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Fulltext High producing tumor necrosis factor alpha gene alleles in protection against severe manifestations of dengue

Sam SS, Teoh BT, Chinna K, AbuBakar S

Int J Med Sci, 2015;12(2):177-86.
PMID: 25589894 DOI: 10.7150/ijms.8988

Dengue virus (DENV) infection usually presents with mild self-limiting dengue fever (DF). Few however, would present with the more severe form of the disease, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). In the present study, the association between IL-12B, IL-10 and TNF-α gene polymorphisms and dengue severity was investigated.
METHODS: A case-control study was performed on a total of 120 unrelated controls, 86 DF patients and 196 DHF/DSS patients. The polymorphisms in IL-12B, IL-10 and TNF-α genes were genotyped using PCR-RFLP and PCR-sequencing methods.
RESULTS: A protective association of TNF-α -308A allele and -308GA genotype against DHF/DSS was observed, while TNF-α -238A allele and -238GA genotype were associated with DHF/DSS. A combination of TNF-α -308GA+AA genotype and IL-10 non-GCC haplotypes, IL-12B pro homozygotes (pro1/pro1, pro2/pro2) and IL-12B 3'UTR AC were significantly correlated with protective effects against DHF/DSS. An association between the cytokine gene polymorphisms and protection against the clinical features of severe dengue including thrombocytopenia and increased liver enzymes was observed in this study.
CONCLUSION: The overall findings of the study support the correlation of high-producer TNF-α genotypes combined with low-producer IL-10 haplotypes and IL-12B genotypes in reduced risk of DHF/DSS.
KEYWORDS: Infectious disease; cytokine; dengue; genetics; polymorphism.; tropical

Matched MeSH terms: Haplotypes/genetics
Fulltext A new nested allele-specific multiplex polymerase chain reaction method for haplotyping of VKORC1 gene to predict warfarin sensitivity

Chua YA, Abdullah WZ, Yusof Z, Gan SH

Biomed Res Int, 2014;2014:316310.
PMID: 24790995 DOI: 10.1155/2014/316310

The vitamin K epoxide reductase complex 1 gene (VKORC1) is commonly assessed to predict warfarin sensitivity. In this study, a new nested allele-specific multiplex polymerase chain reaction (PCR) method that can simultaneously identify single nucleotide polymorphisms (SNPs) at VKORC1 381, 861, 5808, and 9041 for haplotype analysis was developed and validated. Extracted DNA was amplified in the first PCR DNA, which was optimized by investigating the effects of varying the primer concentrations, annealing temperature, magnesium chloride concentration, enzyme concentration, and the amount of DNA template. The amplification products produced from the first round of PCR were used as templates for a second PCR amplification in which both mutant and wild-type primers were added in separate PCR tubes, followed by optimization in a similar manner. The final PCR products were resolved by agarose gel electrophoresis and further analysed by using a VKORC1 genealogic tree to infer patient haplotypes. Fifty patients were identified to have H1H1, one had H1H2, one had H1H7, 31 had either H1H7 or H1H9, one had H1H9, eight had H7H7, and one had H8H9 haplotypes. This is the first method that is able to infer VKORC1 haplotypes using only conventional PCR methods.

Matched MeSH terms: Haplotypes/genetics*
Copy number polymorphisms in new HapMap III and Singapore populations

Ku CS, Teo SM, Naidoo N, Sim X, Teo YY, Pawitan Y, et al.

J Hum Genet, 2011 Aug;56(8):552-60.
PMID: 21677662 DOI: 10.1038/jhg.2011.54

Copy number variations can be identified using newer genotyping arrays with higher single nucleotide polymorphisms (SNPs) density and copy number probes accompanied by newer algorithms. McCarroll et al. (2008) applied these to the HapMap II samples and identified 1316 copy number polymorphisms (CNPs). In our study, we applied the same approach to 859 samples from three Singapore populations and seven HapMap III populations. Approximately 50% of the 1291 autosomal CNPs were found to be polymorphic only in populations of non-African ancestry. Pairwise comparisons among the 10 populations showed substantial differences in the CNPs frequencies. Additionally, 698 CNPs showed significant differences with false discovery rate (FDR)<0.01 among the 10 populations and these loci overlap with known disease-associated or pharmacogenetic-related genes such as CFHR3 and CFHR1 (age related macular degeneration), GSTTI (metabolism of various carcinogenic compounds and cancers) and UGT2B17 (prostate cancer and graft-versus-host disease). The correlations between CNPs and genome-wide association studies-SNPs were investigated and several loci, which were previously unreported, that may potentially be implicated in complex diseases and traits were found; for example, childhood acute lymphoblastic leukaemia, age-related macular degeneration, breast cancer, response to antipsychotic treatment, rheumatoid arthritis and type-1 diabetes. Additionally, we also found 5014 novel copy number loci that have not been reported previously by McCarroll et al. (2008) in the 10 populations.

