Distribution of glyoxalase I (GLO) variants in Western Europe and the Indian subcontinent

Summary English, Italian (including Sardinian), and Spanish populations from Europe and Muslim, Hindu, Sikh, Punjabi, and other populations from the Indian subcontinent currently living either in Birmingham or in India were screened for electrophoretically detectable genetic variants of red cell glyoxalase I (GLO), and their frequencies were reported. All the western European populations investigated, including those reported, exhibited an incidence of close to 44% for the GLO ¹ gene. The frequency distribution of the GLO ¹ gene in various populations from the Indian subcontinent, in contrast, was found to range between 0.15 and 0.33. These observations suggest that the European populations in general are genetically more homogeneous than are the populations of the Indian subcontinent.     

Inter and intra-ethnic differences in the distribution of the molecular variants of TPMT, UGT1A1 and MDR1 genes in the South Indian population

Molecular variants of polymorphic drug metabolizing enzymes and drug transporters are attributed to differences in individual's therapeutic response and drug toxicity in different populations. We sought to determine the genotype and allele frequencies of polymorphisms for major phase II drug-metabolizing enzymes (TPMT, UGT1A1) and drug transporter (MDR1) in South Indians. Allelic variants of TPMT (*2,*3A,*3B,*3C & *8), UGT1A1 (TA)6>7 and MDR1 (2677G>T/A & 3435C>T) were evaluated in 450-608 healthy South Indian subjects. Genomic DNA was extracted by phenol-chloroform method and genotype was determined by PCR-RFLP, qRT-PCR, allele specific PCR, direct sequencing and SNaPshot techniques. The frequency distributions of TPMT, UGT1A1 and MDR1 gene polymorphisms were compared between the individual 4 South Indian populations viz., Tamilian, Kannadiga, Andhrite and Keralite. The combined frequency distribution of the South Indian populations together, was also compared with that of other major populations. The allele frequencies of TPMT*3C, UGT1A1 (TA)7, MDR1 2677T, 2677A and 3435T were 1.2, 39.8, 60.3, 3.7, and 61.6% respectively. The other variant alleles such as TPMT*2, *3A, *3B and *8 were not identified in the South Indian population. Sub-population analysis showed that the distribution of UGT1A1 (TA)6>7 and MDR1 allelic variants differed between the four ethnic groups. However, the frequencies of TPMT*3C allele were similar in the four South Indian populations. The distribution of TPMT, UGT1A1 and MDR1 gene polymorphisms of the South Indian population was significantly different from other populations.     

Incidence of ABO(H) blood group variants among the Bulgarian population.

The result of a screening of ABO (Hh) variants after investigating the blood group of 106,980 persons are presented. The Ax variant is registered most frequently among the Bulgarian population. As a whole the frequencies of ABO blood group variants Ax, Ael, A3, Aend and Am among the Bulgarian population are similar to that established by other authors among the French population and nearly twice as high as among the population of Bombay. The group of H-deficient phenotypes includes AA1Xh, AHm, OHm variants. Their frequency is significantly lower when compared with the frequency of AHm and OHm variants among the population of Thailand. Variants A1 and Aint with unusually high H-content are classified as A1H, A1Hint, Aint H and integrated as a category of H-excess phenotypes. Their incidence among the Bulgarian population is significantly lower than that registered among Maharastrian, South African Bantu and Indian.     

Geographical variability of alpha-1-antitrypsin alleles in China: A study on six Chinese populations

Summary Alpha-1-antitrypsin phenotypes of six Chinese Han populations (20°–45°N. latitude) were determined. The frequency of allele M2 increases from North to South China. The north-south change of M2 appears to be mainly at the expense of alleles M1 and M3. Geographical variability of other variants was also observed. In the northern populations, the most common variants are M4 and Etokyo; in the southern populations, Pweishi, a variant which can not be distinguished electrophoretically from Pyasugi. These results form a distribution pattern of alpha-1-antitrypsin alleles in China.     

