Identification of new variants within the two functional genes CCL3 and CCL3L encoding the CCL3 (MIP‐1α) chemokine: implications for HIV‐1 infection

The CC chemokine CCL3 is encoded by two functional genes, namely CCL3 and CCL3L, and has been identified as a key chemokine in HIV‐1 susceptibility and disease progression. The complete CCL3 and CCL3L genes and core promoters of 43 African mother–infant pairs (86 samples) and 28 Caucasian adults in South Africa were sequenced and extensively analysed for genetic variations. Africans were found to be more polymorphic in both genes with 25 single nucleotide polymorphisms (SNPs) in the CCL3 gene and 14 gene copy number single nucleotide polymorphisms (gcnSNPs) in the CCL3L gene, compared to nine CCL3 SNPs and eight CCL3L gcnSNPs in Caucasians. A total of 14 polymorphisms across the two genes were newly identified in this study, most (12/14) of which were exclusive to the African population. In addition, two indels were identified and characterized in the CCL3 and CCL3L genes of a small number of individuals. Of the numerous unique intragenic haplotypes found in the two genes, none were shared by the two population groups. A newly identified five‐SNP CCL3 haplotype (Hap‐C1) found in a high frequency in Caucasians, however, seems to be evolutionarily related to the most prevalent newly identified African seven‐SNP CCL3 haplotype (Hap‐A1). Hap‐A1 also includes an SNP in the core promoter region and previous CCL3 haplotypes that have been reported to be associated with HIV‐1 infection appear to be smaller haplotypes within Hap‐A1. We thus propose Hap‐A1 as a likely candidate for influencing levels of CCL3 production and in turn outcomes of HIV‐1 infection.     

Genotype and haplotype analysis of cell cycle genes in sporadic colorectal cancer in the Czech Republic

The Czech Republic has one of the highest incidences of colorectal cancer (CRC) in the world. To assess the role of genetic variants on the disease, we genotyped polymorphisms in the TP53 (rs17878362:A₁>A₂, rs1042522:G>C, rs12947788:C>T, and rs17884306:G>A), CDKN1A (rs1801270:C>A and rs1059234:C>T), and CDKN2A (rs3731249:G>A, rs11515:C>G, and rs3088440:C>T) genes in 614 hospital‐based CRC cases and 614 matched controls from the country. Despite the tendency toward differential distribution of variant allele frequencies for some polymorphisms, none was significantly associated with CRC risk. We observed differential distribution of major haplotypes arising from four polymorphisms in the TP53 gene between cases and controls (global P<0.0001). The two most common haplotypes, A₁GCG and A₂CCG, were present in 81% of the cases compared to 71% of the controls. In comparison to the most common haplotype (A₁GCG), the haplotype A₂CCG was associated with an increased risk (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.07–1.82), while the four other haplotypes A₁CCG (OR, 0.60; 95% CI, 0.45–0.79), A₂GCG (OR, 0.53; 95% CI, 0.35–0.81), A₁GTG (OR, 0.31; 95% CI, 0.15–0.64), and A₁GCA (OR, 0.19; 95% CI, 0.07–0.51) were associated with a decreased risk. The effect of haplotypes in the TP53 gene was similar in colon (global P<0.0001) and rectal cancers (P=0.006). No association with the disease was observed with haplotypes of the CDKN1A and CDKN2A polymorphisms. The results from this study suggest that prevalent haplotypes within the TP53 gene may modulate CRC risks in the population. Hum Mutat 0, 1–9, 2009. © 2009 Wiley‐Liss, Inc.     

Genetic Polymorphisms of LMP/TAP Gene and Hepatitis B Virus Infection Risk in the Chinese Population