Matched MeSH terms: Haplotypes/genetics*
Fulltext Evolutionary history of Helicobacter pylori sequences reflect past human migrations in Southeast Asia

Breurec S, Guillard B, Hem S, Brisse S, Dieye FB, Huerre M, et al.

PLoS One, 2011;6(7):e22058.
PMID: 21818291 DOI: 10.1371/journal.pone.0022058

The human population history in Southeast Asia was shaped by numerous migrations and population expansions. Their reconstruction based on archaeological, linguistic or human genetic data is often hampered by the limited number of informative polymorphisms in classical human genetic markers, such as the hypervariable regions of the mitochondrial DNA. Here, we analyse housekeeping gene sequences of the human stomach bacterium Helicobacter pylori from various countries in Southeast Asia and we provide evidence that H. pylori accompanied at least three ancient human migrations into this area: i) a migration from India introducing hpEurope bacteria into Thailand, Cambodia and Malaysia; ii) a migration of the ancestors of Austro-Asiatic speaking people into Vietnam and Cambodia carrying hspEAsia bacteria; and iii) a migration of the ancestors of the Thai people from Southern China into Thailand carrying H. pylori of population hpAsia2. Moreover, the H. pylori sequences reflect iv) the migrations of Chinese to Thailand and Malaysia within the last 200 years spreading hspEasia strains, and v) migrations of Indians to Malaysia within the last 200 years distributing both hpAsia2 and hpEurope bacteria. The distribution of the bacterial populations seems to strongly influence the incidence of gastric cancer as countries with predominantly hspEAsia isolates exhibit a high incidence of gastric cancer while the incidence is low in countries with a high proportion of hpAsia2 or hpEurope strains. In the future, the host range expansion of hpEurope strains among Asian populations, combined with human motility, may have a significant impact on gastric cancer incidence in Asia.

Matched MeSH terms: Haplotypes/genetics
The promoter region of the MDR1 gene is largely invariant, but different single nucleotide polymorphism haplotypes affect MDR1 promoter activity differently in different cell lines

Wang B, Ngoi S, Wang J, Chong SS, Lee CG

Mol. Pharmacol., 2006 Jul;70(1):267-76.
PMID: 16608921

The MDR1 multidrug transporter represents one of the better characterized drug transporters that play an important role in protecting the body against xenobiotic insults. Single nucleotide polymorphisms (SNPs) and SNP haplotypes within this gene have been variously associated with differences in MDR1 expression/function, drug response as well as disease susceptibility. Nonetheless, the effect of polymorphisms at the MDR1 promoter region on its promoter activity remains less characterized. Through the examination of approximately 1.5 kilobases of MDR1 promoter region from five populations, including the Chinese, Malays, Indians, European Americans, and African Americans, we identified eight low-frequency SNPs, of which only two were polymorphic in at least four of the five populations examined. The other SNPs are mainly population-specific, the majority of which occur only in the African-American population. Recapitulation of the various combinations of SNP haplotypes in vitro in promoter-reporter assays revealed a few notable trends. The African and European American-specific haplotypes tended to result in enhanced MDR1 promoter activity only in the human embryonic kidney (HEK) 293 cell line. Haplotype GCTAACC, which occurs at variable frequencies in all the populations examined, with Asians having much lower frequencies (<2%) compared with the European Americans/African Americans (>4%), affected MDR1 promoter activity differently in different cell lines. Compared with the commonest haplotype, GCTA-ACC haplotype resulted in a significant decrease in MDR1 promoter activity in HeLa cells (P < 0.05) but a significant increase in the same promoter activity in HEK293 cells (P < 0.05). These results suggest that the MDR1 promoter region is largely invariant but that different haplotypes have differential effects on the MDR1 promoter activity in different cell lines.