Polymorphism of erythrocyte G-6-PD in the baboon

Blood samples from several populations of baboons (genus Papio) were examined for G-6-PD variants. Several G-6-PD phenotypes were detected by starch gel electrophoresis. The so-called fast variant phenotypes of G-6-PD in baboons differ from human variant phenotypes in several physicochemical constants.     

A study of non-metric (qualitative) variation in Gujarati crania

Three hundred and seventy adult skulls (284 crania of unknown sex, 58 males and 28 females) from Gujarat State of India were examined for the incidence of non-metric variants and compared with other populations to establish the distance between them. In general the Gujarati incidences are of similar order to those in other series. The mean measures of divergence between Gujarati and other populations were all statistically significant (P less than 0.001). The Gujarati differed most from Australian Aborigines, but only slightly from the Burma, Punjab and Egypt samples. From the same material side and sex dimorphism was also tested to ascertain that how far sides and sexes can be pooled in Indian sample for making comparison between populations. In Gujarati population out of 22 cranial variants only four show sex difference and in case of bilateral traits, none of the variant has shown significant (P less than 0.05) side to side difference.     

Evidence for association and linkage between atopy, airway hyper-responsiveness, and the β subunit Glu237Gly variant of the high-affinity receptor for immunoglobulin E in the French-Canadian population

Following detection of linkage between atopy and chromosome 11q13 markers, association between this disorder and variants of the beta subunit of the high-affinity receptor for immunoglobulin E (FcepsilonRI-beta, a candidate gene for asthma-related conditions co-localizing within the same region) was reported in Australian, British and Japanese populations. Investigations in several other ethnic groups failed to replicate these observations. Due to the complexity of defining intermediate phenotypes related to asthma, detection of such associations may have been hampered by clinical misclassifications. To assess whether the FcepsilonRI-beta gene was involved in atopy and/or airway hyperresponsiveness (AHR) in the French-Canadian population, we conducted a case-control study in 200 subjects using strict criteria for asthma and related conditions. The Ile181Leu and Glu237Gly FcepsilonRI-beta sequence variants were tested exploiting two amplification refractory mutation systems. No association was detected between atopy or AHR and the Ile181Leu FcepsilonRI-beta variant. However, a strong association was observed between atopy and the Glu237Gly FcepsilonRI-beta variant (odds ratio=12.25). Four large Eastern Québec families (n=106 subjects) were also recruited to perform a genetic linkage study. We observed suggestive evidence of linkage between atopy and the Glu237Gly FcepsilonRI-beta variant (Zmax=2.30). This study is the first to detect the presence of an association between atopy and the Glu237Gly FcepsilonRI-beta variant in French-Canadians. Our data suggest that a susceptibility locus for atopy is located on chromosome 11q13 in this population.     

The distribution of esterase D variants in different ethnic groups

Summary Blood samples collected from a number of human populations belonging to various ethnic groups were screened on cellogel for red-cell esterase D (ESD) variants. These data gathered during the present study together with those that have already appeared in the literature indicate that the common variant allele ESD ² occurs most frequently in the Mongoloid populations, least frequently in the Negroid, and with intermediate frequencies in the Caucasoids. An east to west cline was noticed in the northern populations of the Indian subcontinent; ESD ² gene frequencies in these populations were found to range between those among the Mongoloids and the Caucasoids.     

Novel variants in the KIT and PAX3 genes in horses with white‐spotted coat colour phenotypes

Variants in the EDNRB, KIT, MITF, PAX3 and TRPM1 genes are known to cause white spotting phenotypes in horses, which can range from the common white markings up to completely white horses. In this study, we investigated these candidate genes in 169 horses with white spotting phenotypes not explained by the previously described variants. We identified a novel missense variant, PAX3:p.Pro32Arg, in Appaloosa horses with a splashed white phenotype in addition to their leopard complex spotting patterns. We also found three novel variants in the KIT gene. The splice site variant c.1346+1G>A occurred in a Swiss Warmblood horse with a pronounced depigmentation phenotype. The missense variant p.Tyr441Cys was present in several part‐bred Arabians with sabino‐like depigmentation phenotypes. Finally, we provide evidence suggesting that the common and widely distributed KIT:p.Arg682His variant has a very subtle white‐increasing effect, which is much less pronounced than the effect of the other described KIT variants. We termed the new KIT variants W18–W20 to provide a simple and unambiguous nomenclature for future genetic testing applications.     

