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1.  MBL2 Variations and Malaria Susceptibility in Indian Populations 
Infection and Immunity  2014;82(1):52-61.
Human mannose-binding lectin (MBL) encoded by the MBL2 gene is a pattern recognition protein and has been associated with many infectious diseases, including malaria. We sought to investigate the contribution of functional MBL2 gene variations to Plasmodium falciparum malaria in well-defined cases and in matched controls. We resequenced the 8.7 kb of the entire MBL2 gene in 434 individuals clinically classified with malaria from regions of India where malaria is endemic. The study cohort included 176 patients with severe malaria, 101 patients with mild malaria, and 157 ethnically matched asymptomatic individuals. In addition, 830 individuals from 32 socially, linguistically, and geographically diverse endogamous populations of India were investigated for the distribution of functional MBL2 variants. The MBL2 −221C (X) allelic variant is associated with increased risk of malaria (mild malaria odds ratio [OR] = 1.9, corrected P value [PCorr] = 0.0036; severe malaria OR = 1.6, PCorr = 0.02). The exon1 variants MBL2*B (severe malaria OR = 2.1, PCorr = 0.036; mild versus severe malaria OR = 2.5, PCorr = 0.039) and MBL2*C (mild versus severe malaria OR = 5.4, PCorr = 0.045) increased the odds of having malaria. The exon1 MBL2*D/*B/*C variant increased the risk for severe malaria (OR = 3.4, PCorr = 0.000045). The frequencies of low MBL haplotypes were significantly higher in severe malaria (14.2%) compared to mild malaria (7.9%) and asymptomatic (3.8%). The MBL2*LYPA haplotypes confer protection, whereas MBL2*LXPA increases the malaria risk. Our findings in Indian populations demonstrate that MBL2 functional variants are strongly associated with malaria and infection severity.
PMCID: PMC3911836  PMID: 24126531
2.  Dynamics of Polymorphism in a Malaria Vaccine Antigen at a Vaccine-Testing Site in Mali 
PLoS Medicine  2007;4(3):e93.
Malaria vaccines based on the 19-kDa region of merozoite surface protein 1 (MSP-119) derived from the 3D7 strain of Plasmodium falciparum are being tested in clinical trials in Africa. Knowledge of the distribution and natural dynamics of vaccine antigen polymorphisms in populations in which malaria vaccines will be tested will guide vaccine design and permit distinction between natural fluctuations in genetic diversity and vaccine-induced selection.
Methods and Findings
Using pyrosequencing, six single-nucleotide polymorphisms in the nucleotide sequence encoding MSP-119 were genotyped from 1,363 malaria infections experienced by 100 children who participated in a prospective cohort study in Mali from 1999 to 2001. The frequencies of 14 MSP-119 haplotypes were compared over the course of the malaria transmission season for all three years, in three age groups, and in consecutive infections within individuals. While the frequency of individual MSP-119 haplotypes fluctuated, haplotypes corresponding to FVO and FUP strains of P. falciparum (MSP-119 haplotypes QKSNGL and EKSNGL, respectively) were most prevalent during three consecutive years and in all age groups with overall prevalences of 46% (95% confidence interval [CI] 44%–49%) and 36% (95% CI 34%–39%), respectively. The 3D7 haplotype had a lower overall prevalence of 16% (95% CI 14%–18%). Multiplicity of infection based on MSP-119 was higher at the beginning of the transmission season and in the oldest individuals (aged ≥11 y). Three MSP-119 haplotypes had a reduced frequency in symptomatic infections compared to asymptomatic infections. Analyses of the dynamics of MSP-119 polymorphisms in consecutive infections implicate three polymorphisms (at positions 1691, 1700, and 1701) as being particularly important in determining allele specificity of anti-MSP-119 immunity.
Parasites with MSP-119 haplotypes different from that of the leading vaccine strain were consistently the most prevalent at a vaccine trial site. If immunity elicited by an MSP-1-based vaccine is allele-specific, a vaccine based on either the FVO or FUP strain might have better initial efficacy at this site. This study, to our knowledge the largest of its kind to date, provides molecular information needed to interpret population responses to MSP-1-based vaccines and suggests that certain MSP-119 polymorphisms may be relevant to cross-protective immunity.
Christopher Plowe and colleagues surveyed local malaria parasites for genetic diversity in MSP-1, a candidate vaccine antigen. These data are needed to interpret population responses to MSP-1-based vaccines during trials planned at this site.
Editors' Summary
Malaria, a tropical parasitic disease, kills about one million people—mainly children—every year. Most of these deaths are caused by Plasmodium falciparum, which is transmitted to humans through the bites of infected mosquitoes. These insects inject a form of the parasite known as sporozoites into people that replicates inside liver cells without causing symptoms. Four to five days later, merozoites (another form of the parasite) are released from the liver cells and invade red blood cells. Here, they replicate 10-fold before bursting out and infecting other red blood cells. This massive increase in parasite burden causes malaria's flu-like symptoms. If untreated, it also causes anemia (a red blood cell deficit) and damages the brain and other organs where parasitized red blood cells sequester. Malaria can be treated with antimalarial drugs and partly prevented by reducing the chances of being bitten by an infected mosquito. In addition, researchers are developing vaccines designed to reduce the global burden of malaria. These contain individual malaria antigens (proteins from the parasite that stimulate an immune response) that should, when injected into people, prime the immune system so that it can rapidly control malaria infections.
Why Was This Study Done?
The development of an effective malaria vaccine is not easy, in part because people can be simultaneously infected with several parasite strains. These often carry different variants (alleles) of the genes encoding antigens, which means that the actual parasite proteins might differ from the ones used for vaccination. If this is the case, the immune response generated by the vaccine might be less effective or even ineffective. An ideal vaccine would therefore stimulate an immune response that recognizes all these strain-specific antigens. However, little is known about their distribution in parasite populations in malarial regions, or about how this distribution changes over time (its dynamics). This information is needed to aid vaccine design and development. In this study, the researchers have investigated the distribution and dynamics of genetic variants of a merozoite antigen called MSP-119, which is included in a vaccine currently being tested in Mali, West Africa. Although most of the MSP-119 sequence is conserved, it contains six strain-specific polymorphisms (genetic variations); the candidate vaccine contains MSP-119 from the 3D7 strain of P. falciparum.
What Did the Researchers Do and Find?
The researchers used rapid DNA sequencing (pyrosequencing) to examine the MSP-119 sequence in more than 1,300 malaria infections in 100 Malian children. They compared the frequencies of 14 MSP-119 haplotypes (sets of polymorphisms at the six variant sites) over three years, in three age groups, and in consecutive infections within individuals. They found that the frequency of individual MSP-119 haplotypes fluctuated in their study population but that those found in P. falciparum FVO and FUP strains were always the commonest, each being present in about 40% of the infections. By contrast, the P. falciparum 3D7 MSP-119 haplotype was present in only 16% of the infections. They also found that mixed infections were more common at the start of each malaria season and in older individuals. In addition, individuals who were infected repeatedly by parasites from different strains (with different MSP-119 variants) seemed to get sick with malaria more often than those infected multiple times by the same strain. The differences might, therefore, be important in determining the specificity of the immune response to MSP-119.
What Do These Findings Mean?
These findings indicate that most parasites that cause malaria at the Malian test site for the malaria vaccine that contains 3D7-specific MSP-119 have a different form of MSP-119. Although early results from field trials suggest that the 3D7-derived vaccine provides some protection against the more common FVO and FUP strains, the immunity stimulated by the vaccine might be mainly allele specific. If this turns out to be the case, these results suggest that a FVO- or FUP-derived vaccine might be more effective in Mali than the 3D7-derived vaccine, though not necessarily elsewhere. More generally, these results show the importance of determining the genetics of pathogen populations before starting vaccine trials. Without this information, a vaccine's ability to prevent infections with specific parasite strains cannot be determined accurately and potentially useful vaccines might be abandoned if they are tested in inappropriate populations. Importantly, baseline information of this sort will also allow vaccine developers to detect any vaccine-induced changes in the pathogen population that might affect the long-term efficacy of their vaccines.
