Frequency In Different Ethnic Groups Research Articles

POLYMORPHISM OF VITAMIN D RECEPTOR (VDR) GENE IN SAMPLING OF EUROPEAN RUSSIA AND PRIURALIYE POPULATION

Aim. To assess the genotype frequencies of VDR BsmI (rs1544410) and FokI (rs10735810) in ethnic Russian population and in different groups of the population of Volgo-Kamsky region and Priuraliye. Materials and methods. Samplings of Russians of the European part of RF ( n = 96) and Eastern Finns including Komi-Permyaks ( n = 71), Komis ( n = 190) and Udmurts ( n = 86) were examined. Genotype frequencies were determined using the method of PCR-amplification. Results. Russians differ for the inhabitants of Moscow (without taking into account ethnic origin) by the distribution of VDR FokI ( p = 0,09001), but not BsmI. Eastern Finns in the regions of their historical residence do not differ by VDR FokI and BsmI, but they differ from Russians by BsmI frequencies ( p = 0,0856). Conclusions. The obtained results agree with the assumption about the specificity of VDR allel frequencies in different ethnic groups.

Dopamine D3 receptor Ser9Gly variant is associated with impulse control disorders in Parkinson’s disease patients

IntroductionImpulse control disorders (ICD) are reported to occur at variable frequencies in different ethnic groups. Genetic vulnerability is suspected to underlie the individual risk for ICD. We investigated whether the allelic variants of dopamine (DRD3), glutamate (GRIN2B) and serotonin (HTR2A) receptors are linked to ICD in Indian Parkinson’s disease (PD) patients. MethodsWe conducted a prospective, case-control study which included PD patients (70 with ICD, 100 without ICD categorized after direct psychiatric interview of patient and caregiver) and 285 healthy controls. Single nucleotide polymorphism (SNP) variants of DRD3 p.S9G (rs6280), GRIN2B c.2664C>T (rs1806201) and HTR2A c.102T>C (rs6313) were genotyped. ResultsMultivariate regression analysis revealed that DRD3 p.Ser9Gly (rs6280) heterozygous variant CT (OR = 2.22, 95% CI: 1.03–4.86, p = 0.041), higher daily Levodopa equivalent doses (LED) of drugs (for 100 mg LED, OR = 1.14, 95% CI: 1.01–1.29, p = 0.041), current dopamine agonist but not Levodopa use (OR = 2.16, 95% CI: 1.03–4.55, p = 0.042) and age of onset of motor symptoms under 50 years (OR 2.09, 95% CI: 1.05–4.18, p = 0.035) were independently associated with ICD. ConclusionDRD3 p.Ser9Gly (rs6280) CT genotype is associated with ICD in Indian PD patients and this association is novel. Enhanced D3 receptor affinity due to gain-of-function conferred by the glycine residues could impair reward-risk assessment in the mesolimbic system and contribute to development of impulsive behaviour, in carriers of this genotype.

Comparison of high-resolution human leukocyte antigen haplotype frequencies in different ethnic groups: Consequences of sampling fluctuation and haplotype frequency distribution tail truncation

High-resolution haplotype frequency estimations and descriptive metrics are becoming increasingly popular for accurately describing human leukocyte antigen diversity. In this study, we compared sample sets of publically available haplotype frequencies from different populations to characterize the consequences of unequal sample size on haplotype frequency estimation. We found that for low samples sizes (a few thousand), haplotype frequencies were overestimated, affecting all descriptive metrics of the underlying distribution, such as most frequent haplotype, the number of haplotypes, and the mean/median frequency. This overestimation was a result of random sample fluctuation and truncation of the tail end of the frequency distribution that comprises the least frequent haplotypes. Finally, we simulated balanced datasets through resampling and contrasted the disparities of descriptive metrics among equal and unequal datasets. This simulation resulted in the global description of the most frequent human leukocyte antigen haplotypes worldwide.