Genetic polymorphisms at the human liver/islet glucose transporter (GLUT2) gene locus in Caucasian and West Indian subjects with type 2 (non-insulin-dependent) diabetes mellitus.

The liver/islet glucose transporter (GLUT2) is mainly expressed in the hepatocytes of the liver and the beta-cells of the pancreatic islets and a defect in this transporter could lead to diabetic phenotypes, such as relative hypoinsulinaemia and reduced uptake and metabolism of glucose in the liver. DNA from unrelated individuals was digested with the restriction endonucleases Bgl-I and Taq-I followed by blotting and hybridisation with a 32P-labelled GLUT2 cDNA which revealed three restriction fragment length polymorphisms (RFLPs) (B1, T1 and T2) in both Caucasian and West Indian populations. Linkage analysis between these variant sites demonstrated that the alleles of these polymorphisms were in strong linkage disequilibrium. Disease association of genetic variants at the GLUT2 locus with type 2 diabetes was examined with these RFLPs in both Caucasian (n = 54) and West Indian (n = 46) populations with type 2 diabetes. There were no significant differences in the frequency of alleles, genotypes or haplotypes between diabetic patients and non-diabetic controls. However, there were significant differences in the allele frequencies of all these three polymorphisms between Caucasian and West Indian populations.     

Genetic Differences between the Determinants of Lipid Profile Phenotypes in African and European Americans: The Jackson Heart Study

Genome-wide association analysis in populations of European descent has recently found more than a hundred genetic variants affecting risk for common disease. An open question, however, is how relevant the variants discovered in Europeans are to other populations. To address this problem for cardiovascular phenotypes, we studied a cohort of 4,464 African Americans from the Jackson Heart Study (JHS), in whom we genotyped both a panel of 12 recently discovered genetic variants known to predict lipid profile levels in Europeans and a panel of up to 1,447 ancestry informative markers allowing us to determine the African ancestry proportion of each individual at each position in the genome. Focusing on lipid profiles—HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), and triglycerides (TG)—we identified the lipoprotein lipase (LPL) locus as harboring variants that account for interethnic variation in HDL-C and TG. In particular, we identified a novel common variant within LPL that is strongly associated with TG (p=2.7×10⁻⁶) and explains nearly 1% of the variability in this phenotype, the most of any variant in African Americans to date. Strikingly, the extensively studied “gain-of-function” S447X mutation at LPL, which has been hypothesized to be the major determinant of the LPL-TG genetic association and is in trials for human gene therapy, has a significantly diminished strength of biological effect when it is found on a background of African rather than European ancestry. These results suggest that there are other, yet undiscovered variants at the locus that are truly causal (and are in linkage disequilibrium with S447X) or that work synergistically with S447X to modulate TG levels. Finally, we find systematically lower effect sizes for the 12 risk variants discovered in European populations on the African local ancestry background in JHS, highlighting the need for caution in the use of genetic variants for risk assessment across different populations.     

Genome-wide Association and Population Genetic Analysis of C-Reactive Protein in African American and Hispanic American Women

