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BackgroundRecent genome-wide association studies of colorectal cancer (CRC) have identified common single-nucleotide polymorphisms (SNPs) mapping to 10 independent loci that confer modest increased risk. These studies have been conducted in European populations and it is unclear whether these observations generalise to populations with different ethnicities and rates of CRC.MethodsAn association study was performed on 892 CRC cases and 890 controls recruited from the Hong Kong Chinese population, genotyping 32 SNPs, which were either associated with CRC in previous studies or are in close proximity to previously reported risk SNPs.ResultsTwelve of the SNPs showed evidence of an association. The strongest associations were provided by rs10795668 on 10p14, rs4779584 on 15q14 and rs12953717 on 18q21.2. There was significant linear association between CRC risk and the number of independent risk variants possessed by an individual (P=2.29 × 10(-5)).ConclusionThese results indicate that some previously reported SNP associations also impact on CRC risk in the Chinese population. Possible reasons for failure of replication for some loci include inadequate study power, differences in allele frequency, linkage disequilibrium structure or effect size between populations. Our results suggest that many associations for CRC are likely to generalise across populations.

Mandy H Chan,1 Patrick WL Leung,2 Ting-pong Ho,3 Se-fong Hung,4 Chi-chiu Lee,5 Chun-pan Tang,5 Ka-chai Cheung,2 Fung-yee Ching,2 Fefe HK Chan,6 Lu-hua Chen,2 Merce Garcia-Barcelo,7 Pak-chung Sham3 1Department of Clinical Psychology, Kowloon Hospital, Hospital Authority, 2Department of Psychology, The Chinese University of Hong Kong, 3Department of Psychiatry, University of Hong Kong, 4Department of Psychiatry, The Chinese University of Hong Kong, 5Department of Psychiatry, Kwai Chung Hospital, Hospital Authority, 6Department of Clinical Psychology, Alice Ho Mui Ling Nethersole Hospital, Hospital Authority, 7Department of Surgery, University of Hong Kong, Hong Kong, People’s Republic of China Background: Methylphenidate (MPH) has been found to be an effective medication for attention-deficit/hyperactivity disorder (ADHD). However, there are neither consistent nor sufficient findings on whether psychiatric comorbidities and associated cognitive functions of ADHD are related to treatment response to MPH in ADHD children.Objectives: This study investigated whether psychiatric comorbidities, IQ, and neurocognitive deficits are related to treatment response to MPH in ADHD children. In some ways, it is preferable to have a drug that the effectiveness of which to a disorder is not affected by its associated cognitive functions and psychiatric comorbidities. On the other hand, it is likely that the baseline symptom severity of ADHD is associated with the effectiveness of MPH treatment on the symptoms post treatment.Methods: A total of 149 Chinese boys (aged 6–12 years) with ADHD, combined type, and normal IQ participated in this study. Assessment of ADHD symptom severity was conducted pre and post MPH treatment, while assessment of psychiatric comorbidities, IQ, and neurocognitive deficits was performed in a non-medicated condition. Treatment response was defined as the ADHD symptom severity post MPH treatment.Results: Results indicated that MPH treatment was effective, significantly improving the ADHD condition. Yet, comorbid disorders, IQ, and neurocognitive deficits were not related to MPH treatment response on ADHD symptoms. These findings indicated that the effectiveness of MPH was not affected by psychiatric comorbidities and associated cognitive functions of ADHD. Instead, as expected, it was the baseline symptom severity that was mainly related to the treatment response, ie, the milder the baseline condition, the better the treatment response.Conclusion: The current findings positively endorse the widespread clinical use of MPH for treating ADHD. It improves the behavioral symptoms of ADHD regardless of varying psychiatric comorbidities, IQ, and neurocognitive deficits. Keywords: ADHD, psychiatric comorbidities, cognitive functions, treatment response, methylphenidate