Despite the availability of effective vaccines, hepatitis B virus (HBV) infection is still commonly seen worldwide. Several reports show that the human major histocompatability complex (MHC) systems were involved in the elimination of HBV via the restrictive antigen-processing pathway. We investigate whether LMP/TAP gene polymorphisms coded by MHC-II region were associated with HBV infection. A total of seven polymorphisms of LMP/TAP gene were identified by polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) assays. Three hundred fifty-six patients and 326 unrelated healthy volunteers were included in the case-control study. Of the seven polymorphisms, three of which (LMP7 codons 145, TAP1 codons 637, and TAP2 codons 651) were observed to have statistically significant association with HBV infection (P < 0.05). We analyzed the three-locus haplotype constructed with three such polymorphisms and found that the frequency of haplotypes D and E increased significantly in patients, in comparison with that in controls (OR = 3.57, 95% CI: 2.09–6.12, P < 0.001; OR = 2.74, 95% CI: 1.35–5.56, P = 0.005, respectively). The results imply that LMP7-145, TAP1-637, and TAP2-651 sites were associated with the risk of HBV infection. Haplotypes D and E might be involved in the development of HBV infection. These data suggest a potential role of LMP/TAP gene as a candidate gene for susceptibility to HBV infection.     

Cladistic Analysis of Human Apolipoprotein A4 Polymorphisms in Relation to Quantitative Plasma Lipid Risk Factors of Coronary Heart Disease

Genetic variation in several genes involved in lipid metabolism is known to affect population variation in quantitative lipid risk factor profiles for coronary heart disease (CHD). The apolipoprotein A‐IV gene (APOA4) is one such candidate gene. We genotyped five polymorphisms in the APOA4 gene (codon 127, codon 130, codon347, codon 360 and 3’ VNTR) and investigated their impact on plasma lipid trait levels in three populations comprising 604 U.S. non‐Hispanic Whites (NHWs), 408 U.S. Hispanics and 708 Nigerian Blacks. Cladistic analysis was carried out to identify 5‐site haplotypes that were associated with significant phenotypic differences in each population. The distribution of APOA4 genotypes was significantly different between ethnic groups. The Africans were monomorphic for two of the five sites (codons 130 and 360), but possess a unique 12 bp insertion that was not observed in NHWs and Hispanics. Due to linkage disequilibrium between the sites, only 6 haplotypes were observed in NHWs and Hispanics, and 4 in Africans. Several gender‐and ethnic‐specific associations between genotypes and plasma lipid traits were observed when single sites were used. Several haplotypes were identified by cladistic analysis that may carry functional mutations that affect plasma lipid trait levels.     

Association of Single Nucleotide Polymorphisms in the IL27 Gene with Rheumatoid Arthritis

Rheumatoid arthritis (RA) is one of the autoimmune diseases, where different polymorphisms in cytokine genes play a pathogenic role. Interleukin 27 (IL‐27) is a novel pro‐/anti‐inflammatory cytokine, an excellent candidate for chronic inflammatory disease studies. The aim of the study was to identify polymorphisms in the IL‐27 gene and their possible association with susceptibility to and severity of RA. Two hundred and seventy‐four patients with RA and of 295 healthy individuals were examined for ?924A/G and 4730T/C IL27 gene polymorphisms using PCR‐RFLP method and TaqMan SNP genotyping assay, respectively. Haplotype frequencies of IL‐27 polymorphisms were estimated using SHEsis platform. Frequencies of the ?924GG genotype and the ?924G allele were statistically higher in RA patients comparing with the healthy control group (P = 0.008 and P = 0.004, respectively). Overall, strong LD was observed between the IL27 gene ?924A/G and 4730 T/C polymorphisms (D′ = 0.613, r2 = 0.199). From four possible haplotypes, frequencies of two (CA and CG) showed significant differences between both examined groups (respectively: P < 0.001 and P = 0.001062). The genotype–phenotype analysis showed significant association between the IL‐27 4730 T/C polymorphism and HAQ score and means value of the ESR, additionally they revealed that individuals with the polymorphic allele ?924G had more advanced disease than wild‐type allele carriers. Present findings indicated that IL27 ?924A/G polymorphism may be involved in susceptibility to RA in the Polish population.     