Additional Information.
Please access these Web sites via the online version of this summary at
A related PLoS Medicine Perspective by Colin Sutherland discusses variation in malaria antigens as a challenge in vaccine development
The malaria program of the University of Maryland Center for Vaccine Development performs research on many aspects of malaria
Information on malaria and the development of vaccines is available from the Malaria Vaccine Initiative
The World Health Organization provides links to general information on malaria plus some specific information on malaria vaccine development
MedlinePlus encyclopedia has entries on malaria and on vaccination
US Centers for Disease Control and Prevention provides information for patients and professionals on malaria
US National Institute of Allergy and Infectious Diseases has information on malaria, including research into vaccines
PMCID: PMC1820605  PMID: 17355170
3.  The Origin and Evolution of Variable Number Tandem Repeat of CLEC4M Gene in the Global Human Population 
PLoS ONE  2012;7(1):e30268.
CLEC4M is a C-type lectin gene serving as cell adhesion receptor and pathogen recognition receptor. It recognizes several pathogens of important public health concern. In particular, a highly polymorphic variable number tandem repeat (VNTR) at the neck-region of CLEC4M had been associated with genetic predisposition to some infectious diseases. To gain insight into the origin and evolution of this VNTR in CLEC4M, we studied 21 Africans, 20 Middle Easterns, 35 Europeans, 38 Asians, 13 Oceania, and 18 Americans (a total of 290 chromosomes) from the (Human Genome Diversity Panel) HGDP-CEPH panel; these samples covered most of alleles of this VNTR locus present in human populations. We identified a limited number of haplotypes among the basic repeat subunits that is 69 base pairs in length. Only 8 haplotypes were found. Their sequence identities were determined in the 290 chromosomes. VNTR alleles of different repeat length (from 4 to 9 repeats) were analyzed for composition and orientation of these subunits. Our results showed that the subunit configuration of the same repeat number of VNTR locus from different populations were, in fact, virtually identical. It implies that most of the VNTR alleles existed before dispersion of modern humans outside Africa. Further analyses indicate that the present diversity profile of this locus in worldwide populations is generated from the effect of migration of different tribes and neutral evolution. Our findings do not support the hypothesis that the origin of the VNTR alleles were arisen by independent (separate) mutation events and caused by differential allele advantage and natural selection as suggested by previous report based on SNP data.
PMCID: PMC3261175  PMID: 22279577
4.  IL4 gene polymorphism and previous malaria experiences manipulate anti-Plasmodium falciparum antibody isotype profiles in complicated and uncomplicated malaria 
Malaria Journal  2009;8:286.
The IL4-590 gene polymorphism has been shown to be associated with elevated levels of anti-Plasmodium falciparum IgG antibodies and parasite intensity in the malaria protected Fulani of West Africa. This study aimed to investigate the possible impact of IL4-590C/T polymorphism on anti-P. falciparum IgG subclasses and IgE antibodies levels and the alteration of malaria severity in complicated and uncomplicated malaria patients with or without previous malaria experiences.
Anti-P.falciparum IgG subclasses and IgE antibodies in plasma of complicated and uncomplicated malaria patients with or without previous malaria experiences were analysed using ELISA. IL4-590 polymorphisms were genotyped using RFLP-PCR. Statistical analyses of the IgG subclass levels were done by Oneway ANOVA. Genotype differences were tested by Chi-squared test.
The IL4-590T allele was significantly associated with anti-P. falciparum IgG3 antibody levels in patients with complicated (P = 0.031), but not with uncomplicated malaria (P = 0.622). Complicated malaria patients with previous malaria experiences carrying IL4-590TT genotype had significantly lower levels of anti-P. falciparum IgG3 (P = 0.0156), while uncomplicated malaria patients with previous malaria experiences carrying the same genotype had significantly higher levels (P = 0.0206) compared to their IL4-590 counterparts. The different anti-P. falciparum IgG1 and IgG3 levels among IL4 genotypes were observed. Complicated malaria patients with previous malaria experiences tended to have lower IgG3 levels in individuals carrying TT when compared to CT genotypes (P = 0.075). In contrast, complicated malaria patients without previous malaria experiences carrying CC genotype had significantly higher anti-P. falciparum IgG1 than those carrying either CT or TT genotypes (P = 0.004, P = 0.002, respectively).
The results suggest that IL4-590C or T alleles participated differently in the regulation of anti-malarial antibody isotype profiles in primary and secondary malaria infection and, therefore, could play an important role in alteration of malaria severity.
PMCID: PMC2799430  PMID: 20003246
5.  Variable number of tandem repeat polymorphisms of DRD4: re-evaluation of selection hypothesis and analysis of association with schizophrenia 
Associations have been reported between the variable number of tandem repeat (VNTR) polymorphisms in the exon 3 of dopamine D4 receptor gene gene and multiple psychiatric illnesses/traits. We examined the distribution of VNTR alleles of different length in a Japanese cohort and found that, as reported earlier, the size of allele ‘7R' was much rarer (0.5%) in Japanese than in Caucasian populations (∼20%). This presents a challenge to an earlier proposed hypothesis that positive selection favoring the allele 7R has contributed to its high frequency. To further address the issue of selection, we carried out sequencing of the VNTR region not only from human but also from chimpanzee samples, and made inference on the ancestral repeat motif and haplotype by use of a phylogenetic analysis program. The most common 4R variant was considered to be the ancestral haplotype as earlier proposed. However, in a gene tree of VNTR constructed on the basis of this inferred ancestral haplotype, the allele 7R had five descendent haplotypes in relatively long lineage, where genetic drift can have major influence. We also tested this length polymorphism for association with schizophrenia, studying two Japanese sample sets (one with 570 cases and 570 controls, and the other with 124 pedigrees). No evidence of association between the allele 7R and schizophrenia was found in any of the two data sets. Collectively, this study suggests that the VNTR variation does not have an effect large enough to cause either selection or a detectable association with schizophrenia in a study of samples of moderate size.
PMCID: PMC2947105  PMID: 19092778
DRD4; VNTR; selection; phylogenetic network; schizophrenia
6.  Polymorphisms of TNF-enhancer and gene for FcγRIIa correlate with the severity of falciparum malaria in the ethnically diverse Indian population 
Malaria Journal  2008;7:13.
Susceptibility/resistance to Plasmodium falciparum malaria has been correlated with polymorphisms in more than 30 human genes with most association analyses having been carried out on patients from Africa and south-east Asia. The aim of this study was to examine the possible contribution of genetic variants in the TNF and FCGR2A genes in determining severity/resistance to P. falciparum malaria in Indian subjects.
Allelic frequency distribution in populations across India was first determined by typing genetic variants of the TNF enhancer and the FCGR2A G/A SNP in 1871 individuals from 55 populations. Genotyping was carried out by DNA sequencing, single base extension (SNaPshot), and DNA mass array (Sequenom). Plasma TNF was determined by ELISA. Comparison of datasets was carried out by Kruskal-Wallis and Mann-Whitney tests. Haplotypes and LD plots were generated by PHASE and Haploview, respectively. Odds ratio (OR) for risk assessment was calculated using EpiInfo™ version 3.4.
A novel single nucleotide polymorphism (SNP) at position -76 was identified in the TNF enhancer along with other reported variants. Five TNF enhancer SNPs and the FCGR2A R131H (G/A) SNP were analyzed for association with severity of P. falciparum malaria in a malaria-endemic and a non-endemic region of India in a case-control study with ethnically-matched controls enrolled from both regions. TNF -1031C and -863A alleles as well as homozygotes for the TNF enhancer haplotype CACGG (-1031T>C, -863C>A, -857C>T, -308G>A, -238G>A) correlated with enhanced plasma TNF levels in both patients and controls. Significantly higher TNF levels were observed in patients with severe malaria. Minor alleles of -1031 and -863 SNPs were associated with increased susceptibility to severe malaria. The high-affinity IgG2 binding FcγRIIa AA (131H) genotype was significantly associated with protection from disease manifestation, with stronger association observed in the malaria non-endemic region. These results represent the first genetic analysis of the two immune regulatory molecules in the context of P. falciparum severity/resistance in the Indian population.