Hirschsprung disease (HSCR, OMIM 142623) involves congenital intestinal obstruction caused by dysfunction of neural crest cells and their progeny during enteric nervous system (ENS) development. HSCR is a multifactorial disorder; pathogenetic variants accounting for disease phenotype are identified only in a minority of cases, and the identification of novel disease-relevant genes remains challenging. In order to identify and to validate a potential disease-causing relevance of novel HSCR candidate genes, we established a complementary study approach, combining whole exome sequencing (WES) with transcriptome analysis of murine embryonic ENS-related tissues, literature and database searches, in silico network analyses, and functional readouts using candidate gene-specific genome-edited cell clones. WES datasets of two patients with HSCR and their non-affected parents were analysed, and four novel HSCR candidate genes could be identified: ATP7A, SREBF1, ABCD1 and PIAS2. Further rare variants in these genes were identified in additional HSCR patients, suggesting disease relevance. Transcriptomics revealed that these genes are expressed in embryonic and fetal gastrointestinal tissues. Knockout of these genes in neuronal cells demonstrated impaired cell differentiation, proliferation and/or survival. Our approach identified and validated candidate HSCR genes and provided further insight into the underlying pathomechanisms of HSCR., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics Laboratories.

Objective: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. CD247 (CD3Z, TCRZ) plays a vital role in antigen recognition and signal transduction in antigen-specific immune responses, and is known to be involved in SLE pathogenesis. Weak disease association was reported for genetic variants in this gene in Caucasian studies for SLE, Crohn's disease and systemic sclerosis, but its role as a genetic risk factor was never firmly established., Methods: In this study, using a collection of 612 SLE patients and 2193 controls of Chinese ethnicity living in Hong Kong in a genome-wide study, single nucleotide polymorphisms (SNPs) in and around CD247 were identified as being associated with SLE. The two most significant SNPs in this locus were selected for further replication using TaqMan genotyping assay in 3339 Asian patients from Hong Kong, Mainland China, and Thailand, as well as 4737 ethnically and geographically matched controls., Results: The association of CD247 with SLE in Asian populations was confirmed (rs704853: odds ratio [OR] = 0. 81, p = 2.47 × 10(-7); rs858543: OR = 1.10, p = 0.0048). Patient-only analysis suggested that rs704853 is also linked to oral ulcers, hematologic disorders and anti-double-stranded DNA (dsDNA) antibody production., Conclusion: A significant association between variants in CD247 and SLE was demonstrated in Asian populations. Understanding the involvement of CD247 in SLE may shed new light on disease mechanisms and development of new treatment paradigms.

Receptor tyrosine kinase (RET) single nucleotide polymorphisms (SNPs) are associated with the Hirschsprung's disease (HSCR). We investigated whether the amount of RET expressed in the ganglionic gut of human was dependent on the genotype of three regulatory SNPs (-5G>A rs10900296 and -1A>C rs10900297 in the promoter, and C>T rs2435357 in intron 1). We examined the effects of three regulatory SNPs on the RET gene expression in 67 human ganglionic gut tissues using quantitative real-time PCR. Also, 315 Chinese HSCR patients and 325 ethnically matched controls were genotyped for the three SNPs by polymerase chain reaction (PCR) and direct sequencing. The expression of RET mRNA in human gut tissue did indeed correlate with the genotypes of the individuals. The lowest RET expression was found for those individuals homozygous for the three risk alleles (A-C-T/A-C-T), and the highest for those homozygous for the 'wild-type' counterpart (G-A-C/G-A-C), with expression values ranging from 218.32 +/- 125.69 (mean +/- SE) in tissues from individuals carrying G-A-C/G-A-C to 31.42 +/- 8.42 for individuals carrying A-C-T/A-C-T (P = 0.018). As expected, alleles -5A, -1C and intron 1 T were associated with HSCR (P = 5.94 x 10(-31), 3.12 x 10(-24) and 5.94 x 10(-37), respectively) as was the haplotype encompassing the three associated alleles (A-C-T) when compared with the wild-type counterpart G-A-C (chi2 = 155.29, P << 0.0001). To our knowledge, this is the first RET expression genotype-phenotype correlation study conducted on human subjects to indicate common genetic variants in the regulatory region of RET may play a role in mediating susceptibility to HSCR, by conferring a significant reduction of the RET expression.

