published_or_final_version / Pathology / Master / Master of Medical Sciences

Background and objectives: Recent genome-wide association (GWA) studies conducted in Caucasian populations have significantly expanded the list of confirmed and potential susceptibility genes for obesity and type 2 diabetes. The major objective of this thesis was to establish the role of the previously identified obesity- and T2DM-susceptibility genes in the Hong Kong Southern Chinese population. Major findings: In a cross-sectional case-control study of Southern Chinese which involved 470 obese cases and 700 normal-weight controls, significant associations with obesity were demonstrated in 7 of 13 single nucleotide polymorphisms (SNPs) that have shown significant associations with obesity and/or body mass index (BMI) in previous Caucasian GWA studies. These SNPs are located within or near the GNPDA2, FTO, MC4R, KCTD15, SFRS10-ETV5-DGKG, SEC16B-RASAL2 and NEGR1 loci. The combined genetic risk score (GRS) of the 13 studied SNPs was associated with an increased risk for obesity. The GNPDA2 rs10938397, FTO rs8050136, and MC4R rs17782313, which showed the most significant associations with obesity, were further examined for their associations with persistent central obesity and the metabolic syndrome (MetS). Both rs8050136 and rs10938397 were significantly associated with persistent central obesity. rs10938397 was also associated with the MetS. The combined GRS of these 3 SNPs showed significant associations with both persistent central obesity and persistent MetS. Nineteen multimarker-tagging SNPs that span a well-defined LD block of the FTO gene were evaluated for their associations with obesity in a case-control study which involved 249 cases and 400 controls. rs16952522 was found to be significantly associated with obesity, in addition to the well-known SNP rs8050136. These 2 SNPs were nominally associated with T2DM, although the associations were abolished after adjustment for age, sex and BMI. However, the GA haplotype composed of the risk alleles of these 2 SNPs was significantly associated with T2DM, independent of BMI. Seventeen previously identified T2DM-associated SNPs were investigated for the associations with glycaemic progression in an 8-year follow-up study which involved 518 cases and 998 controls. Their combined GRS was associated with an increased risk for glycaemic progression. A significant association with glycaemic progression was found with CDKN2A/B rs10811661. Moreover, KCNJ11 rs5219 and IGF2BP2 rs11711477 also showed potential associations with glycaemic progression. In the subsequent 12-year follow-up study, which involved 200 cases and 903 controls, the CDKN2A/B rs10811661 showed a significant independent association with incident T2DM. The KCNJ11 E23K (rs5219) variant was examined for its association with diabetes development in a 12-year prospective study. It was found to be significantly associated with the development of prediabetes but not with the development of T2DM. However, in a meta-analysis which involved 15680 subjects across different populations, this variant could indeed predict T2DM. Conclusions: The findings of this thesis have provided novel evidence supporting the role of the GWA studies-identified obesity- and T2DM-associated genetic variants as genetic markers of obesity and T2DM among Southern Chinese in Hong Kong, and suggest that the GNPDA2, FTO and MC4R genes confer susceptibility to obesity and that the CDKN2A/B and KCNJ11 genes may play a role in diabetes development. / published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

published_or_final_version / Paediatrics and Adolescent Medicine / Doctoral / Doctor of Philosophy