Association of specific TNF and FCGR2A SNPs with cytokine levels and disease severity/resistance was indicated in patients from areas with differential disease endemicity. The data emphasizes the need for addressing the contribution of human genetic factors in malaria in the context of disease epidemiology and population genetic substructure within India.
PMCID: PMC2245971  PMID: 18194515
7.  IL10A genotypic association with decreased IL-10 circulating levels in malaria infected individuals from endemic area of the Brazilian Amazon 
Malaria Journal  2015;14:30.
Cytokines play an important role in human immune responses to malaria and variation in their production may influence the course of infection and determine the outcome of the disease. The differential production of cytokines has been linked to single nucleotide polymorphisms in gene promoter regions, signal sequences, and gene introns. Although some polymorphisms play significant roles in susceptibility to malaria, gene polymorphism studies in Brazil are scarce.
A population of 267 individuals from Brazilian Amazon exposed to malaria was genotyped for five single nucleotide polymorphisms (SNPs), IFNG + 874 T/A, IL10A-1082G/A, IL10A-592A/C, IL10A-819 T/C and NOS2A-954G/C. Specific DNA fragments were amplified by polymerase chain reaction, allowing the detection of the polymorphism genotypes. The polymorphisms IL10A-592A/C and IL10A-819 T/C were estimated by a single analysis due to the complete linkage disequilibrium between the two SNPs with D’ = 0.99. Plasma was used to measure the levels of IFN-γ and IL-10 cytokines by Luminex and nitrogen radicals by Griess reaction.
No differences were observed in genotype and allelic frequency of IFNG + 874 T/A and NOS2A-954G/C between positive and negative subjects for malaria infection. Interesting, the genotype NOS2A-954C/C was not identified in the study population. Significant differences were found in IL10A-592A/C and IL10A-819 T/C genotypes distribution, carriers of IL10A -592A/-819 T alleles (genotypes AA/TT + AC/TC) were more frequent among subjects with malaria than in negative subjects that presented a higher frequency of the variant C allele (p < 0.0001). The presence of the allele C was associated with low producer of IL-10 and low parasitaemia. In addition, the GTA haplotypes formed from combinations of investigated polymorphisms in IL10A were significantly associated with malaria (+) and the CCA haplotype with malaria (−) groups. The IL10A-1082G/A polymorphism showed high frequency of heterozygous AG genotype in the population, but it was not possible to infer any association of the polymorphism because their distribution was not in Hardy Weinberg equilibrium.
This study shows that the IL10A-592A/C and IL10A-819 T/C polymorphisms were associated with malaria and decreased IL-10 levels and low parasite density suggesting that this polymorphism influence IL-10 levels and may influence in the susceptibility to clinical malaria.
PMCID: PMC4334410  PMID: 25627396
Malaria disease; Cytokines; Nitric oxide synthase; Polymorphism
8.  Association of endothelial nitric oxide synthase gene polymorphisms with endometrial carcinoma: a preliminary study 
To investigate the relationship between specific endothelial nitric oxide synthase (eNOS) gene polymorphisms and endometrial cancer (ECa).
Material and Methods
The study group consisted of 89 patients histologically diagnosed with the endometrioid type of endometrial carcinoma. The control group consisted of 60 randomly selected individuals who had undergone total hysterectomy. Genomic DNA was isolated from paraffin-embedded endometrial tissues. We investigated the G894T polymorphisms (G894T) and variable number tandem repeats polymorphisms in intron 4 (VNTR intron 4) in the eNOS gene by using polymerase chain reaction (PCR) and/or restriction fragment length polymorphism (RFLP). The genotype distributions and allele frequencies of the two groups were compared.
Analysis of the VNTR intron 4 polymorphisms in eNOS gene revealed that the frequency of the AA genotype was significantly higher in the control group, whereas the frequency of the BB genotype was significantly higher in the ECa group. Analysis of the G894T polymorphisms in eNOS gene revealed a significantly higher frequency of the GG genotype in the control group but a significantly higher frequency of the TT genotype in the endometrial cancer group.
The G894T and VNTR intron 4 polymorphisms in eNOS gene could be an intriguing susceptibility factor that modulates an individual’s risk of ECa in the Turkish population.
PMCID: PMC3939255  PMID: 24592000
eNOS gene polymorphisms; endometrial carcinoma
9.  Tracking the genetic imprints of lost Jewish tribes among the gene pool of Kuki-Chin-Mizo population of India 
Genome Biology  2004;6(1):P1.
DNA markers from the Kuki-Chin-Mizo population of Mizoram, India, who claim their descent from the ten lost tribes of Israel that were exiled by the Assyrians, show no evidence of Cohanim origin but some genetic relatedness to Near Eastern lineages.
The Kuki-Chin-Mizo population comprising traditionally endogamous tribal groups residing in the state of Mizoram, India claim their descent from the ten lost tribes of Israel that were exiled by the Assyrians. To ascertain their oral history, we analysed DNA markers comprising 15 autosomal microsatellite markers, 5 biallelic and 20 microsatellite markers on Y-chromosome and the maternally inherited mitochondrial DNA sequence variations on 414 individuals belonging to 5 tribal communities from Mizoram (Hmar, Kuki, Mara, Lai and Lusei). The genetic profiles obtained were compared either with populations sharing Jewish ancestry or with local populations along the probable route of migration of the Jewish ancestry claimant Mizoram tribes.
Y-STR analyses showed absence of the Cohen Modal Haplotype, the genetic signature of Cohanim origin. Y-chromosomal biallelic marker analyses revealed the presence of East and Southeast Asian-specific lineages and absence of haplogroup J predominant among Jewish populations. The mitochondrial DNA sequence analyses however revealed traces of genetic relatedness between the Jewish ancestry claimant Mizoram tribes and Near Eastern lineages. Autosomal analyses showed moderate degree of genetic differentiation among the different Mizoram tribes.
Migration of the lost tribes through China resulting in subsequent genetic admixture over a long period of time has probably diluted the extant gene pool of the Kuki-Chin-Mizo population. Although their paternal lineages do not exhibit any trace of Jewish ancestry, incidence of maternal Near Eastern lineages among the Mizoram tribals suggests their claim to Jewish ancestry cannot be excluded.
PMCID: PMC4071260
10.  Haemoglobin S and βThal: Their Distribution in Maharashtra, India 
It has been more than six decades since the first report of sickle cell anaemia in Indian subcontinent. Since then the researchers have been reported various haemoglobin varients prevalent in India, they are HbS, HbβT, HbE and HbD. Earlier studies were confined to tribal and scheduled castes populations as if sickle haemoglobin was restricted to these two groups only. Since a decade or so, few studies on haemoglobinopathies from other Indian populations are available. Examination of premarital age group of 5172 Indian subjects (2762 males and 2410 females) from eastern Maharashtra of India showed high incidences of HbS (0-33 per cent) and HbβT (0-10 per cent) in different ethnic groups. In present study cumulative gene frequency for HbS and HbβT was found to be of 6.1 per cent and 2.3 per cent respectively. In present study sickle cell gene has been found in general categories of Indian populations besides scheduled castes and tribal populations. In Scheduled tribes HbS ranges from 0-24 per cent, in Scheduled castes and Nomadic tribal groups, HbS ranges from 0-13 per cent, in Other Backward caste categories it varies from 0-20 per cent while in higher caste populations it ranges from 0-5 per cent. The incidences of HbS are much higher among tribal groups than that found in other caste populations. The incidences of homozygous individuals are very few in HbS and HbβT. The hitherto regional and populations specific HbβT haemoglobin variant in Sindhi and Bengali communities is gradually spreading in other populations of Maharashtra as evident from the present study. Lesser value of MCV, MCH and MCHC in homozygous HbβT is due to impairments of synthesis β-globin chain. The subject with the presence of β-thalassaemia is accompanied by raised level of HbA2. Unusual higher values of RBC and WBC suggest the high concentration of hypochromic microcytosis in anemia. The means of MCV MCH and MCHC in HbβT are much lower than the normal ranges compared to HbS.