Matched MeSH terms: Haplotypes/genetics*
Fulltext Susceptibility and gene interaction study of the angiotensin II type 1 receptor (AGTR1) gene polymorphisms with non-alcoholic fatty liver disease in a multi-ethnic population

Zain SM, Mohamed Z, Mahadeva S, Rampal S, Basu RC, Cheah PL, et al.

PLoS One, 2013;8(3):e58538.
PMID: 23484035 DOI: 10.1371/journal.pone.0058538

Angiotensin II type 1 receptor (AGTR1) has been reported to play a fibrogenic role in non-alcoholic fatty liver disease (NAFLD). In this study, five variants of the AGTR1 gene (rs3772622, rs3772627, rs3772630, rs3772633, and rs2276736) were examined for their association with susceptibility to NAFLD. Subjects made up of 144 biopsy-proven NAFLD patients and 198 controls were genotyped using TaqMan assays. The liver biopsy specimens were histologically graded and scored according to the method of Brunt. Single locus analysis in pooled subjects revealed no association between each of the five variants with susceptibility to NAFLD. In the Indian ethnic group, the rs2276736, rs3772630 and rs3772627 appear to be protective against NAFLD (p = 0.010, p = 0.016 and p = 0.026, respectively). Haplotype ACGCA is shown to be protective against NAFLD for the Indian ethnic subgroup (p = 0.03). Gene-gene interaction between the AGTR1 gene and the patatin-like phospholipase domain-containing 3 (PNPLA3) gene, which we previously reported as associated with NAFLD in this sample, showed a strong interaction between AGTR1 (rs3772627), AGTRI (rs3772630) and PNPLA3 (rs738409) polymorphisms on NAFLD susceptibility (p = 0.007). Further analysis of the NAFLD patients revealed that the G allele of the AGTR1 rs3772622 is associated with increased fibrosis score (p = 0.003). This is the first study that replicates an association between AGTR1 polymorphism and NAFLD, with further details in histological features of NAFLD. There is lack of evidence to suggest an association between any of the five variants of the AGTR1 gene and NAFLD in the Malays and Chinese. In the Indians, the rs2276736, rs3772630 and rs3772627 appear to protect against NAFLD. We report novel findings of an association between the G allele of the rs3772622 with occurrence of fibrosis and of the gene-gene interaction between AGTR1gene and the much-studied PNPLA3 gene.

Matched MeSH terms: Haplotypes/genetics
Relationship between immunoglobulin allotypes and susceptibility to nasopharyngeal carcinoma in Malaysia

Tarone RE, Levine PH, Yadav M, Pandey JP

Cancer Res, 1990 Jun 1;50(11):3186-8.
PMID: 1692255

The relationship between immunoglobulin allotypes and risk of developing nasopharyngeal carcinoma was examined in a comparative study of 50 Chinese cases and 140 Chinese controls and 50 Malay cases and 79 Malay controls residing in Malaysia. Although the most common Gm phenotype was elevated in both Chinese and Malay nasopharyngeal carcinoma patients compared to their controls, there were no significant differences between cases and controls in the distribution of Gm haplotypes in either population. There were no differences between cases and controls in the distribution of Km alleles in either population. Thus a previously reported association of Km(1) with increased nasopharyngeal carcinoma risk in Tunisia is not confirmed in two Mongoloid populations in Malaysia.

Matched MeSH terms: Haplotypes/genetics*
Fulltext Selected neuropeptide genes show genetic differentiation between Africans and non-Africans

