allele associated with reduced count, P = 1.5 × 10−7). We further determined that the rs10754833 [T] was associated with a decreased melanoma risk in 2368 melanoma cases and 7432 controls [for CT genotype: odds ratio (OR) = 0.86, 95% confidence interval (CI) = 0.75–0.99, P = 0.04; for TT genotype: OR = 0.84, 95% CI = 0.71–0.98, P = 0.03]. Expression level of the NID1 locus was 2-fold higher for the rs10754833 T allele carriers than that with the CC genotype (P = 0.017) in the 87 HapMap CEU cell lines. The NID1 gene is a biologically plausible locus for nevogenesis and melanoma development, with decreased expression levels of NID1 in benign nevi (P = 3.5 × 10−6) and in primary melanoma (P = 4.6 × 10−4) compared with the normal skin.
PMCID: PMC3110001  PMID: 21478494
6.  Mapping of numerous disease-associated expression polymorphisms in primary peripheral blood CD4+ lymphocytes 
Human Molecular Genetics  2010;19(23):4745-4757.
Genome-wide association studies of human gene expression promise to identify functional regulatory genetic variation that contributes to phenotypic diversity. However, it is unclear how useful this approach will be for the identification of disease-susceptibility variants. We generated gene expression profiles for 22 184 mRNA transcripts using RNA derived from peripheral blood CD4+ lymphocytes, and genome-wide genotype data for 516 512 autosomal markers in 200 subjects. We screened for cis-acting variants by testing variants mapping within 50 kb of expressed transcripts for association with transcript abundance using generalized linear models. Significant associations were identified for 1585 genes at a false discovery rate of 0.05 (corresponding to P-values ranging from 1 × 10−91 to 7 × 10−4). Importantly, we identified evidence of regulatory variation for 119 previously mapped disease genes, including 24 examples where the variant with the strongest evidence of disease-association demonstrates strong association with specific transcript abundance. The prevalence of cis-acting variants among disease-associated genes was 63% higher than the genome-wide rate in our data set (P = 6.41 × 10−6), and although many of the implicated loci were associated with immune-related diseases (including asthma, connective tissue disorders and inflammatory bowel disease), associations with genes implicated in non-immune-related diseases including lipid profiles, anthropomorphic measurements, cancer and neurologic disease were also observed. Genetic variants that confer inter-individual differences in gene expression represent an important subset of variants that contribute to disease susceptibility. Population-based integrative genetic approaches can help identify such variation and enhance our understanding of the genetic basis of complex traits.
PMCID: PMC2972694  PMID: 20833654
7.  Pathway Analysis for Genome-Wide Association Study of Basal Cell Carcinoma of the Skin 
PLoS ONE  2011;6(7):e22760.
Recently, a pathway-based approach has been developed to evaluate the cumulative contribution of the functionally related genes for genome-wide association studies (GWASs), which may help utilize GWAS data to a greater extent.
In this study, we applied this approach for the GWAS of basal cell carcinoma (BCC) of the skin. We first conducted the BCC GWAS among 1,797 BCC cases and 5,197 controls in Caucasians with 740,760 genotyped SNPs. 115,688 SNPs were grouped into gene transcripts within 20 kb in distance and then into 174 Kyoto Encyclopedia of Genes and Genomes pathways, 205 BioCarta pathways, as well as two positive control gene sets (pigmentation gene set and BCC risk gene set). The association of each pathway with BCC risk was evaluated using the weighted Kolmogorov-Smirnov test. One thousand permutations were conducted to assess the significance.
Both of the positive control gene sets reached pathway p-values<0.05. Four other pathways were also significantly associated with BCC risk: the heparan sulfate biosynthesis pathway (p  =  0.007, false discovery rate, FDR  =  0.35), the mCalpain pathway (p  =  0.002, FDR  =  0.12), the Rho cell motility signaling pathway (p  =  0.011, FDR  =  0.30), and the nitric oxide pathway (p  =  0.022, FDR  =  0.42).
We identified four pathways associated with BCC risk, which may offer new insights into the etiology of BCC upon further validation, and this approach may help identify potential biological pathways that might be missed by the standard GWAS approach.
PMCID: PMC3145747  PMID: 21829505
8.  Genome Wide Association Study to predict severe asthma exacerbations in children using random forests classifiers 
BMC Medical Genetics  2011;12:90.
Personalized health-care promises tailored health-care solutions to individual patients based on their genetic background and/or environmental exposure history. To date, disease prediction has been based on a few environmental factors and/or single nucleotide polymorphisms (SNPs), while complex diseases are usually affected by many genetic and environmental factors with each factor contributing a small portion to the outcome. We hypothesized that the use of random forests classifiers to select SNPs would result in an improved predictive model of asthma exacerbations. We tested this hypothesis in a population of childhood asthmatics.
In this study, using emergency room visits or hospitalizations as the definition of a severe asthma exacerbation, we first identified a list of top Genome Wide Association Study (GWAS) SNPs ranked by Random Forests (RF) importance score for the CAMP (Childhood Asthma Management Program) population of 127 exacerbation cases and 290 non-exacerbation controls. We predict severe asthma exacerbations using the top 10 to 320 SNPs together with age, sex, pre-bronchodilator FEV1 percentage predicted, and treatment group.
