Yong-Bing Xiang

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.

Identification of genetic susceptibility loci for colorectal tumors in a genome-wide meta-analysis

BACKGROUND & AIMS Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis. METHODS We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent. RESULTS Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10(-8): an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10(-8)). We also found evidence for 3 additional loci with P values less than 5.0 × 10(-7): a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10(-8)), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10(-8)), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10(-7)). CONCLUSIONS In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.

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).

Identification of New Genetic Risk Variants for Type 2 Diabetes

Although more than 20 genetic susceptibility loci have been reported for type 2 diabetes (T2D), most reported variants have small to moderate effects and account for only a small proportion of the heritability of T2D, suggesting that the majority of inter-person genetic variation in this disease remains to be determined. We conducted a multistage, genome-wide association study (GWAS) within the Asian Consortium of Diabetes to search for T2D susceptibility markers. From 590,887 SNPs genotyped in 1,019 T2D cases and 1,710 controls selected from Chinese women in Shanghai, we selected the top 2,100 SNPs that were not in linkage disequilibrium (r2<0.2) with known T2D loci for in silico replication in three T2D GWAS conducted among European Americans, Koreans, and Singapore Chinese. The 5 most promising SNPs were genotyped in an independent set of 1,645 cases and 1,649 controls from Shanghai, and 4 of them were further genotyped in 1,487 cases and 3,316 controls from 2 additional Chinese studies. Consistent associations across all studies were found for rs1359790 (13q31.1), rs10906115 (10p13), and rs1436955 (15q22.2) with P-values (per allele OR, 95%CI) of 6.49×10−9 (1.15, 1.10–1.20), 1.45×10−8 (1.13, 1.08–1.18), and 7.14×10−7 (1.13, 1.08–1.19), respectively, in combined analyses of 9,794 cases and 14,615 controls. Our study provides strong evidence for a novel T2D susceptibility locus at 13q31.1 and the presence of new independent risk variants near regions (10p13 and 15q22.2) reported by previous GWAS.

The 5p15.33 locus is associated with risk of lung adenocarcinoma in never-smoking females in Asia.

Genome-wide association studies of lung cancer reported in populations of European background have identified three regions on chromosomes 5p15.33, 6p21.33, and 15q25 that have achieved genome-wide significance with p-values of 10−7 or lower. These studies have been performed primarily in cigarette smokers, raising the possibility that the observed associations could be related to tobacco use, lung carcinogenesis, or both. Since most women in Asia do not smoke, we conducted a genome-wide association study of lung adenocarcinoma in never-smoking females (584 cases, 585 controls) among Han Chinese in Taiwan and found that the most significant association was for rs2736100 on chromosome 5p15.33 (p = 1.30×10−11). This finding was independently replicated in seven studies from East Asia totaling 1,164 lung adenocarcinomas and 1,736 controls (p = 5.38×10−11). A pooled analysis achieved genome-wide significance for rs2736100. This SNP marker localizes to the CLPTM1L-TERT locus on chromosome 5p15.33 (p = 2.60×10−20, allelic risk = 1.54, 95% Confidence Interval (CI) 1.41–1.68). Risks for heterozygote and homozygote carriers of the minor allele were 1.62 (95% CI; 1.40–1.87), and 2.35 (95% CI: 1.95–2.83), respectively. In summary, our results show that genetic variation in the CLPTM1L-TERT locus of chromosome 5p15.33 is directly associated with the risk of lung cancer, most notably adenocarcinoma.

Validity and reproducibility of the food-frequency questionnaire used in the Shanghai men's health study.

We evaluated the validity and reproducibility of the FFQ used in the Shanghai Mens Health Study (SMHS). The study included 195 randomly selected participants of the SMHS who completed one FFQ at baseline, twelve 24-hour dietary recalls (24-HDR) (once a month for twelve consecutive months) and a second FFQ at the end of the study. The FFQ accounted for 88.78% of the foods recorded in the 24-HDR surveys. The validity of the FFQ was evaluated by comparing nutrient and food group intake levels from the second FFQ and the multiple 24-HDR. Correlation coefficients ranged from 0.38 to 0.64 for macronutrients, 0.33 to 0.58 for micronutrients and 0.35 to 0.72 for food groups. Misclassification to opposite quartiles for nutrients and food groups was rare, ranging from 1.5 to 7.7%, while exact agreement rates were between 31.8 and 53.3%. The reliability of the FFQ was assessed by comparing the intake levels from the two FFQ. Correlation coefficients were 0.39 to 0.53 for macronutrients, 0.38 to 0.52 for micronutrients and 0.39 to 0.64 for food groups. Exact agreement rates for quartile distribution were between 31.8 and 49.2%, while misclassification to opposite quartiles was between 1.5 and 6.2%. These data indicate that the SMHS FFQ can reasonably categorise usual intake of nutrients and food groups among men living in urban Shanghai.