Hirschsprung's disease (HSCR) is a developmental disorder characterized by the absence of ganglion cells in the lower digestive tract. Aganglionosis is attributed to a disorder of the enteric nervous system (ENS) whereby ganglion cells fail to innervate the lower gastrointestinal tract during embryonic development. HSCR is a complex disease that results from the interaction of several genes and manifests with low, sex-dependent penetrance and variability in the length of the aganglionic segment. The genetic complexity observed in HSCR can be conceptually understood in light of the molecular and cellular events that take place during the ENS development. DNA alterations in any of the genes involved in the ENS development may interfere with the colonization process, and represent a primary etiology for HSCR. This review will focus on the genes known to be involved in HSCR pathology, how they interact, and on how technology advances are being employed to uncover the pathological processes underlying this disease.

Background: The combination of partial absence of the sacrum, anorectal anomalies, and presacral mass constitutes Currarino syndrome (CS), which is associated with mutations in HLXB9., Methods: We analyzed 5 CS families and 6 sporadic cases for HLXB9 mutations by direct sequencing. Potentially pathologic expansions of HLXB9 GCC repeats were analyzed in patients, 4 general populations [Chinese, Japanese, Yoruba, and Centre du Etude Polymorphisme Human (CEPH)] from the HapMap project, and 145 healthy Chinese., Results: We identified 6 novel mutations affecting highly conserved residues (Ser185X, Trp215X, Ala26fs, Ala75fs, Met1Ile, and Arg273Cys). GCC allele and genotype distributions showed marked statistically significant differences. (GCC)11 was the most common allele overall; its frequency ranged from 90% in CEPH to 68% in Yoruba and 50% in Chinese and Japanese populations. (GCC)9 was almost as common as (GCC)11 in Chinese and Japanese populations, whereas its frequency was <10% in Yoruba and CEPH populations. The Yoruba population had the highest frequency of the largest alleles [(GCC)12 and (GCC)13], which were almost absent in the other groups., Conclusions: Lack of HLXB9 mutations in some patients and the presence of variable phenotypes suggest DNA alterations in HLXB9 noncoding regions and/or in other genes encoding HLXB9 regulatory molecules or protein partners. If HLXB9, like other homeobox genes, has a threshold beyond which triplet expansions are pathologic, those populations enriched with larger alleles would be at a higher risk. The data illustrate the importance of ethnicity adjustment if these polymorphic markers are to be used in association studies.

Background: Hirschsprung disease (HSCR) is a congenital disorder characterized by an absence of ganglion cells in the nerve plexuses of the lower digestive tract. HSCR has a complex pattern of inheritance and is sometimes associated with mutations in genes of the receptor tyrosine kinase (RET) and endothelin receptor B (EDNRB) signaling pathways, which are crucial for development of the enteric nervous system., Methods: Using PCR amplification and direct sequencing, we screened for mutations and polymorphisms in the coding regions and intron/exon boundaries of the RET, GDNF, EDNRB, and EDN3 genes of 84 HSCR patients and 96 ethnically matched controls., Results: We identified 10 novel and 2 previously described mutations in RET, and 4 and 2 novel mutations in EDNRB and in EDN3, respectively. Potential disease-causing mutations were detected in 24% of the patients. The overall mutation rate was 41% in females and 19% in males (P = 0.06). RET mutations occurred in 19% of the patients. R114H in RET was the most prevalent mutation, representing 7% of the patients or 37% of the patients with RET mutations. To date, such a high frequency of a single mutation has never been reported in unrelated HSCR patients. Mutations in EDNRB, EDN3, and GDNF were found in four, two, and none of the patients, respectively. Two patients with mutations in genes of the EDNRB pathway also harbored a mutation in RET. Three novel and three reported polymorphisms were found in EDNRB, EDN3, and GDNF., Conclusion: This study identifies additional HSCR disease-causing mutations, some peculiar to the Chinese population, and represents the first comprehensive genetic analysis of sporadic HSCR disease in Chinese.