PMCID: PMC3708271  PMID: 23847457
haemoglobinopathies; sickle cell anemia; thalassaemia; eastern maharashtra; India
11.  Effect of the 3'APOB-VNTR polymorphism on the lipid profiles in the Guangxi Hei Yi Zhuang and Han populations 
BMC Medical Genetics  2007;8:45.
Apolipoprotein (Apo) B is the major component of low-density lipoprotein (LDL), very low-density lipoprotein (VLDL) and chylomicrons. Many genetic polymorphisms of the Apo B have been described, associated with variation of lipid levels. However, very few studies have evaluated the effect of the variable number of tandem repeats region 3' of the Apo B gene (3'APOB-VNTR) polymorphism on the lipid profiles in the special minority subgroups in China. Thus, the present study was undertaken to study the effect of the 3'APOB-VNTR polymorphism on the serum lipid levels in the Guangxi Hei Yi Zhuang and Han populations.
A total of 548 people of Hei Yi Zhuang were surveyed by a stratified randomized cluster sampling. The epidemiological survey was performed using internationally standardized methods. Serum lipid and apolipoprotein levels were measured. The 3'APOB-VNTR alleles were determined by polymerase chain reaction (PCR) followed by electrophoresis in polyacrylamide gels, and classified according to the number of repeats of a 15-bp hypervariable elements (HVE). The sequence of the most common allele was determined using the PCR and direct sequencing. The possible association between alleles of the 3'APOB-VNTR and lipid variables was examined. The results were compared with those in 496 people of Han who also live in that district.
Nineteen alleles ranging from 24 to 64 repeats were detected in both Hei Yi Zhuang and Han. HVE56 and HVE58 were not be detected in Hei Yi Zhuang whereas HVE48 and HVE62 were totally absent in Han. The frequencies of HVE26, HVE30, HVE46, heterozygote, and short alleles (< 38 repeats) were higher in Hei Yi Zhuang than in Han. But the frequencies of HVE34, HVE38, HVE40, homozygote, and long alleles (≥ 38 repeats) were lower in Hei Yi Zhuang than in Han (P < 0.05–0.01). The levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and Apo B in Hei Yi Zhuang but not in Han were higher in VNTR-LS (carrier of one long and one short alleles) than in VNTR-LL (the individual carrying two long alleles) genotypes. The levels of TC, triglycerides (TG), LDL cholesterol, and Apo B in Hei Yi Zhuang were higher in both HVE34 and HVE36 alleles than in HVE32 allele. The levels of TC, TG, HDL-C and Apo B in Hei Yi Zhuang were also higher in homozygotes than in heterozygotes. There were no significant differences in the detected lipid parameters between the VNTR-SS (carrier of two short alleles) and VNTR-LS or VNTR-LL genotypes in both ethnic groups.
There were significant differences of the 3'APOB-VNTR polymorphism between the Hei Yi Zhuang and Han populations. An association between the 3'APOB-VNTR polymorphism and serum lipid levels was observed in the Hei Yi Zhuang but not in the Han populations.
PMCID: PMC1939985  PMID: 17640344
12.  Morphological and Dimensional Characteristics of Dental Arch among Tribal and Non-tribal Population of Central India: A Comparative Study 
Differences in the dental arch among Bhil Aboriginals were investigated and compared with non-tribal individuals residing in a tribal zone of Central India. Plaster models (120) were made with the help of alginate impression of tribal adults as well as non-tribal adults residing in the same area. The supposition as aboriginals being primitive due to dietary practices maxillary arch size and mandibular arch size is distended in comparison to the non-tribal population as adaptation of soft refined diet has disrupted the growth of the jaws. Hence, an attempt was made to evaluate the arch widths of tribal population and to associate it with non-tribe population in the same area of Central India.
Materials and Methods:
Difference in morphology and dimension of the maxillary and mandibular arches was aimed at Bhil tribes as well as non-tribal residents of tribe rich zone of Central India. The study was steered amid 120 individuals both tribal and non-tribe equally around 60 each through a well-organized out-reach program intermittently. Study models were made of dental arches of all participants. All measurements of the arch dimension were patent on the study casts using an electronic digital sliding caliper. Pair t-test was applied by using SPSS software version-19.0.
In the maxillary arch, on appraisal the non-tribal and Bhil tribe’s subjects, it showed a statistically significant difference in inter-incisor width (2.95 mm), inter-canine width (2.60 mm), arch depth (3.25 mm). While inter premolar width (0.20 mm) and inter molar width (0.80 mm) anterior arch length (0.60 mm), and posterior arch length (0.10 mm) showed statistically not significant difference between non-tribal population and Bhil tribe subjects.
In the mandibular arch, it showed a statistically significant difference in inter-canine width (1.00 mm). Although, inter-incisor width (0.72 mm), inter-molar width (0.80 mm), arch depth (0.90 mm), anterior arch length (0.30 mm), posterior arch length (0.35 mm), and curve of Spee (0.13 mm) showed statistically not significant difference between general population and Bhil tribe subjects.
When associated non-tribal population to Bhil tribes subjects, for the morphological and dimensional characteristics of dental arches Bhil tribe subjects exhibited: A narrower and shorter maxilla; reduced mandible size; smaller incisor widths for the maxillary and mandibular arches.
PMCID: PMC4295450  PMID: 25628479
Arch depth; bhil tribe; dental arch
13.  Haplotype diversity and linkage disequilibrium at the DRD2 locus among the tribes of western and southern regions of India 
Dopamine receptor D2 (DRD2) is an important gene having functional significance in the fields of neuropsychiatry and pharmacology and also has importance in evolutionary studies.
This study was undertaken to find out the haplotype distribution and linkage disequilibrium (LD) pattern for the three TaqI sites (TaqI ‘A’, TaqI ‘B’ and TaqI ‘D’) in the DRD2 gene in 232 unrelated individuals from five ethno-linguistically distinct endogamous tribal populations; Siddis and Gonds of Uttara Kannada district, Karnataka; Varli and Kolgha of Valsad district, Gujarat; and Dangi Konkana of Dang district, Gujarat. The genotype data obtained after molecular analysis of the three DRD2 sites was subjected to statistical analysis such as calculation of allele frequencies, haplotype frequencies among others. Subsequently, a neighbor-joining tree was also constructed from the data obtained.
The three DRD2 sites were found to be polymorphic in all the populations. All the populations showed high levels of heterozygosities. Out of the eight possible haplotypes, most populations shared seven haplotypes. Of all the populations, Siddis showed the highest frequency of the ancestral haplotype B2D2A1 (11.4%). Significant LD was found to exist for TaqI ‘A’ and TaqI ‘B’ sites in both the populations.
The findings are in concurrence with those from other Indian studies, especially from Dravidian-speaking South Indian populations. Similar pattern of diversity observed for ethnically and linguistically diverse populations in the present study is indicative of complex structure of Indian populations.
PMCID: PMC2955952  PMID: 21031052
Ancestral haplotype; ethno-linguistic diversity; haplotype analysis; linkage disequilibrium; population structure
14.  Analysis of Polymorphisms and Haplotype Structure of the Human Thymidylate Synthase Genetic Region: A Tool for Pharmacogenetic Studies 
PLoS ONE  2012;7(4):e34426.
5-fluorouracil (5FU), a widely used chemotherapeutic drug, inhibits the DNA replicative enzyme, thymidylate synthase (Tyms). Prior studies implicated a VNTR (variable numbers of tandem repeats) polymorphism in the 5′-untranslated region (5′-UTR) of the TYMS gene as a determinant of Tyms expression in tumors and normal tissues and proposed that these VNTR genotypes could help decide fluoropyrimidine dosing. Clinical associations between 5FU-related toxicity and the TYMS VNTR were reported, however, results were inconsistent, suggesting that additional genetic variation in the TYMS gene might influence Tyms expression. We thus conducted a detailed genetic analysis of this region, defining new polymorphisms in this gene including mononucleotide (poly A:T) repeats and novel single nucleotide polymorphisms (SNPs) flanking the VNTR in the TYMS genetic region. Our haplotype analysis of this region used data from both established and novel genetic variants and found nine SNP haplotypes accounting for more than 90% of the studied population. We observed non-exclusive relationships between the VNTR and adjacent SNP haplotypes, such that each type of VNTR commonly occurred on several haplotype backgrounds. Our results confirmed the expectation that the VNTR alleles exhibit homoplasy and lack the common ancestry required for a reliable marker of a linked adjacent locus that might govern toxicity. We propose that it may be necessary in a clinical trial to assay multiple types of genetic polymorphisms in the TYMS region to meaningfully model linkage of genetic markers to 5FU-related toxicity. The presence of multiple long (up to 26 nt), polymorphic monothymidine repeats in the promoter region of the sole human thymidylate synthetic enzyme is intriguing.