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.

Cruciferous vegetables intake and the risk of colorectal cancer: a meta-analysis of observational studies

BACKGROUND Epidemiological studies have reported inconsistent associations between cruciferous vegetable (CV) intake and colorectal cancer (CRC) risk. To our knowledge, a comprehensive and quantitative assessment of the association between CV intake and CRC has not been reported. METHODS Relevant articles were identified by searching MEDLINE. We pooled the relative risks (RR) from individual studies using a random-effect model and carried out heterogeneity and publication bias analyses. RESULTS Twenty-four case-control and 11 prospective studies were included in our analysis. When all studies were pooled, we yielded a significantly inverse association between CV (RR: 0.82; 95% confidence interval 0.75-0.90) intake and CRC risk. Specific analysis for cabbage and broccoli yielded similar result. When separately analyzed, case-control studies of CV intake yield similar results, and the results from the prospective studies showed borderline statistical significance. Moreover, significant inverse associations were also observed in colon cancer and its distal subsite both among prospective and case-control studies. CONCLUSIONS Findings from this meta-analysis provide evidence that high intake of CV was inversely associated with the risk of CRC and colon cancer in humans. Further analysis on other specific CV, food preparation methods, stratified results by anatomic cancer site, and subsite of colon cancer should be extended in future study.

Preserved foods in relation to risk of nasopharyngeal carcinoma in Shanghai, China

A population‐based case‐control study was conducted in Shanghai, China, to investigate the association between dietary factors and risk of nasopharyngeal carcinoma (NPC). The study included 935 NPC patients aged 15 to 74 years and 1,032 community controls. Exposures to salted fish and other protein‐containing preserved food were associated with increased risk of NPC. Individuals who ate salted fish at least once a week had an 80% increase in risk of NPC relative to those who ate salted fish less than once a month (p = 0.07). Compared with those in the lowest quartile of protein‐containing preserved foods, subjects in the highest quartile of intake experienced a statistically significant 78% increase in risk of NPC [odds ratio (OR) = 1.78, 95% confidence interval (CI) = 1.37–2.31], with a dose‐dependent relationship (p for linear trend < 0.001). A similar association between intake of preserved vegetables and NPC risk was observed (OR = 1.39, p for linear trend = 0.003). In contrast, high intake of oranges/tangerines was associated with a statistically significant reduction in risk of NPC (OR = 0.55, p for linear trend < 0.001). When we examined the joint effect of preserved food and oranges/tangerines on risk of NPC, subjects in the highest tertile of preserved food and the lowest tertile of orange/tangerine intake had a 3‐fold increase in risk (95% CI = 2.08–4.91) compared with those in the lowest tertile of preserved food and the highest tertile of orange/tangerine intake. Int. J. Cancer 85:358–363, 2000. ©2000 Wiley‐Liss, Inc.

Genome-wide association analyses in east Asians identify new susceptibility loci for colorectal cancer

To identify new genetic factors for colorectal cancer (CRC), we conducted a genome-wide association study in east Asians. By analyzing genome-wide data in 2,098 cases and 5,749 controls, we selected 64 promising SNPs for replication in an independent set of samples, including up to 5,358 cases and 5,922 controls. We identified four SNPs with association P values of 8.58 × 10−7 to 3.77 × 10−10 in the combined analysis of all east Asian samples. Three of the four were replicated in a study conducted in 26,060 individuals of European descent, with combined P values of 1.22 × 10−10 for rs647161 (5q31.1), 6.64 × 10−9 for rs2423279 (20p12.3) and 3.06 × 10−8 for rs10774214 (12p13.32 near the CCND2 gene), derived from meta-analysis of data from both east Asian and European-ancestry populations. This study identified three new CRC susceptibility loci and provides additional insight into the genetics and biology of CRC.