C-reactive protein (CRP) is a systemic inflammation marker that predicts future cardiovascular risk. CRP levels are higher in African Americans and Hispanic Americans than in European Americans, but the genetic determinants of CRP in these admixed United States minority populations are largely unknown. We performed genome-wide association studies (GWASs) of 8,280 African American (AA) and 3,548 Hispanic American (HA) postmenopausal women from the Women''s Health Initiative SNP Health Association Resource. We discovered and validated a CRP-associated variant of triggering receptors expressed by myeloid cells 2 (TREM2) in chromosomal region 6p21 (p = 10⁻¹⁰). The TREM2 variant associated with higher CRP is common in Africa but rare in other ancestral populations. In AA women, the CRP region in 1q23 contained a strong admixture association signal (p = 10⁻¹⁷), which appears to be related to several independent CRP-associated alleles; the strongest of these is present only in African ancestral populations and is associated with higher CRP. Of the other genomic loci previously associated with CRP through GWASs of European populations, most loci (LEPR, IL1RN, IL6R, GCKR, NLRP3, HNF1A, HNF4A, and APOC1) showed consistent patterns of association with CRP in AA and HA women. In summary, we have identified a common TREM2 variant associated with CRP in United States minority populations. The genetic architecture underlying the CRP phenotype in AA women is complex and involves genetic variants shared across populations, as well as variants specific to populations of African descent.     

Wolbachia Variants Induce Differential Protection to Viruses in Drosophila melanogaster: A Phenotypic and Phylogenomic Analysis

Wolbachia are intracellular bacterial symbionts that are able to protect various insect hosts from viral infections. This tripartite interaction was initially described in Drosophila melanogaster carrying wMel, its natural Wolbachia strain. wMel has been shown to be genetically polymorphic and there has been a recent change in variant frequencies in natural populations. We have compared the antiviral protection conferred by different wMel variants, their titres and influence on host longevity, in a genetically identical D. melanogaster host. The phenotypes cluster the variants into two groups — wMelCS-like and wMel-like. wMelCS-like variants give stronger protection against Drosophila C virus and Flock House virus, reach higher titres and often shorten the host lifespan. We have sequenced and assembled the genomes of these Wolbachia, and shown that the two phenotypic groups are two monophyletic groups. We have also analysed a virulent and over-replicating variant, wMelPop, which protects D. melanogaster even better than the closely related wMelCS. We have found that a ∼21 kb region of the genome, encoding eight genes, is amplified seven times in wMelPop and may be the cause of its phenotypes. Our results indicate that the more protective wMelCS-like variants, which sometimes have a cost, were replaced by the less protective but more benign wMel-like variants. This has resulted in a recent reduction in virus resistance in D. melanogaster in natural populations worldwide. Our work helps to understand the natural variation in wMel and its evolutionary dynamics, and inform the use of Wolbachia in arthropod-borne disease control.     

Red cell glutathione peroxidase (GPX1) variation in Afro-Jamaican,Asiatic Indian,and Dutch populations

Summary A Cellogel procedure for screening the electrophoretic variants of the human red cell glutathione peroxidase (GPX1) was described. Three hundred and ninety eight Dutch persons living in various parts of The Netherlands, 385 individuals born in various states of India, and 72 Jamaicans of African origin livig in Birmingham, UK, were screened for GPX1 variants. The Dutch were monomorphic, while one Afro-Jamaican female and two males and one female of the 116 Punjabis were found to be variants indistinguishable from each other in their pattern of electrophoresis. The clear five banded pattern of the variant indicated that the subunit structure of the human red cell glutathione peroxidase is most probably a tetramer and suggested that the variant is the expression of a heterozygote due to alleles at an autosomal locus. The corresponding phenotype was designated tentatively as GPX1 2-1 and the alleles as GPX1 ^*1 and GPX1 ^*2 respectively. The variant 2-1 was found to be identical to the Thomas variant described by Beutler and West (1974). Thus so far, in addition to the Afro-Americans and Ashkenazi Jews (Beutler et al. 1974), the Punjabis of the Indian subcontinent (this report) were found to exhibit the GPX1 polymorphism due to the GPX1 ^*2 allele. The data discussed in this paper (which included unpublished observations on several African and non-African populations) suggest that the GPX1 ^*2 allele is originally an African variant and hint that the present day Punjabis of Indian subcontinent, like Ashkenazi Jews, are predominantly of Mediterranean origin with some proportion of African ancestry (Mourant et al. 1976).     