PMCID: PMC3320636  PMID: 22496803
15.  Association of −31T>C and −511 C>T polymorphisms in the interleukin 1 beta (IL1B) promoter in Korean keratoconus patients 
Molecular Vision  2008;14:2109-2116.
To investigate the genetic association between unrelated Korean keratoconus patients and interleukin 1 alpha (IL1A), interleukin 1 beta (IL1B), and IL1 receptor antagonist (IL1RN) gene polymorphisms.
We investigated the association between IL1A (rs1800587, rs2071376, and rs17561), IL1B (rs1143627, rs16944, rs1143634, and rs1143633), and IL1RN (rs419598, rs423904, rs424078, and rs315952, variable number tandem repeat [VNTR]) polymorphisms in 100 unrelated Korean keratoconus patients. One hundred control individuals without any corneal disease were selected from the general population. Polymerase chain reaction (PCR) – restriction fragment length polymorphism (RFLP) analysis and direct sequencing were used to screen for genetic variations in the IL1 gene cluster. Haplotypes for the IL1 gene cluster were constructed using Haploview version 4.0.
We analyzed a total of 12 polymorphic sites in the IL1 gene cluster. Among them, the −511 (rs16944) and −31 (rs1143627) positions in the promoter region of IL1B were significantly different between patient and control groups. The C allele of rs16944 (−511C>T, p=0.022, odds ratio of risk [OR]=1.46, 95% confidence intervals [CI] 0.94<2.27) and the T allele of rs1143627 (−31T>C, p=0.025, OR=1.43, 95% CI 0.92<2.22) were associated with a significantly increased risk of keratoconus in Korean patients. Linkage of the two alleles, −31*C and −511*T, was associated with an increased risk for keratoconus with OR=2.38 (p=0.012, 95% CI=1.116–5.046). The *C/*A genotype of rs2071376 in IL1A intron 6 was significantly different between the keratoconus patients and control subjects (p=0.034, OR=0.59, 95% CI 0.32<1.11). Other polymorphisms did not show an association with keratoconus risk.
This is the first report of IL1 gene cluster mutation screening in Korean keratoconus patients. Significant differences in allelic frequency of IL1B between keratoconus patients and the control group suggest that IL1B polymorphisms may play a role in the susceptibility of unrelated Koreans to develop keratoconus.
PMCID: PMC2588426  PMID: 19043479
16.  Functional Genomics of Attention-Deficit/ Hyperactivity Disorder (ADHD) Risk Alleles on Dopamine Transporter Binding in ADHD and Healthy Control Subjects 
Biological psychiatry  2012;74(2):84-89.
The main aim of this study was to examine the relationship between dopamine transporter (DAT) binding in the striatum in individuals with and without attention-deficit/hyperactivity disorder (ADHD), attending to the 3′-untranslated region of the gene (3′-UTR) and intron8 variable number of tandem repeats (VNTR) polymorphisms of the DAT (SLC6A3) gene.
Subjects consisted of 68 psychotropic (including stimulant)-naïve and smoking-naïve volunteers between 18 and 55 years of age (ADHD n = 34; control subjects n = 34). Striatal DAT binding was measured with positron emission tomography with 11C altropane. Genotyping of the two DAT (SLC6A3) 3′-UTR and intron8 VNTRs used standard protocols.
The gene frequencies of each of the gene polymorphisms assessed did not differ between the ADHD and control groups. The ADHD status (t = 2.99; p < .004) and 3′-UTR of SLC6A3 9 repeat carrier status (t = 2.74; p < .008) were independently and additively associated with increased DAT binding in the caudate. The ADHD status was associated with increased striatal (caudate) DAT binding regardless of 3′-UTR genotype, and 3′-UTR genotype was associated with increased striatal (caudate) DAT binding regardless of ADHD status. In contrast, there were no significant associations between polymorphisms of DAT intron8 or the 3′-UTR-intron8 haplotype with DAT binding.
The 3′-UTR but not intron8 VNTR genotypes were associated with increased DAT binding in both ADHD patients and healthy control subjects. Both ADHD status and the 3′-UTR polymorphism status had an additive effect on DAT binding. Our findings suggest that an ADHD risk polymorphism (3′-UTR) of SLC6A3 has functional consequences on central nervous system DAT binding in humans.
PMCID: PMC3700607  PMID: 23273726
ADHD; altropane; dopamine; dopamine transporter; genetics; PET imaging
17.  Association of IL-4 gene VNTR variant with deep venous thrombosis in Behçet’s disease and its effect on ocular involvement 
Molecular Vision  2013;19:675-683.
Behçet’s disease (BD) is a systemic vasculitis characterized by inflammatory lesions of the urogenital mucosa, eyes, skin, central nervous system, and joints. Vein thrombosis constitutes the most frequent vascular manifestation of the disease, and may cause such ocular vascular thrombotic events as central retinal vein and central retinal artery thrombosis. Thrombosis is a serious problem, and often leads to irreversible vision loss. Previous studies have shown that genetic factors predispose individuals to BD. Several cytokine genes might play crucial roles in host susceptibility to BD and to thrombophilia. Various polymorphic regions of the interleukin-4 (IL-4) gene (−1098G and 590T) are associated with BD in the Turkish population. This study was conducted in Turkish patients with BD to determine the frequency of the IL-4 gene 70 bp variable number of tandem repeats (VNTR) variant, and its association with clinical findings.
Genomic DNA obtained from 488 individuals (238 patients with Behçet’s disease and 250 healthy controls) was used in the study. Genomic DNA was isolated and genotyped using PCR assay for the IL-4 gene 70 bp VNTR polymorphism determined by using PCR with the specific primers.
There was statistical significance between the groups regarding IL-4 genotype distribution (p<0.001, odds ratio: 2.55 [1.629–4.052], 95% confidence interval) and allele frequencies (p<0.0012.381[1.586–3.617], 95% confidence interval). When we examined IL-4 genotype frequencies according to the clinical characteristics, we observed a statistically significant association between the P2P2 genotype and deep venous thrombosis (p=0.01). Deep venous thrombosis was also associated with ocular involvement in our study group (p=0.014).
Our findings suggest that the IL-4 gene 70 bp VNTR polymorphism is associated with susceptibility to development of BD. Deep venous thrombosis is also associated with ocular involvement in BD. The IL-4 gene could be a genetic biomarker in Behçet’s disease in a Turkish study population.
PMCID: PMC3611952  PMID: 23559861
18.  G6PD Deficiency Prevalence and Estimates of Affected Populations in Malaria Endemic Countries: A Geostatistical Model-Based Map 
PLoS Medicine  2012;9(11):e1001339.
Rosalind Howes and colleagues present a map of glucose-6-phosphate dehydrogenase deficiency prevalence and severity. Individuals with the deficiency are at risk of mild to severe hemolysis when taking the antimalarial primaquine.
Primaquine is a key drug for malaria elimination. In addition to being the only drug active against the dormant relapsing forms of Plasmodium vivax, primaquine is the sole effective treatment of infectious P. falciparum gametocytes, and may interrupt transmission and help contain the spread of artemisinin resistance. However, primaquine can trigger haemolysis in patients with a deficiency in glucose-6-phosphate dehydrogenase (G6PDd). Poor information is available about the distribution of individuals at risk of primaquine-induced haemolysis. We present a continuous evidence-based prevalence map of G6PDd and estimates of affected populations, together with a national index of relative haemolytic risk.