Testing in an independent set of the CAMP population shows that severe asthma exacerbations can be predicted with an Area Under the Curve (AUC) = 0.66 with 160-320 SNPs in comparison to an AUC score of 0.57 with 10 SNPs. Using the clinical traits alone yielded AUC score of 0.54, suggesting the phenotype is affected by genetic as well as environmental factors.
Our study shows that a random forests algorithm can effectively extract and use the information contained in a small number of samples. Random forests, and other machine learning tools, can be used with GWAS studies to integrate large numbers of predictors simultaneously.
PMCID: PMC3148549  PMID: 21718536
9.  Variant ABO Blood Group Alleles, Secretor Status and Risk of Pancreatic Cancer: Results from the Pancreatic Cancer Cohort Consortium 
Subjects with non-O ABO blood group alleles have increased risk of pancreatic cancer. Glycosyltransferase activity is greater for the A1 versus A2 variant, while O01 and O02 variants are nonfunctioning. We hypothesized: (1) A1 allele would confer greater risk than A2 allele, (2) protective effect of the O allele would be equivalent for O01 and O02 variants, (3) secretor phenotype would modify the association with risk.
We determined ABO variants and secretor phenotype from single nucleotide polymorphisms in ABO and FUT2 genes in 1533 cases and 1582 controls from 12 prospective cohort studies. Adjusted odds ratios (ORs) for pancreatic cancer were calculated using logistic regression.
An increased risk was observed in participants with A1, but not A2 alleles. Compared to subjects with genotype O/O, genotypes A2/O, A2/A1, A1/O, and A1/A1 had ORs of 0.96 (95% confidence interval [CI], 0.72–1.26), 1.46 (95%CI, 0.98–2.17), 1.48 (95%CI, 1.23–1.78), and 1.71 (95%CI, 1.18–2.47). Risk was similar for O01 and O02 variant O alleles. Compared to O01/O01, the ORs for each additional allele of O02, A1, and A2 were 1.00 (95%CI, 0.87–1.14), 1.38 (95%CI, 1.20–1.58), and 0.96 (95%CI, 0.77–1.20); P-value, O01 versus O02=0.94, A1 versus A2=0.004. Secretor phenotype was not an effect modifier (P-interaction=0.63).
Among participants in a large prospective cohort consortium, ABO allele subtypes corresponding to increased glycosyltransferase activity were associated with increased pancreatic cancer risk.
These data support the hypothesis that ABO glycosyltransferase activity influences pancreatic cancer risk, rather than actions of other nearby genes on chromosome 9q34.
PMCID: PMC3005538  PMID: 20971884
Pancreatic cancer; ABO blood group; glycosyltransferase; secretor status; prospective cohort study
10.  Modulation of Lgl1 by steroid, retinoic acid, and Vitamin D models complex transcriptional regulation during alveolarization 
Pediatric research  2010;67(4):375-381.
Alveolarization depends on circulating glucocorticoid (GC), retinoid (RA) and Vitamin D (VitD). Bronchopulmonary dysplasia (BPD), a leading cause of neonatal morbidity, is associated with arrested alveolarization. In hyperoxia-exposed rats displaying features of BPD, reduced levels of Lgl1 normalize during recovery. We show that GC (100nM) stimulates (7–115 fold) and VitD (100µM) suppresses (2 fold) Lgl1 expression. RA (all trans/9-cis, 10µM) effects are biphasic. From postnatal (PN) days 7–10, RA was stimulatory (2 fold) at 24h, after which effects were inhibitory (3–15 fold). Lgl1 promoter-luciferase reporter assays confirmed that these agents operated at the transcriptional level. Interestingly, the individual inhibitory effects of VitD and RA on GC induction of Lgl1 were abrogated when both agents were present, suggesting that steric hindrance may influence promoter accessibility. Analysis of the proximity (<50 base pairs) of binding sites for overlapping VitD and RA receptors to that of the GC receptor identified 81% of promoters in 66 genes (including Lgl1) important in human lung development compared to 48% in a random set of 1000 genes. Complex integration of the effects of GC, RA, and VitD on gene expression in the postnatal lung is likely to contribute to the timely advance of alveolarization without attendant inflammation.
PMCID: PMC3104505  PMID: 20057335
11.  Genomics and genome-wide association studies: An integrative approach for expression QTL mapping 
Genomics  2008;92(3):129-133.
Expression QTL mapping by integrating genome-wide gene expression and genotype data is a promising approach for identifying functional genetic variation, but is hampered by the large number of multiple comparisons inherent to such studies. A novel approach for addressing multiple testing problems in genome-wide family-based association studies is screening candidate markers using heritability or conditional power. We apply these methods for the setting in which microarray gene expression data are used as phenotypes, screening for SNPs near the expressed genes. We perform association analyses for phenotypes using a univariate approach. Simulations were also performed on trios with large numbers of causal SNPs to determine the optimal number of markers to use in a screen. We demonstrate that our family-based screening approach performs well in the analysis of integrative genomic datasets, and that screening using either heritability or conditional power produce similar, though not identical, results.
PMCID: PMC2572725  PMID: 18586451
gene expression; association study; SNP; power; heritability; screening; multiple testing

Results 1-11 (11)