Distribution of chelonid fibropapillomatosis-associated herpesvirus variants in Florida: molecular genetic evidence for infection of turtles following recruitment to neritic developmental habitats

Marine turtle fibropapillomatosis is associated with chelonid fibropapilloma-associated herpesvirus (C-FP-HV) and commonly affects juvenile green turtles (Chelonia mydas) in neritic (nearshore) habitats. Green turtles have a complex life history, characterized by shifts in trophic level as well as habitat during ontogeny. Thus, several hypotheses can be proposed for when turtles become infected with C-FP-HV. They may acquire the virus at an early stage in the life cycle, including prenatal, hatchling, or the posthatchling pelagic stages. Alternatively, they may become infected later in life after they emigrate from the open ocean to neritic habitats. Each hypothesis generates predictions about the spatial distribution of genetic variants of C-FP-HV among nearshore sites within a region. Sequencing of polymerase chain reaction-amplified viral DNA from fibropapillomas of individual turtles was used to genotype the viral variants present in marine turtles from different coastal areas in Florida. We found four distinct virus variants (A, B, C, and D), two of which (A and C) were present in multiple turtle species. Green turtles in Florida were infected with variants A, B, and C. Variant A was found in green turtles from all three areas. Outside the Indian River Lagoon, variant A was most commonly detected and was found in >94% of diseased green turtles and 70% of loggerhead sea turtles (Caretta caretta) in the Florida Bay/Florida Keys. However, in the Indian River Lagoon, variant B was found in >94% of affected green turtles. Variant B was not detected outside of the Indian River system. Chi-square analysis strongly supported (P<0.001) an association between viral variant distribution in green turtles and location. On the basis of the assumption that juvenile green turtles found in Florida's west-central coast, Florida Keys, and Indian River Lagoon areas represented recruits from a mixed pelagic population, we expected that the distribution of viral variants in these turtles would be relatively homogeneous among locations; this would correspond to infection in the earlier phases of their life cycle. The heterogeneous distribution of viral variants in green turtle tumors from different Florida coastal locations strongly supports the hypothesis that, during epizootics, turtles are infected with specific C-FP-HV variants after they arrive as juveniles in neritic habitats. The conclusion that C-FP-HV is acquired after turtles recruit to nearshore habitats should help focus further research efforts on understanding the mechanisms of transmission and raises the possibility that the effect of fibropapillomatosis on turtle populations might be reduced by management strategies designed to break the cycle of transmission in these locations.     

Association of the functional KL-VS variant of Klotho gene with early-onset ischemic stroke

Genetic variants of Klotho have been reported to be associated with human longevity and atherosclerotic vascular events and risk factors. However, very few studies have explored their association with ischemic stroke. We hypothesized that the functional KL-VS and the exonic C1818T variants of Klotho gene may be associated with ischemic stroke in Indian population. We enrolled a total of 460 patients with ischemic stroke and 574 age- and gender-matched controls for the study. Genotyping was done by polymerase chain reaction and restriction fragment length polymorphism. Contrary to other Asian reports, KL-VS variant was polymorphic in our population, with a frequency distribution similar to that of Caucasians. The frequency distribution of the C1818T variant was similar to previously reports in Asians. A differential effect of age on association of Klotho KL-VS variant with ischemic stroke was observed. In subjects aged ≤40 years, the KL-VS homozygotes, 352FF and 352VV, had ~1.5-fold (OR=1.57; 95% CI: 1.02-2.40, p=0.038) and ~3-fold (OR=3.29; 95%CI: 1.02-10.56, p=0.046) higher risk of stroke compared to heterozygotes, whereas in the older group (aged >40 years) no significant association was observed. The C1818T variant was not associated with ischemic stroke. We conclude that KL-VS homozygosity could contribute to early-onset stroke in India. Larger studies in other ethnic populations are warranted to determine the role of these gene variants in the etiology of stroke occurring in the young.     

Genetic variants of soluble malate dehydrogenase in new guinea populations

Summary 10 cases of an S-MDH variant have been detected in New Guinea. 3 cases were found among 199 samples from the Fore linguistic group and 6 cases among 9 related members of a family from the Agarabi linguistic group, both groups being located in the Eastern Highlands. 1 case was found in 24 samples from the Sepik district. The new variant has been given the trivial name S-MDH New Guinea-1.     