Family‐based genetic association study of DLGAP3 in Tourette Syndrome

Tourette syndrome (TS) is a childhood‐onset neuropsychiatric disorder that is familial and highly heritable. Although genetic influences are thought to play a significant role in the development of TS, no definite TS susceptibility genes have been identified to date. TS is believed to be genetically related to both obsessive‐compulsive disorder (OCD) and grooming disorders (GD) such as trichotillomania (TTM). SAP90/PSD95‐associated protein 3 (SAPAP3/DLGAP3) is a post‐synaptic scaffolding protein that is highly expressed in glutamatergic synapses in the striatum and has recently been investigated as a candidate gene in both OCD and GD studies. Given the shared familial relationship between TS, OCD and TTM, DLGAP3 was evaluated as a candidate TS susceptibility gene. In a family‐based sample of 289 TS trios, 22 common single nucleotide polymorphisms (SNPs) in the DLGAP3 region were analyzed. Nominally significant associations were identified between TS and rs11264126 and two haplotypes containing rs11264126 and rs12141243. Secondary analyses demonstrated that these results cannot be explained by the presence of comorbid OCD or TTM in the sample. Although none of these results remained significant after correction for multiple hypothesis testing, DLGAP3 remains a promising candidate gene for TS. © 2010 Wiley‐Liss, Inc.     

Differentiation of Caucasians and Chinese at Bone Mass Candidate Genes: Implication for Ethnic Difference of Bone Mass

Bone mineral density (BMD) is an important risk factor for osteoporosis and has strong genetic determination. While average BMD differs among major ethnic groups, several important candidate genes have been shown to underlie BMD variation within populations of the same ethnicity. To investigate whether important candidate genes may contribute to ethnic differences in BMD, we studied the degree of genetic differentiation among several important candidate genes between two major ethnic groups: Caucasians and Chinese. The genetic variability of these two populations (1131 randomly selected individuals) was studied at six restriction sites exhibiting polymorphisms of five important candidate genes for BMD: the BsaHI polymorphism of the calcium‐sensing receptor (CASR) gene, the SacI polymorphism of the α₂HS‐glycoprotein (AHSG) gene, the PvuII and XbaI polymorphisms of the estrogen receptor α (ESR1) gene, the ApaI polymorphism of the vitamin D receptor (VDR) gene, and the BstBI polymorphism of the parathyroid hormone (PTH) gene. The two ethnic groups showed significant allelic and genotypic differentiation of all the polymorphisms studied. The mean F_ST was 0.103, which significantly differed from zero (P < 0.01) . The Chinese population had lower mean heterozygosity (0.331) than the Caucasian one (0.444); the CASR‐BsaHI and PTH‐BstBI polymorphisms contributed most significantly to this difference. Analysis of the intra‐ and inter‐population variability suggests that various types of natural selection may affect the observed patterns of variation at some loci. If some of the candidate genes we studied indeed underlie variation in BMD, their population differentiation revealed here between ethnic groups may contribute to understanding ethnic difference in BMD.     

Heterogeneity of vitamin D receptor gene association with celiac disease and type 1 diabetes mellitus

Objective: Vitamin D has been shown to exert multiple immunomodulatory effects and is known to suppress T-cell activation by binding to the vitamin D receptor (VDR). To determine whether VDR gene polymorphisms are related to the susceptibility to celiac disease, we investigated its implication as a candidate gene in the Basque population. Because celiac disease and type 1 diabetes share common susceptibility loci, we also analyzed families with type 1 diabetes mellitus.

Methods: A total of 37 families with celiac disease and 64 type 1 diabetic families of Basque origin with at least one affected offspring were genotyped for four VDR restriction-site polymorphisms (Fok I, Bsm I, Apa I and Taq I). The AFBAC approach was used to test for association.

Results: Comparison of VDR genotypes of the patients with those of 88 healthy individuals identified “ff” as a risk genotype for celiac disease [p = 0.01; OR = 3.45 (1.12–10.79)]. On the other hand, a significantly higher frequency of haplotype “fBAt” was observed in the type 1 diabetic group [p_c = 0.02; OR = 4.4 (1.5–15.3)].

Conclusion: Our findings suggest that polymorphisms within the vitamin D receptor gene are markers of susceptibility to or protection from autoimmune diseases, although, at least in the Basque population, association of VDR variants with celiac disease and type 1 diabetes seems to be heterogeneous.     