Colorectal cancer (CRC) is the second most common cancer in Hong Kong. While high-penetrance germline mutations account for up to 6% of cases, much of the variation in genetic risk may be attributable to multiple low-penetrance variants. Previous genome wide association studies (GWAS) have identified a number of CRC susceptibility alleles in Caucasian populations. Our GWAS investigated the association between genetic variants with CRC risk in the Han Chinese population in Hong Kong. In Stage I, genomic DNA samples from 455 female Chinese CRC subjects were genotyped using the Illumina 610 Quad SNP chip. Association analysis was performed on 439 cases and 771 general population female controls recruited for a study on bone mineral density. Population stratification was examined through principal components analysis using EIGENSTRAT version 2.0. From the association results, 46 SNPs (Group 1) were selected for follow-up replication (Stage II), together with 10 SNPs (Group 2) from previous GWAS studies. Genomic DNA samples from 3,571 Chinese subjects were genotyped using Sequenom MassARRAY system. Association analysis was performed on 1,505 cases and 1,452 controls. 5 SNPs (rs835378, rs2652007, rs2139273, rs2139273 and rs9286410) exceeded the genome-wide significance level in stage I, although none replicated in Stage 2, suggesting genotyping error. Results from stage II showed that the three most significant SNP were among those selected from the previous studies, yet their significance levels in Stage I were very weak . None of the SNPs selected from Stage I was significant at p<0.01 in Stage 2. Two composite scores of genetic susceptibility, one for each group of SNPs, were calculated in stage II genotype data, as the total number of high-risk alleles (according to the direction of effect in Stage I results or previous GWAS) present in an individual. Both composite scores were significantly associated with CRC risk in Stage 2 (Group 1, p=2.38 x 10-5, beta=0.046, SE=0.012; Group 2 p=1.06 x 10-7, beta=0.10, SE=0.019), suggesting that while we had insufficient power to confirm individual SNPs identified in our GWAS and the previous GWAS, these findings indicate that the SNP sets selected from Stage I results, as well as those selected from previous GWAS, contain SNPs with genuine effects on CRC risk. One SNP, rs10795668 (OR = 0.79 [CI] 95%:0.71 – 0.87 p=3.78 x 10-6), was significantly associated with CRC risk in Stage II after adjustment for multiple testing. Two further SNPs, rs6983267 and rs4939827, also achieved suggestive p-values in Stage II. All these SNPs were selected from previous GWAS in the Caucasian population, demonstrating that shared genetic factors operate for CRC in diverse populations. / published_or_final_version / Psychiatry / Master / Master of Philosophy

Polycomb group (PcG) proteins governs the regulation of diverse cellular functions, such as cell fate decision, cell cycle progression, maintenance of embryonic stem cell pluripotency, and DNA damage repair. Although aberrant expression of PcG proteins has been frequently reported in different cancer types, CBX8 is one of the least studied PcG family members in cancer. Recently, a study showed that forced expression of CBX8 in normal human and mouse fibroblasts demonstrated that cells could bypass senescence via INK4a-ARF repression; while another report demonstrated that CBX8 was involved in MLL-AF9-linked leukemogenesis. Despite accumulating evidence on CBX8-related carcinogenic functions, the role of CBX8 in solid cancers has not been investigated thus far. This study is therefore initiated to investigate and establish the functional role of CBX8 in colorectal cancer. In this study, expression of CBX8 in 121 pairs of human CRC samples was analyzed by immunohistochemistry; and data were correlated with different clinicopathological parameters. To evaluate the functional effects of CBX8, CBX8 overexpressed and downregulated clones were established from three CRC cell lines. The in vitro effects of CBX8 on cell proliferation, cell cycle progression and apoptosis profiles were investigated; and the effects of CBX8 on tumorigenicity in vivo were further demonstrated in mice xenograft models. The results showed that CBX8 expression was downregulated or loss in approximately 48.8% of human colorectal tumors, and downregulated or loss of CBX8 expression were mainly observed in tumors with intermediate to later stages (stage II to IV). Moreover, expression of CBX8 showed a significant inverse correlation with colorectal tumor sizes (P < 0.0001). Ectopic expression of CBX8 in CRC cell lines resulted in inhibition of cell proliferation, clonogenic ability and anchorage-independent growth, which are hallmarks of tumorigenesis. Conversely, downregulation of CBX8 promoted proliferation and clonogenic ability. Moreover, it was found that restoring CBX8 expression could induce G0/G1 arrest of cell cycle. The tumor suppressive role of CBX8 in colorectal cells was further demonstrated in vivo through subcutaneous and orthotropic mice tumor models; followed by immuno-staining of the proliferation marker Ki-67. To unveil the possible mechanisms behind the tumor suppressing effects of CBX8, two signalling pathways commonly engaged in CRC were evaluated. At least part of the effects could be attributed to the mediation of MAPK signaling pathway; whereas the Wnt signalling was not affected by CBX8. This study demonstrated for the first time the loss of CBX8 expression in intermediate and late stage tumors, and was the first to report the tumor suppressing ability of CBX8 in solid cancers. The effects of CBX8 in this study were different to the functional implications reported in the current literature. This functional divergence in distinct cell types suggested a dynamic role of CBX8 depending on specific cellular context. / published_or_final_version / Surgery / Master / Master of Philosophy

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published_or_final_version / abstract / Medicine / Doctoral / Doctor of Philosophy

published_or_final_version / Microbiology / Master / Master of Philosophy

published_or_final_version / Pathology / Master / Master of Philosophy