Tai KY, Wong K, Aghakhanian F, Parhar IS, Dhaliwal J, Ayub Q

BMC Genet, 2020 03 14;21(1):31.
PMID: 32171244 DOI: 10.1186/s12863-020-0835-8

BACKGROUND: Publicly available genome data provides valuable information on the genetic variation patterns across different modern human populations. Neuropeptide genes are crucial to the nervous, immune, endocrine system, and physiological homeostasis as they play an essential role in communicating information in neuronal functions. It remains unclear how evolutionary forces, such as natural selection and random genetic drift, have affected neuropeptide genes among human populations. To date, there are over 100 known human neuropeptides from the over 1000 predicted peptides encoded in the genome. The purpose of this study is to analyze and explore the genetic variation in continental human populations across all known neuropeptide genes by examining highly differentiated SNPs between African and non-African populations.
RESULTS: We identified a total of 644,225 SNPs in 131 neuropeptide genes in 6 worldwide population groups from a public database. Of these, 5163 SNPs that had ΔDAF |(African - non-African)| ≥ 0.20 were identified and fully annotated. A total of 20 outlier SNPs that included 19 missense SNPs with a moderate impact and one stop lost SNP with high impact, were identified in 16 neuropeptide genes. Our results indicate that an overall strong population differentiation was observed in the non-African populations that had a higher derived allele frequency for 15/20 of those SNPs. Highly differentiated SNPs in four genes were particularly striking: NPPA (rs5065) with high impact stop lost variant; CHGB (rs6085324, rs236150, rs236152, rs742710 and rs742711) with multiple moderate impact missense variants; IGF2 (rs10770125) and INS (rs3842753) with moderate impact missense variants that are in linkage disequilibrium. Phenotype and disease associations of these differentiated SNPs indicated their association with hypertension and diabetes and highlighted the pleiotropic effects of these neuropeptides and their role in maintaining physiological homeostasis in humans.
CONCLUSIONS: We compiled a list of 131 human neuropeptide genes from multiple databases and literature survey. We detect significant population differentiation in the derived allele frequencies of variants in several neuropeptide genes in African and non-African populations. The results highlights SNPs in these genes that may also contribute to population disparities in prevalence of diseases such as hypertension and diabetes.

Matched MeSH terms: Haplotypes/genetics
Fulltext Haplotype CGC from XPD, hOGG1 and ITGA2 polymorphisms increases the risk of nasopharyngeal carcinoma in Malaysia

Ban EZ, Lye MS, Chong PP, Yap YY, Lim SYC, Abdul Rahman H

PLoS One, 2017;12(11):e0187200.
PMID: 29121049 DOI: 10.1371/journal.pone.0187200

BACKGROUND: 8-oxoG, a common DNA lesion resulting from reactive oxygen species (ROS), has been shown to be associated with cancer initiation. hOGG1 DNA glycosylase is the primary enzyme responsible for excision of 8-oxoG through base excision repair (BER). Integrins are members of a family of cell surface receptors that mediate the cell-cell and extracellular matrix (ECM) interactions. Integrins are involved in almost every aspect of carcinogenesis, from cell differentiation, cell proliferation, metastasis to angiogenesis. Loss of ITGA2 expression was associated with enhanced tumor intravasation and metastasis of breast and colon cancer. XPD gene encodes DNA helicase enzyme that is involved in nucleotide excision repair (NER). It is shown in previous research that XPD homozygous wildtype Lys/Lys genotype was associated with higher odds of NPC.
METHODS: We conducted a 1 to N case-control study involving 300 nasopharyngeal carcinoma (NPC) cases and 533 controls matched by age, gender and ethnicity to investigate the effect of hOGG1 Ser326Cys, ITGA2 C807T and XPD Lys751Gln polymorphisms on NPC risk. Linkage disequilibrium and haplotype analysis were conducted to explore the association of allele combinations with NPC risk. Restriction fragment length polymorphism (RFLP-PCR) was used for DNA genotyping.
RESULTS: No significant association was observed between hOGG1 Ser326Cys and ITGA2 C807T polymorphisms with NPC risk after adjustment for age, gender, ethnicity, cigarette smoking, alcohol and salted fish consumption. Lys/Lys genotype of XPD Lys751Gln polymorphism was associated with increased NPC risk (OR = 1.60, 95% CI = 1.06-2.43). Subjects with history of smoking (OR = 1.81, 95% CI = 1.26-2.60), and salted fish consumption before age of 10 (OR = 1.77, 95% CI = 1.30-2.42) were observed to have increased odds of NPC. The odds of developing NPC of CGC haplotype was significantly higher compared to reference AGC haplotype (OR = 2.20, 95% CI = 1.06-4.58).
CONCLUSION: The allele combination of CGC from hOGG1, ITGA2 and XPD polymorphisms was significantly associated with increased odds of NPC.