Lack of association of histamine-N-methyltransferase (HNMT) polymorphisms with asthma in the Indian population

Histamine plays a major role in allergic disorders, including asthma. A major pathway of histamine biotransformation in the lungs is mediated by histamine N-methyltransferase (HNMT). We investigated the association of a functional SNP C314T; a SNP A929G, a (CA)_n repeat in intron 5, and a novel (CA)_n repeat (BV677277), 7.5 kb downstream of the HNMT gene with asthma and its associated traits such as total serum IgE levels in a case-control as well as in a family-based study design. In contrast to a previous study, no association was observed for the polymorphisms investigated with asthma (P>0.05). When haplotypes were constructed for these loci and compared, no significant difference was observed in the distribution between cases and controls. In the family-based design, no biased transmission was observed for any of the polymorphisms and haplotypes with asthma using the additive model of inheritance in family-based association test (FBAT). Thus, consistent with the case-control findings, the polymorphisms and haplotypes in the HNMT gene are not associated with asthma in the Indian population.Accession No.: BV677277     

HAVCR1 Gene Haplotypes and Infection by Different Viral Hepatitis C Virus Genotypes

The hepatitis A virus cellular receptor 1 (HAVCR1) gene is highly polymorphic, and several variants have been associated with susceptibility to allergic and autoimmune diseases. The HAVCR1 gene region was identified as a candidate for hepatitis C virus (HCV) natural clearance in a genotyping study of selected immune response genes in both European-American and African-American populations. The aim of the present study was to explore the influence of HAVCR1 in the outcome of HCV infection in the Spanish population. Three cohorts, consisting of 354 subjects with persistent HCV infection (285 with persistent HCV monoinfection and 69 with natural clearance), 182 coinfected HIV/HCV patients, and 320 controls, were included. Samples were genotyped in several polymorphic positions, insertion/deletion variants in exon 4 and tag single nucleotide polymorphisms (SNPs), in order to define previously described HAVCR1 haplotypes (haplotypes A to D). No statistically significant differences were observed with spontaneous resolution of infection or with viral clearance after treatment. Nevertheless, different rates of infection by viral genotypes (G''s) were observed among the HAVCR1 haplotypes. Individuals bearing haplotype C had the highest viral G1 infection rate when compared to individuals bearing other haplotypes (75.82% versus 57.72%, respectively; corrected P value [P_c], 3.2 × 10⁻⁴; odds ratio [OR], 2.30; 95% confidence interval [CI], 1.51 to 3.47). Thus, HAVCR1 could be involved in susceptibility or resistance to infection by a particular HCV genotype.     

Linkage of congenital isolated adrenocorticotropic hormone deficiency to the corticotropin releasing hormone locus using simple sequence repeat polymorphisms

Genetic screening techniques using simple sequence repeat polymorphisms were applied to investigate the molecular nature of congenital isolated adrenocorticotropic hormone (ACTH) deficiency. We hypothesize that this rare cause of hypocortisolism shared by a brother and sister with two unaffected sibs and unaffected parents is inherited as an autosomal recessive single gene mutation. Genes involved in the hypothalamic-pituitary axis controlling cortisol sufficiency were investigated for a causal role in this disorder. Southern blotting showed no detectable mutations of the gene encoding pro-opiomelanocortin (POMC), the ACTH precursor. Other candidate genes subsequently considered were those encoding neuroendocrine convertase-1, and neuroendocrine convertase-2 (NEC-1, NEC-2), and corticotropin releasing hormone (CRH). Tests for linkage were performed using polymorphic di- and tetranucleotide simple sequence repeat markers flanking the reported map locations for POMC, NEC-1, NEC-2, and CRH. The chromosomal haplotypes determined by the markers flanking the loci for POMC, NEC-1, and NEC-2 were not compatible with linkage. However, 22 individual markers defining the chromosomal haplotypes flanking CRH were compatible with linkage of the disorder to the immediate area of this gene on chromosome 8. Based on these data, we hypothesize that the ACTH deficiency in this family is due to an abnormality of CRH gene structure or expression. These results illustrate the useful application of high density genetic maps constructed with simple sequence repeat markers for inclusion/exclusion studies of candidate genes in even very small nuclear families segregating for unusual phenotypes. © 1996 Wiley-Liss, Inc.     