Genetic variants associated with the white blood cell count in 13,923 subjects in the eMERGE Network

White blood cell count (WBC) is unique among identified inflammatory predictors of chronic disease in that it is routinely measured in asymptomatic patients in the course of routine patient care. We led a genome-wide association analysis to identify variants associated with WBC levels in 13,923 subjects in the electronic Medical Records and Genomics (eMERGE) Network. We identified two regions of interest that were each unique to subjects of genetically determined ancestry to the African continent (AA) or to the European continent (EA). WBC varies among different ancestry groups. Despite being ancestry specific, these regions were identifiable in the combined analysis. In AA subjects, the region surrounding the Duffy antigen/chemokine receptor gene (DARC) on 1q21 exhibited significant association (p value?=?6.71e-55). These results validate the previously reported association between WBC and of the regulatory variant rs2814778 in the promoter region, which causes the Duffy negative phenotype (Fy-/-). A second missense variant (rs12075) is responsible for the two principal antigens, Fya and Fyb of the Duffy blood group system. The two variants, consisting of four alleles, act in concert to produce five antigens and subsequent phenotypes. We were able to identify the marginal and novel interaction effects of these two variants on WBC. In the EA subjects, we identified significantly associated SNPs tagging three separate genes in the 17q21 region: (1) GSDMA, (2) MED24, and (3) PSMD3. Variants in this region have been reported to be associated with WBC, neutrophil count, and inflammatory diseases including asthma and Crohn's disease.     

Antiporter NHX2 differentially induced in Mesembryanthemum crystallinum natural genetic variant under salt stress

Plants exhibit several mechanisms to survive under high salinity conditions. The uptake and compartmentalization of Na⁺ ion by the NHX antiporter is a crucial mechanism in homeostasis maintenance. Therefore, we evaluated McNHX2 gene expression and several physiological responses induced in three natural genetic variants of ice plants under salt stress. Based on morphology and growth behavior of wild type populations from an arid region of northwestern Mexico, we identified three ice plant natural genetic variants and called P0, P9, and P11. Several physiological parameters, such as water potential, relative water content, chlorophyll, and Na⁺ and K⁺ ion contents from all natural genetic variants exhibited a differential response under high salinity conditions. Specifically, the P0 variant showed lower water potential changes and least perturbation of Na⁺/K⁺ ratio than those of the P9 and P11 variants under saline conditions, suggesting that the P0 variant is the most salt tolerant. Unexpectedly, McNHX2 expression was repressed in the P11 variant while it was upregulated in the P0 and P9 variants under saline treatments. The McNHX2 gene was sequenced showing 15 introns and 16 exons; polymorphisms were found among the cDNAs sequences from the three natural genetic variants. All these data suggest that differential responses to high salinity involve different mechanisms operating in each variant for counteracting saline stress effects.

     

Hemoglobin variant found in Koreans, Chinese, and North American Indians: alpha-2 beta-2 22 Glu Ala

Hemoglobin G Taegu, an electrophoretically slow hemoglobin variant found in four among 6700 apparently normal Korean subjects, has been shown to have a structural anomaly at position 22 of the beta-chain where an alanyl residue occurs in place of the glutamyl group normally found at that position in Hemoglobin A. The same structural anomaly initially was established by other workers in slow hemoglobin variants occurring in North American Indians and more recently has been reported in a Northern Chinese subject. The identical hemoglobins in the three ethnic groups are Hemoglobins G Coushatta, found in several Alabama-Coushatta Indians in Tex.; G Saskatoon, seen in a few descendants of Santee Indians currently living in Canada; G Hsin-Chu, in a Chinese from the northern province of Liaoning and currently living in Taiwan; and G Taegu in Koreans. It is assumed that the Chinese and Korean subjects have the same hemoglobin variant because of gene flow. No similar assumption connecting these two groups with the North American Indian subjects is considered warranted with the presently limited available information.