Matched MeSH terms: Haplotypes/genetics*
Haplotype diversity in 11 candidate genes across four populations

Beaty TH, Fallin MD, Hetmanski JB, McIntosh I, Chong SS, Ingersoll R, et al.

Genetics, 2005 Sep;171(1):259-67.
PMID: 15965248

Analysis of haplotypes based on multiple single-nucleotide polymorphisms (SNP) is becoming common for both candidate gene and fine-mapping studies. Before embarking on studies of haplotypes from genetically distinct populations, however, it is important to consider variation both in linkage disequilibrium (LD) and in haplotype frequencies within and across populations, as both vary. Such diversity will influence the choice of "tagging" SNPs for candidate gene or whole-genome association studies because some markers will not be polymorphic in all samples and some haplotypes will be poorly represented or completely absent. Here we analyze 11 genes, originally chosen as candidate genes for oral clefts, where multiple markers were genotyped on individuals from four populations. Estimated haplotype frequencies, measures of pairwise LD, and genetic diversity were computed for 135 European-Americans, 57 Chinese-Singaporeans, 45 Malay-Singaporeans, and 46 Indian-Singaporeans. Patterns of pairwise LD were compared across these four populations and haplotype frequencies were used to assess genetic variation. Although these populations are fairly similar in allele frequencies and overall patterns of LD, both haplotype frequencies and genetic diversity varied significantly across populations. Such haplotype diversity has implications for designing studies of association involving samples from genetically distinct populations.

Matched MeSH terms: Haplotypes/genetics*
Fulltext Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer

Lesseur C, Diergaarde B, Olshan AF, Wünsch-Filho V, Ness AR, Liu G, et al.

Nat Genet, 2016 Dec;48(12):1544-1550.
PMID: 27749845 DOI: 10.1038/ng.3685

We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 × 10-8), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2-TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci-9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301-HLA-DQA1*0103-HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 × 10-9). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 × 10-6) than in HPV-negative (OR = 0.75, P = 0.16) cancers.

Matched MeSH terms: Haplotypes/genetics
Molecular basis of beta-thalassemia in the Maldives

Furuumi H, Firdous N, Inoue T, Ohta H, Winichagoon P, Fucharoen S, et al.

Hemoglobin, 1998 Mar;22(2):141-51.
PMID: 9576331

We have systematically analyzed beta-thalassemia genes using polymerase chain reaction-related techniques, dot-blot hybridization with oligonucleotide probes, allele specific-polymerase chain reaction, and sequencing of amplified DNA fragments from 41 unrelated patients, including 37 beta-thalassemia homozygotes, three with beta-thalassemia/Hb E, and one with beta-thalassemia/Hb S. Four different beta-thalassemia mutations were detected in 78 alleles. These are the IVS-I-5 (G-->C), codon 30 (AGG-->ACG) [also indicated as IVS-I (-1)], IVS-I-1 (G-->A), and codons 41/42 (-TTCT) mutations. The distribution of the beta-thalassemia mutations in the Maldives is 58 alleles (74.3%) with the IVS-I-5 (G-->C) mutation, 12 (15.4%) with the codon 30 (AGG-->ACG) mutation, seven (9%) with the IVS-I-1 (G-->A) mutation, and one with the codons 41/42 (-TTCT) mutation. The first three mutations account for 98.7% of the total number of beta-thalassemia chromosomes studied. These mutations are clustered in the region spanning 6 bp around the junction of exon 1 and the first intervening sequence of the beta-globin gene. These observations have significant implications for setting up a thalassemia prevention and control program in the Maldives. Analysis of haplotypes and frameworks of chromosomes bearing each beta-thalassemia mutation suggested that the origin and spread of these mutations were reflected by the historical record.

Matched MeSH terms: Haplotypes/genetics
Fulltext Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation

Ghoussaini M, French JD, Michailidou K, Nord S, Beesley J, Canisus S, et al.

Am J Hum Genet, 2016 Oct 06;99(4):903-911.
PMID: 27640304 DOI: 10.1016/j.ajhg.2016.07.017

Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER+) breast cancer (per-g allele OR ER+ = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10-30). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER-) breast cancer (lead SNP rs6864776: per-a allele OR ER- = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10-12), and a single signal 3 SNP (rs200229088: per-t allele OR ER+ = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10-05). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.

Matched MeSH terms: Haplotypes/genetics

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