Transmission disequilibrium studies of the serotonin 5‐HT2A receptor gene (HTR2A) in autism

Hyperserotonemia in autism is one of the longest‐standing biochemical findings in a psychiatric disorder. This well‐replicated finding and subsequent studies of platelet serotonin receptors in autism indicate that the serotonin 2A receptor gene (HTR2A) on chromosome 13q is a primary candidate gene in autism. Converging data from recent genome screens also implicates the genomic region containing HTR2A. Based on these lines of evidence, the transmission/disequilibrium test (TDT) was used to assess transmission disequilibrium between autism and haplotypes of three polymorphisms, including the promoter ‐1438 G/A single nucleotide polymorphism (SNP) in perfect linkage disequilibrium with the 102 T/C SNP in previous studies, a newly identified SNP in intron 1 near exon 2, and the SNP responsible for the His452Tyr amino acid change in exon 3. Because expression studies have shown HTR2A to be polymorphically imprinted in the brain, secondary analyses were split into maternal and paternal transmissions. No evidence was found for unequal transmission of haplotypes; however, power analysis reveals low power to detect a parent‐of‐origin effect in this sample size. © 2002 Wiley‐Liss, Inc.     

Identification of sequence polymorphisms of the COMP (cartilage oligomeric matrix protein) gene and association study in osteoarthrosis of the knee and hip joints

Osteoarthrosis (OA) is a common cause of musculoskeletal disability characterized by late-onset degeneration of articular cartilage. Although several candidate genes have been reported, susceptibility genes for OA remain to be determined. Hereditary osteochondral dysplasias produce severe, early-onset OA and hence are models for common idiopathic OA. Among them are pseudoachondroplasia and multiple epiphyseal dysplasia, both of which are caused by mutations in the cartilage oligomeric matrix protein (COMP) gene. Therefore, COMP may be a susceptibility gene for OA. We screened for polymorphisms by direct sequencing of all exons of the COMP gene with their flanking intron sequences and the promoter region. We identified 16 polymorphisms, of which 12 were novel. Using six polymorphisms spanning the entire COMP gene, we examined the association of COMP in Japanese patients with OA of the knee and hip joints. Genotype and allele frequencies of the polymorphisms were not significantly different between OA and control groups, and there was no significant difference in haplotypes. These results do not support an association between COMP and OA in the Japanese population. Received: March 30, 2001 / Accepted: May 7, 2001     

Allelic association analysis of the dopamine D2, D3, 5‐HT2A,and GABAAγ2 receptors and serotonin transporter genes with heroin abuse in Chinese subjects

Five candidate genes, the receptors DRD2, DRD3, HTR2A and GABA_Aγ2, and the serotonin transporter (5‐HTT) were analyzed for association with heroin abuse. We examined three polymorphisms (promoter ? 141ΔC, Ser311Cys, and TaqI) in the DRD2 gene, one polymorphism (Ser9Gly) in the DRD3 gene, two polymorphisms (promoter ? 1438G/A and T102C) in the HTR2A gene, two polymorphisms (VNTR and Del/Ins) in 5‐HTT gene, and one polymorphism (G3145A) in GABA_Aγ2 gene in 121 Chinese heroin addicts and 194 controls. None of the polymorphisms differed significantly for allele, genotype, or haplotype frequencies, except for the DRD2 promoter polymorphism ? 141ΔC (genotype‐wise and allele‐wise, P = 0.05, uncorrected). An additional 344 subjects with heroin abuse and 104 controls were investigated for the ? 141ΔC polymorphism. In the second sample, there were no significant difference of genotype or allele frequencies between subjects with heroin abuse and normal controls. When we divided the sample by route of administration into nasal inhalers and IM or IV injectors, however, it produced a significant difference between inhalers of heroin and controls (genotype‐wise, P = 0.006, allele‐wise, P = 0.016) but not for injectors of heroin (genotype‐wise, P = 0.81, allele‐wise, P = 0.69). We also found that LD between all polymorphisms we examined in the gene was weak, possibly explaining why we see association of this polymorphism with heroin abuse but not with other markers in the gene. Overall our results indicates that the HTR2A, 5‐HTT, DRD3 and GABA_Aγ2 genes are not likely to be a major genetic risk factor for heroin abuse in this population, with the exception of possible association between nasal inhalation and DRD2 promoter ? 141ΔC polymorphism. © 2002 Wiley‐Liss, Inc.     