Methods and Findings
Representative community surveys of phenotypic G6PDd prevalence were identified for 1,734 spatially unique sites. These surveys formed the evidence-base for a Bayesian geostatistical model adapted to the gene's X-linked inheritance, which predicted a G6PDd allele frequency map across malaria endemic countries (MECs) and generated population-weighted estimates of affected populations. Highest median prevalence (peaking at 32.5%) was predicted across sub-Saharan Africa and the Arabian Peninsula. Although G6PDd prevalence was generally lower across central and southeast Asia, rarely exceeding 20%, the majority of G6PDd individuals (67.5% median estimate) were from Asian countries. We estimated a G6PDd allele frequency of 8.0% (interquartile range: 7.4–8.8) across MECs, and 5.3% (4.4–6.7) within malaria-eliminating countries. The reliability of the map is contingent on the underlying data informing the model; population heterogeneity can only be represented by the available surveys, and important weaknesses exist in the map across data-sparse regions. Uncertainty metrics are used to quantify some aspects of these limitations in the map. Finally, we assembled a database of G6PDd variant occurrences to inform a national-level index of relative G6PDd haemolytic risk. Asian countries, where variants were most severe, had the highest relative risks from G6PDd.
G6PDd is widespread and spatially heterogeneous across most MECs where primaquine would be valuable for malaria control and elimination. The maps and population estimates presented here reflect potential risk of primaquine-associated harm. In the absence of non-toxic alternatives to primaquine, these results represent additional evidence to help inform safe use of this valuable, yet dangerous, component of the malaria-elimination toolkit.
Please see later in the article for the Editors' Summary
Editors' Summary
Malaria is a parasitic infection that is transmitted to people through the bites of infected mosquitoes. Of the four parasites that cause malaria, Plasmodium falciparum is the most deadly and P. vivax is the commonest and most widely distributed. Malaria parasites have a complex life cycle. Infected mosquitoes inject “sporozoites” into people, a form of the parasite that replicates inside human liver cells. After a few days, the liver cells release “merozoites,” which invade red blood cells where they replicate rapidly before bursting out and infecting other red blood cells. This increase in the parasitic burden causes malaria's characteristic fever and can cause organ damage and death. Infected red blood cells also release “gametocytes,” which infect mosquitoes when they take a blood meal. In the mosquito, gametocytes multiply and develop into sporozoites, thus completing the parasite's life cycle. Malaria can be prevented by controlling the mosquitoes that spread the parasite and by avoiding mosquito bites by sleeping under insecticide-treated bed nets. Treatment with effective antimalarial drugs also decreases malaria transmission.
Why Was This Study Done?
The Global Malaria Action Plan aims to reduce malaria deaths to zero by 2015 and to eradicate malaria in the long-term through its progressive elimination in malaria-endemic countries (countries where malaria is always present). Primaquine is a key drug for malaria elimination. It is the only treatment effective against the gametocytes that transmit malaria between people and mosquitoes and against P. vivax “hypnozoites,” which hibernate in the liver and cause malaria relapses. Unfortunately, primaquine induces mild to severe destruction of red blood cells (hemolysis) in people who have a deficiency in the enzyme glucose-6-phosphate dehydrogenase (G6PD). G6PD deficiency (G6PDd) is common in some ethnic groups but the global distribution of individuals at risk of primaquine-induced hemolysis is unknown and there is no practical field test for G6PDd. Consequently, it is hard to design and implement primaquine treatment practices that balance the benefits of malaria transmission reduction and relapse prevention against the risk of hemolysis. Here, the researchers use a geostatistical model to map the prevalence (frequency in a population) of G6PDd in malaria-endemic countries and to estimate how many people are affected in these countries. They also develop a national index of relative hemolytic risk.
What Did the Researchers Do and Find?
The researchers fed data from community surveys of the prevalence of phenotypic G6PDd (reduced enzyme activity) for 1,734 sites (including 1,289 sites in malaria-endemic countries) into a geostatistical model originally developed to map global malaria endemicity. The model predicted that G6PDd is widespread across malaria-endemic regions, with the lowest prevalences in the Americas and the highest in tropical Africa and the Arabian Peninsula, but that most G6PDd individuals live in Asian countries. The predicted prevalence of G6PDd varied considerably over relatively short distances in many areas but, averaged across malaria-endemic countries it was 8%, which corresponds to about 350 million affected individuals; averaged across countries that are currently planning for malaria elimination, the prevalence was 5.3% (nearly 100 million affected individuals). Finally, the researchers used data on the geographical occurrence of G6PD variants classified according to their enzyme activity levels as mild or severe to derive an index of hemolytic risk from G6PDd for each malaria-endemic country. The greatest risk was in the Arabian Peninsula and west Asia where the predicted prevalence of G6PDd and the occurrence of severe G6PD variants were both high.
What Do These Findings Mean?
These findings suggest that G6PDd is widespread and spatially heterogeneous across most of the malaria-endemic countries where primaquine would be valuable for malaria control and elimination. The accuracy of these findings is limited, however, by the assumptions made in the geostatistical model, by the accuracy of the data fed into the model, and by the lack of data for some malaria-endemic countries. Moreover, there is considerable uncertainty associated with the proposed index of hemolysis risk because it is based on phenotypic G6PDd enzyme activity classifications, which is presumed, but not widely demonstrated, to be a surrogate marker for hemolysis. Nevertheless, these findings pave the way for further data collection and for the refinement of G6PDd maps that, in the absence of non-toxic alternatives to primaquine, will guide the design of safe primaquine regimens for the elimination of malaria.
Additional Information
Please access these Web sites via the online version of this summary at
Information is available from the World Health Organization on malaria; its 2011 World Malaria Report provides details of the current global malaria situation (some information is available in several languages)
The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish), including a selection of personal stories about malaria
Information is available from the Roll Back Malaria Partnership on the global control of malaria and on the Global Malaria Action Plan
Information on the global mapping of malaria is available at the Malaria Atlas Project website where G6PD deficiency prevalence maps, population estimates and the data used in this study can also be accessed
Information about G6PD deficiency for affected families can be found on KidsHealth from the Nemous Children's Health System and the G6PD Deficiency Association website
MedlinePlus provides links to additional information on malaria; the MedlinePlus Encyclopedia provides information about G6PD deficiency (in English and Spanish)
PMCID: PMC3496665  PMID: 23152723
19.  AVPR1a and SLC6A4 Gene Polymorphisms Are Associated with Creative Dance Performance 
PLoS Genetics  2005;1(3):e42.
Dancing, which is integrally related to music, likely has its origins close to the birth of Homo sapiens, and throughout our history, dancing has been universally practiced in all societies. We hypothesized that there are differences among individuals in aptitude, propensity, and need for dancing that may partially be based on differences in common genetic polymorphisms. Identifying such differences may lead to an understanding of the neurobiological basis of one of mankind's most universal and appealing behavioral traits—dancing. In the current study, 85 current performing dancers and their parents were genotyped for the serotonin transporter (SLC6A4: promoter region HTTLPR and intron 2 VNTR) and the arginine vasopressin receptor 1a (AVPR1a: promoter microsatellites RS1 and RS3). We also genotyped 91 competitive athletes and a group of nondancers/nonathletes (n = 872 subjects from 414 families). Dancers scored higher on the Tellegen Absorption Scale, a questionnaire that correlates positively with spirituality and altered states of consciousness, as well as the Reward Dependence factor in Cloninger's Tridimensional Personality Questionnaire, a measure of need for social contact and openness to communication. Highly significant differences in AVPR1a haplotype frequencies (RS1 and RS3), especially when conditional on both SLC6A4 polymorphisms (HTTLPR and VNTR), were observed between dancers and athletes using the UNPHASED program package (Cocaphase: likelihood ratio test [LRS] = 89.23, p = 0.000044). Similar results were obtained when dancers were compared to nondancers/nonathletes (Cocaphase: LRS = 92.76, p = 0.000024). These results were confirmed using a robust family-based test (Tdtphase: LRS = 46.64, p = 0.010). Association was also observed between Tellegen Absorption Scale scores and AVPR1a (Qtdtphase: global chi-square = 26.53, p = 0.047), SLC6A4 haplotypes (Qtdtphase: chi-square = 2.363, p = 0.018), and AVPR1a conditional on SCL6A4 (Tdtphase: LRS = 250.44, p = 0.011). Similarly, significant association was observed between Tridimensional Personality Questionnaire Reward Dependence scores and AVPR1a RS1 (chi-square = 20.16, p = 0.01). Two-locus analysis (RS1 and RS3 conditional on HTTLPR and VNTR) was highly significant (LRS = 162.95, p = 0.001). Promoter repeat regions in the AVPR1a gene have been robustly demonstrated to play a role in molding a range of social behaviors in many vertebrates and, more recently, in humans. Additionally, serotonergic neurotransmission in some human studies appears to mediate human religious and spiritual experiences. We therefore hypothesize that the association between AVPR1a and SLC6A4 reflects the social communication, courtship, and spiritual facets of the dancing phenotype rather than other aspects of this complex phenotype, such as sensorimotor integration.