Background: The cytochrome P450 CYP2D6 enzyme debrisoquine 4-hydroxylase metabolizes many different classes of commonly used drugs, such as tricyclic antidepressants and neuroleptics. Genetic polymorphism of the CYP2D6 gene is responsible for pronounced interindividual and interracial differences in the metabolism of these drugs. The CYP2D6*10 allele and its variants are the most frequent alleles found in Orientals, and they are responsible for diminished debrisoquine 4-hydroxylase activity because of the presence of a C(188)-->T mutation in exon 1., Methods: One hundred nineteen Hong Kong Chinese subjects were genotyped by means of allele-specific PCR, PCR, and restriction enzyme analysis for 10 CYP2D6 alleles (CYP2D6*1, *2, *4D, *5, *8/*14, *10A, *10B, *15, *16, and J9)., Results: CYP2D6*10B was the most prevalent allele, and CYP2D6*10/CYP2D6*10 was the most frequent genotype, representing 41.17% [corrected] of the population., Conclusions: There was no significant difference in the prevalence of the alleles analyzed between our study and the Chinese populations genotyped previously. This is the largest study in terms of the number of CYP2D6 alleles analyzed in an Oriental population and the first one conducted in a Hong Kong Chinese population.

Compartmentalization of human cytosolic malate dehydrogenase, hcMDH, together with its isozyme partner-mitochondrial form, hmMDH, plays an important role in the aerobic metabolism of the malate-aspartate shuttle and the citric acid cycle. However, they share few structural homology at the molecular level. The pseudogenes of mMDH has been reported in mice but hcMDH has no pseudogenes as shown by Southern blot analysis. A single band only was detected for the EcoRI digestion with 9.4 kb long of human genomic DNA and HindIII cutting with 2.8 kb long. hcMDH gene was mapped to chromosome 2 by somatic cell hybrid analysis and further localised to 268.72 cR from the top telomere of Chromosome 2 (near 2p15) by radiation hybrid mapping. The genes falling into this region may be related to dilated cardiomyopathy (DCM), several types of cancers and immunoregulation mechanism of cancers.

The mycolate pattern of a recently recognized mycobacterial pathogen, Mycobacterium mucogenicum (formerly Mycobacterium chelonae-like organism), was established for the first time. The reference strains, together with 31 environmental and clinical isolates belonging to this species, were examined for their mycolate composition by thin-layer chromatography. All strains tested exhibited the same mycolate profile. Mycolates were identified as belonging to the type without additional oxygenated chemical groups (mycolate I) and the type with a dicarboxylic group (mycolate VI); the identification of the latter was reinforced by the presence of 2-octadecanol, as seen by gas-liquid capillary chromatography. This mycolate profile permits the clear differentiation of M. mucogenicum from other related species, as members of the Mycobacterium fortuitum complex. This fact is especially important-because strains of M. mucogenicum are very difficult to differentiate from other species of the M. fortuitum complex by means of conventional biochemical tests. Moreover, the characteristic mycolate profile exhibited by the strains of M. mucogenicum supports the recent proposal which considers them as members of a new species.

We found that Mycobacterium porcinum ATCC 33776T (T = type strain) contains a new kind of mycolic acid with a methoxy group at the omega-1 position. This mycolic acid was identified by comparing it with the previously described methoxymycolic acids. The patterns of mycolic acid methyl esters from 418 strains belonging to 44 species of mycobacteria were studied by using thin-layer chromatography. In addition to M. procinum ATCC 33776T, representative strains of M. porcinum, Mycobacterium fortuitum, "Mycobacterium peregrinum," Mycobacterium senegalense, and a recently isolated Mycobacterium sp. contained appreciable amounts of the newly described mycolic acid.