Associations Between G/A1229, A/G3944, T/C30875, C/T48200 and C/T65013 Genotypes and Haplotypes in the Vitamin D Receptor Gene, Ultraviolet Radiation and Susceptibility to Prostate Cancer

Ultraviolet radiation (UVR) may protect against prostate cancer via a mechanism involving vitamin D. Thus, the vitamin D receptor (VDR) gene is a susceptibility candidate, though published data are discrepant. We studied the association of prostate cancer risk with five VDR single nucleotide polymorphisms (SNPs): G/A¹²²⁹ (SNP 1), A/G³⁹⁴⁴ (SNP 2), T/C³⁰⁸⁷⁵ (SNP 3), C/T⁴⁸²⁰⁰ (SNP 4) and C/T⁶⁵⁰¹³ (SNP 5), in 430 cancer and 310 benign prostatic hypertrophy (BPH) patients. The SNP 2 GG genotype frequency was lower in cancer than BPH patients (odds ratio = 0.63, 95% CI = 0.41–0.98, p = 0.039). SNPs 1 and 2, and SNPs 4 and 5, were in linkage disequilibrium. Two copies of haplotypes comprising SNPs 1‐2, G‐G (odds ratio = 0.63, p = 0.039), SNPs 2‐3 G‐C (odds ratio = 0.45, p = 0.008) and SNPs 1‐2‐3 G‐G‐C (odds ratio = 0.44, p = 0.006), but not SNPs 1‐3, G‐C (odds ratio = 0.81, p = 0.34), were associated with reduced risk (reference, no copies of the haplotypes) . These associations were observed after stratification of subjects by extent of UVR exposure. These data show that SNP 2 GG genotype mediates prostate cancer risk, complementing studies reporting this allele is protective in malignant melanoma pathogenesis. They further suggest that published associations of risk with SNP 1 may result from linkage disequilibrium with SNP 2.     

Sequence variation at the human ABO locus

The ABO blood group is the most important blood group system in transfusion medicine. Since the ABO gene was cloned and the molecular basis of the three major alleles delineated about 10 years ago, the gene has increasingly been examined by a variety of DNA‐based genotyping methods and analysed in detail by DNA sequencing. A few coherent observations emerge from these studies. First, there is extensive sequence heterogeneity underlying the major ABO alleles that produce normal blood groups A, B, AB and O when in correct combination with other alleles. Second, there is also extensive heterogeneity underlying the molecular basis of various alleles producing ABO subgroups such as A₂, A_x and B₃. There are over 70 ABO alleles reported to date and these alleles highlight the extensive sequence variation in the coding region of the gene. A unifying system of nomenclature is proposed to name these alleles. Third, extensive sequence variation is also found in the non‐coding region of the gene, including variation in minisatellite repeats in the 5′ untranslated region (UTR), 21 single nucleotide polymorphisms (SNPs) in intron 6 and one SNP in the 3′ UTR. The haplotypes of these variations reveal a specific relationship with the major ABO alleles. Fourth, excluding the common alleles, about half of the remaining alleles are due to new mutations and the other half can better be explained by intragenic recombination (both crossover and gene conversion) between common alleles. In particular, the recombination sites in hybrid alleles can be quite precisely defined through haplotype analysis of the SNPs in intron 6. This indicates that recombination is equally as important as point mutations in generating the genetic diversity of the ABO locus. Finally, a large number of ABO genotyping methods are available and are based on restriction analysis, allele specific amplification, mutation screening techniques or their combinations.     

A novel (TG) n (GA) m repeat polymorphism 254 bp downstream of the mast cell chymase (CMA1) gene is associated with atopic asthma and total serum IgE levels

The gene for mast cell chymase (CMA1) is an ideal candidate for investigating genetic predisposition to atopic asthma, as it is an important mediator of inflammation and remodeling in the asthmatic lung. Various studies have examined the association between –1903 G/A polymorphism and allergic phenotypes, but inconsistent results have been obtained. We investigated the association of this SNP and a novel (TG)_n(GA)_m repeat polymorphism (accession no. BV210164) 254 bp downstream of the gene with asthma and its associated traits in a case-control study in two independent cohorts recruited from the Indian population. A significant association was observed for the (TG)_n(GA)_m repeat with asthma (p<0.05) in both the cohorts. Although no association was observed for the –1903 G/A SNP with asthma, a significant association was observed between the genotypes and serum IgE levels (p=0.003 and 0.0004 for cohort A and B). When haplotypes were compared between patients and controls, the haplotype G_43 was found at higher frequency in controls (p=0.05). Also, on comparing major haplotypes (>5%) with respect to log total serum IgE levels, a significant difference was obtained (p=0.018 and p=0.046 for cohorts A and B). These results suggest that the CMA1 gene contributes to asthma susceptibility and may be involved in regulating IgE levels in atopic asthma.     