Dancing, integrally related to music, likely has its origins close to the birth of Homo sapiens. The authors hypothesized that there are differences in aptitude, propensity, and need for dancing that may be based on differences in common genetic polymorphisms. Identifying such differences may lead to an understanding of the neurobiological basis of dancing.
Variants of the serotonin transporter and the arginine vasopressin receptor 1a genes were examined in performing dancers, elite athletes, and nonathletes/nondancers. The serotonin transporter regulates the level of serotonin, a brain transmitter that contributes to spiritual experience. The vasopressin receptor has been shown in many animal studies to modulate social communication and affiliative behaviors. Notably, dancers scored high on the Tellegen Absorption Scale, a correlate of spirituality, and the Reward Dependence factor in Cloninger's Tridimensional Personality Questionnaire, a measure of empathy, social communication, and need for social contact. Significant differences were observed in allele frequencies for both genes when dancers were compared to athletes as well as to nondancers/nonathletes. These two genes were also associated with scores on the Tellegen Absorption Scale and Tridimensional Personality Questionnaire Reward Dependence, suggesting that the association between these genes and dance is mediated by personality factors reflecting the social communication, courtship, and spiritual facets of the dancing phenotype.
PMCID: PMC1239939  PMID: 16205790
20.  Association Between PAH Mutations and VNTR Alleles in the West Azerbaijani PKU Patients 
Mædica  2014;9(3):242-247.
We report the frequency of IVS10nt546, R261Q, S67P, R252W, and R408W mutations linked to PAH VNTR alleles in the west Azerbaijani PKU patients.
Material and methods:
VNTR alleles and IVS10nt546, R261Q, S67P, R252W, R408W mutations were studied in a total of 20 PKU patients by PCR and RFLP-PCR.
Our analysis showed that 95% of cases were homozygote for an allele containing eight-repeat VNTR (VNTR8); while 5% were homozygote for an allele containing three-repeat VNTR (VNTR3). The IVS10nt546, R252W, and R261Q mutations were associated with VNTR8 allele, and also, R252W and S67P mutations were associated with VNTR3 allele. VNTR8 was common among mutant alleles as were IVS10nt546–VNTR8 (50%), R252W–VNTR8 (2.5%), and R261Q–VNTR8 (22.5%). The association of VNTR3 was found as R252W–VNTR3 (2.5%) and S67P–VNTR3 (2.5%) among studied cases. The frequency of IVS10nt546–VNTR8/IVS10nt546–VNTR8, IVS10nt546–VNTR8/ND–VNTR8, IVS10nt546–VNTR8/R252W–VNTR8, R261Q–VNTR8/R261Q–VNTR8, R261Q–VNTR8/ND–VNTR8, and S67P–VNTR3/ R252W–VNTR3 were 30%, 35%, 5%, 20%, 5%, and 5%, respectively. R408W mutation was not found in this study.
The present report is the first in its own kind in the west Azerbaijani population (Iran) and implies that the most common PKU mutation in this population, IVS10nt546, is exclusively associated with VNTR8 allele, and IVS10nt546–VNTR8 alleles testing should be considered for routine carrier screening and prenatal diagnostic setting.
PMCID: PMC4305991
PAH gene; VNTR alleles; west Azerbaijan; PKU
21.  Chronotype and a PERIOD3 variable number tandem repeat polymorphism in Han Chinese pilots 
An association has been determined between variable number tandem-repeat (VNTR) polymorphisms in the PERIOD3 gene (PER3, rs57875989) and chronotype. An association has been found in which the longer PER3(5) allele is correlated with diurnal preference and shorter PER3(4) allele is linked with preference for evening, respectively. In this study, we explored the genotype frequency and relationship to the chronotype of a PER3 VNTR polymorphism in Han Chinese pilots compared to other populations to further develop aviation safety research. DNA samples were genotyped with respect to the 4-repeat and 5-repeat alleles of the PER3 VNTR polymorphism. We compared and analyzed PER3 VNTR genotype frequencies of a general Han Chinese population and Han Chinese pilots. The chronotypes of our subjects were evaluated by the morningness-eveningness questionnaire (MEQ). The distribution of PER3 VNTR genotype frequencies from 240 Han Chinese was determined (PER3(4/4), 78.3%; PER3(4/5), 20.0%; PER3(5/5), 1.7%) and compared to the genotype frequencies of 126 Han Chinese pilots (PER3(4/4), 71.4%; PER3(4/5), 26.1%; PER3(5/5), 2.4%). Statistical analysis revealed no significant difference between the general Han Chinese population and Han Chinese pilots regarding the PER3 VNTR genotype and allele frequencies (x2 = 2.170, p > 0.05). Furthermore, MEQ results showed no association between the PER3 VTNR polymorphism and chronotype. However, PER3 VNTR genotype frequencies differed significantly between Han Chinese and other ethnic groups previously reported, such as Caucasians, African Americans and Italians. These data indicate that the proposed role of the PER3 VNTR needs further clarification and the role of PER3(5) allele in sleep regulation needs to be investigated in more detail. In particular, a study of PER3 polymorphisms with a larger sample size of Han Chinese individuals and Han Chinese pilots may be required.
PMCID: PMC4238505  PMID: 25419431
PER3 VNTR; chronotype; circadian rhythm; sleep deprivation; diurnal preference; gene frequency; Han Chinese
22.  Association of IL-4 and IL-10 maternal haplotypes with immune responses to P. falciparum in mothers and newborns 
BMC Infectious Diseases  2013;13:215.
Particular cytokine gene polymorphisms are involved in the regulation of the antibody production. The consequences of already described IL-4, IL-10 and IL-13 gene polymorphisms on biological parameters and antibody levels were investigated among 576 mothers at delivery and their newborns in the context of P. falciparum placental malaria infection.
The study took place in the semi-rural area of Tori-Bossito, in south-west Benin, where malaria is meso-endemic. Six biallelic polymorphisms were determined by quantitative PCR using TaqMan® Pre-Designed SNP Genotyping Assays, in IL-4 (rs2243250, rs2070874), IL-10 (rs1800896, rs1800871, rs1800872) and IL-13 (rs1800925) genes. Antibody responses directed to P. falciparum MSP-1, MSP-2, MSP-3, GLURP-R0, GLURP-R2 and AMA-1 recombinant proteins were determined by ELISA.
The maternal IL-4−590*T/IL-4+33*T haplotype (one or two copies) was associated with favorable maternal condition at delivery (high haemoglobin levels, absence of placental parasites) and one of its component, the IL-4−590TT genotype, was related to low IgG levels to MSP-1, MSP-2/3D7 and MSP-2/FC27. Inversely, the maternal IL-10−1082AA was positively associated with P. falciparum placenta infection at delivery. As a consequence, the IL-10−819*T allele (in CT and TT genotypes) as well as the IL-10−1082*A/IL-10−819*T/IL-10−592*A haplotype (one or two copies) in which it is included, were related to an increased risk for anaemia in newborns. The maternal IL-10−1082AA genotype was related to high IgG levels to MSP-2/3D7 and AMA-1 in mothers and newborns, respectively. The IL-13 gene polymorphism was only involved in the newborn’s antibody response to AMA-1.
These data revealed that IL-4 and IL-10 maternal gene polymorphisms are likely to play a role in the regulation of biological parameters in pregnant women at delivery (anaemia, P. falciparum placenta infection) and in newborns (anaemia). Moreover, IL-4, IL-10 and IL-13 maternal gene polymorphisms were related to IgG responses to MSP-1, MSP-2/3D7 and MSP-2/FC27 in mothers as well as to AMA-1 in newborns.
PMCID: PMC3679728  PMID: 23668806
Malaria; P. falciparum; Cytokine gene polymorphisms; IL-4; IL-10; IL-13; Pregnancy; Cord blood; Recombinant proteins; Specific antibodies
23.  Association of Variable Number of Tandem Repeats in the Coding Region of the FAM46A Gene, FAM46A rs11040 SNP and BAG6 rs3117582 SNP with Susceptibility to Tuberculosis 
PLoS ONE  2014;9(3):e91385.
We analyzed for association between the Family with sequence similarity 46, member A (FAM46A) gene (located on chromosome 6q14.1), BCL2-Associated Athanogene 6 (BAG6) gene (located on chromosome 6p21.3) and tuberculosis in Croatian Caucasian. We genotyped the FAM46A rs11040 SNP, FAM46A VNTR and BAG6 rs3117582 polymorphisms in a case-control study with 257 tuberculosis patients and 493 healthy individuals in a Croatian Caucasian population. We found that genotype FAM46A 3/3 (three VNTR repeats homozygote) was associated with susceptibility to tuberculosis (p<0.0015, Pcorr.<0.029, Odds ratio = 2.42, 95% Confidence Interval = 1.34–4.3). This association suggests that the protein domain encoded by the VNTR might be important for the function of the FAM46A protein, which, in turn, could be relevant in developing tuberculosis. In addition, we found that FAM46A rs11040 SNP:FAM46A VNTR:BAG6 haplotype 132 (G-3-C) is associated with susceptibility to tuberculosis (p<0.012, pcorr.<0.024, Odds ratio 3.45, 95% Confidence Interval = 1.26–9.74). This may suggests that the interaction between the FAM46A and BAG6 proteins may be involved in tuberculosis etiology. We found also that infection of human macrophages with heat-killed M. tuberculosis (H37Rv) led to over-expression of FAM46A (VNTR 3/4) transcript. This is the first study to show associations between the FAM46A gene VNTR polymorphisms, FAM46A rs11040 SNP:FAM46A VNTR:BAG6 haplotypes and any disease.
PMCID: PMC3953334  PMID: 24625963
24.  Relationships between endothelial nitric oxide synthase gene polymorphisms and osteoporosis in postmenopausal women*  
Objective: To investigate the relationships between endothelial nitric oxide synthases (eNOS) G894T and 27 bp-variable number tandem repeat (VNTR) gene polymorphisms and osteoporosis in the postmenopausal women of Chinese Han nationality. Methods: In the present study, 281 postmenopausal women from Xi’an urban area in West China were recruited, and divided into osteoporosis, osteopenia, and normal groups according to the diagnostic criteria of osteoporosis proposed by World Health Organization (WHO). The bone mineral density (BMD) values of lumbar vertebrae and left hips were determined by QDR-2000 dual energy X-ray absorptiometry. Blood samples were tested for plasma biochemical indicators including testosterone, estradiol, calcitonin, osteocalcin, and procollagen type I amino-terminal propeptide by enzyme-linked immunosorbent assay (ELISA), tartrate-resistant acid phosphatase by spectrophotometric method, and the content of nitric oxide by Griess method. Genome DNA was extracted from whole blood, and G894T polymorphism of eNOS gene was analyzed by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and 27 bp-VNTR polymorphism of eNOS gene was genotyped by PCR method. Then the relationships between genotypes and biochemical indicators, genotypes and osteoporosis, and haplotypes and osteoporosis were analyzed. Results: The average BMD values of the femoral neck, ward’s triangle and lumbar vertebrae 1~4 (L1~L4) in the subjects with T/T genotype in eNOS G894T locus were significantly higher than those in the subjects with G/T and G/G genotypes (P<0.05). The average BMD of the femoral neck in the subjects with a/a genotype of eNOS 27 bp-VNTR locus was evidently higher than that in the subjects with b/b genotype (P<0.05). The plasma testosterone and osteocalcin concentrations in the subjects of eNOS G894T G/T genotype were evidently higher than those in the subjects of other genotypes (P<0.05); the plasma estradiol concentration in the subjects of eNOS 27 bp-VNTR a/a genotype was obviously higher than that in the subjects of b/b genotype (P<0.01). eNOS G/G homozygous frequencies in osteoporosis women, osteopenia women, and normal women were 85.37%, 76.38%, and 83.87%, respectively (P>0.05). 0% osteoporosis woman, 0.79% osteopenia women, and 3.23% normal women were eNOS a/a homozygous (P<0.05). The frequencies of eNOS 27 bp-VNTR a allele were 5.33% in the osteoporosis group, 10.24% in the osteopenia group, and 16.13% in the normal group (P<0.05, odds ratio (OR)=0.29, 95% confidence interval (CI)=0.11~0.77), suggesting that a/a genotype and a allele might have protective effects on osteoporosis. The haplotype analysis showed that G-b was 87.7% (214/244) in the osteoporosis group (P<0.05, OR=2.48, 95% CI=1.18~5.18). G-a was 5.3% (13/244) in the osteoporosis group (P<0.05, OR=0.29, 95% CI=0.11~0.77). G-b was a risk factor for osteoporosis, and G-a a protective factor. Conclusion: eNOS G894T G/T genotype influenced the plasma testosterone and osteocalcin concentrations, and T/T genotype influenced BMD. eNOS 27 bp-VNTR a/a genotype increased plasma estradiol concentration to have a protective effect on osteoporosis.
PMCID: PMC2722703  PMID: 19650200
Postmenopausal women; Osteoporosis; Endothelial nitric oxide synthase; Gene polymorphisms; Bone mineral density
25.  Barriers to Malaria Control among Marginalized Tribal Communities: A Qualitative Study 
PLoS ONE  2013;8(12):e81966.
Malaria infection accounts for over one million deaths worldwide annually. India has the highest number of malaria deaths outside Africa, with half among Indian tribal communities. Our study sought to identify barriers to malaria control within tribal populations in malaria-endemic Gadchiroli district, Maharashtra.
Methods and Findings
This qualitative study was conducted via focus groups and interviews with 84 participants, and included tribal villagers, traditional healers, community health workers (CHWs), medical officers, and district officials. Questions assessed knowledge about malaria, behavior during early stages of infection, and experiences with prevention among tribal villagers and traditional healers. CHWs, medical officers, and district officials were asked about barriers to treating and preventing malaria among tribal populations. Data were inductively analyzed and assembled into broader explanation linking barriers to geographical, cultural and social factors. Findings indicate lack of knowledge regarding malaria symptoms and transmission. Fever cases initially present to traditional healers or informal providers who have little knowledge of malaria or high-risk groups such as children and pregnant women. Tribal adherence with antimalarial medications is poor. Malaria prevention is inadequate, with low-density and inconsistent use of insecticide-treated nets (ITNs). Malaria educational materials are culturally inappropriate, relying on dominant language literacy. Remote villages and lack of transport complicate surveillance by CHWs. Costs of treating malaria outside the village are high.
Geographic, cultural, and social factors create barriers to malaria control among tribal communities in India. Efforts to decrease malaria burden among these populations must consider such realities. Our results suggest improving community-level knowledge about malaria using culturally-appropriate health education materials; making traditional healers partners in malaria control; promoting within-village rapid diagnosis and treatment; increasing ITN distribution and promoting their use as potential strategies to decrease infection rates in these communities. These insights may be used to shape malaria control programs among marginalized populations.
PMCID: PMC3869659  PMID: 24376507

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