Association of haplotypes of interleukin-10 gene with the risk of cancer

Polymorphisms of promotor region of IL-8, IL-10, and IL-12 genes were analyzed in cancer patients and subjects without history of cancer. The distribution of alleles of the analyzed polymorphisms in the control group coincided with that in other Caucasian populations. The incidences of three IL-10 gene polymorphisms (G-1082A, C-819T, and C-592A) significantly differed in controls and patients. Of 8 theoretically probable IL-10 gene haplotypes determined by these polymorphisms, 3 variants were revealed. Haplotype ACC was more incident in cancer patients, while ATA haplotype was rarer. The results are in line with the findings of other studies indicating the involvement of the immune system genes in the pathogenesis of cancer. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Supplement 2, pp. 8–12, April, 2007     

Genetic relationship between the 3'-VNTR and diallelic apolipoprotein B gene polymorphisms: Haplotype analysis in individuals of European and South Asian origin

The genetic relationship amongst apolipoprotein B (apo B) gene polymorphisms (signal peptide insertion/deletion (Leu-Ala-Leu_-16/-14), XbaI (Thr₂₄₈₈), EcoRI (Glu₄₁₅₄→ Lys), Asn₄₃₁₁→ Ser, 3′ -VNTR) has been investigated in samples of South Asian (Indian) and Swedish individuals. The frequency distribution of alleles at all these sites was found to be significantly different between the South Asian and the Swedish samples (deletion allele: 0·20 v. 0·31, X + (presence of XbaI cutting site): 0·29 v. 0·55, R- (absence of EcoRI cutting site): 0·11 v. 0·19, Ser₄₃₁₁: 0·45 v. 0·19). The distribution of allele frequencies at the VNTR site was bimodal in both populations. However, in South Asians, the most common allele was a 35 repeat unit allele, whilst in the Swedish sample, and in all other reports from Caucasian samples the 37 repeat unit allele was the most frequent (South Asian v. Swedish: 35 allele: 0·36 v. 0·19, 37 allele: 0·25 v. 0·48). Furthermore, four new alleles at the apo B gene 3′ -VNTR site (15, 17, 32, 38 repeat unit alleles) were observed in South Asians, of which two (15 and 17 repeat unit alleles) were well outside the bimodal distribution. In both samples, strong linkage disequilibrium and allelic association were detected between alleles at the 3′ -VNTR and each of the other sites, and also between the ins/del and XbaI sites and between the XbaI and Asn₄₃₁₁→ Ser sites. The same five common haplotypes as defined by ins/del, XbaI, EcoRI and Asn₄₃₁₁→ Ser were found to be present in both samples comprising 97 and 99 % of the haplotypes observed in the South Asian and Swedish samples respectively. Detailed analysis revealed the predominant occurrence of certain 3′ -VNTR alleles on specific haplotypes and demonstrates the usefulness of the VNTR site for haplotyping and representative association studies. A model for the evolutionary relationship of the major haplotypes including the 3′ -VNTR site is presented. These findings support a mechanism of replication slippage as a major factor for the generation of new alleles at the apo B 3′ -VNTR locus rather than unequal crossing over.     

Physical map of the region containing the gene for Batten disease (CLN3)

CLN3 has been mapped genetically to 16p12, to the interval between D16S288 and D16S383, a sex-averaged genetic distance of 2.1 cM. Analysis of disease haplotypes for four microsatellite markers in this interval, D16S288, D16S299, D16S298, and SPN, has shown significant allelic association between one allele at each of these loci and CLN3. All four of the associated markers were used as nucleation sites in the isolation of genomic clones (YACs). A contig was assembled which contains 3 of the 4 associated markers and which confirmed the relative order of these markers. Marker D16S272 has been located on the physical map between D16S288 and D16S299. Restriction mapping has demonstrated the location of possible CpG islands. One gene, STP, has been localised on the YAC contig proximal to D16S298 and is therefore a candidate for CLN3. Other genes, including IL4R, SGLT2, and UQCRC2, have been excluded from this region. © 1995 Wiley-Liss, Inc.