Polymorphic Cytochrome P450 Enzymes (CYPs) and Their Role in Personalized Therapy

The cytochrome P450 (CYP) enzymes are major players in drug metabolism. More than 2,000 mutations have been described, and certain single nucleotide polymorphisms (SNPs) have been shown to have a large impact on CYP activity. Therefore, CYPs play an important role in inter-individual drug response and their genetic variability should be factored into personalized medicine. To identify the most relevant polymorphisms in human CYPs, a text mining approach was used. We investigated their frequencies in different ethnic groups, the number of drugs that are metabolized by each CYP, the impact of CYP SNPs, as well as CYP expression patterns in different tissues. The most important polymorphic CYPs were found to be 1A2, 2D6, 2C9 and 2C19. Thirty-four common allele variants in Caucasians led to altered enzyme activity. To compare the relevant Caucasian SNPs with those of other ethnicities a search in 1,000 individual genomes was undertaken. We found 199 non-synonymous SNPs with frequencies over one percent in the 1,000 genomes, many of them not described so far. With knowledge of frequent mutations and their impact on CYP activities, it may be possible to predict patient response to certain drugs, as well as adverse side effects. With improved availability of genotyping, our data may provide a resource for an understanding of the effects of specific SNPs in CYPs, enabling the selection of a more personalized treatment regimen.

Identifying improved TSPO PET imaging probes through biomathematics: The impact of multiple TSPO binding sites in vivo

To date, 11C-(R)-PK11195 has been the most widely used TSPO PET imaging probe, although it suffers from high non-specific binding and low signal to noise. A significant number of 2nd generation TSPO radioligands have been developed with higher affinity and/or lower non-specific binding, however there is substantial inter-subject variation in their affinity for the TSPO. TSPO from human tissue samples binds 2nd generation TSPO radioligands with either high affinity (high affinity binders, HABs), or low affinity (LABs) or expresses both HAB and LAB binding sites (mixed affinity binders, MABs). The expression of these different TSPO binding sites in human is encoded by the rs6971 polymorphism in the TSPO gene. Here, we use a predictive biomathematical model to estimate the in vivo performances of three of these 2nd generation radioligands (18F-PBR111, 11C-PBR28, 11C-DPA713) and 11C-(R)-PK11195 in humans. The biomathematical model only relies on in silico, in vitro and genetic data (polymorphism frequencies in different ethnic groups) to predict the radioactivity time course in vivo. In particular, we provide estimates of the performances of these ligands in within-subject (e.g. longitudinal studies) and between-subject (e.g. disease characterisation) PET studies, with and without knowledge of the TSPO binding class. This enables an assessment of the different radioligands prior to radiolabelling or acquisition of any in vivo data.The within-subject performance was characterised in terms of the reproducibility of the in vivo binding potential (%COV[BPND]) for each separate TSPO binding class in normal and diseased states (50% to 400% increase in TSPO density), whilst the between-subject performance was characterised in terms of the number of subjects required to distinguish between different populations.The results indicated that the within-subject variability for 18F-PBR111, 11C-PBR28 and 11C-DPA713 (0.9% to 2.2%) was significantly lower than 11C-(R)-PK11195 (16% to 36%) for HABs and MABs in both normal and diseased states. For between-subject studies, sample sizes required to detect 50% differences in TSPO density with the 2nd generation tracers are approximately half that required with 11C-(R)-PK11195 when binding class information is known a priori. As binding class can be identified using a simple genetic test or from peripheral blood assays, the combination of binding class information with 2nd generation TSPO imaging data should provide superior tools to investigate inflammatory processes in humans in vivo.

Estimation of carrier frequencies of six autosomal-recessive Mendelian disorders in the Korean population

Although many studies have been performed to identify mutations in Korean patients with various autosomal-recessive Mendelian disorders (AR-MDs), little is known about the carrier frequencies of AR-MDs in the Korean population. Twenty common mutations from six AR-MDs, including Wilson disease (WD), non-syndromic hearing loss (NSHL), glycogen storage disease type Ia (GSD Ia), phenylketonuria (PKU), congenital hypothyroidism (CH), and congenital lipoid adrenal hyperplasia (CLAH) were selected to screen for based on previous studies. A total of 3057 Koreans were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry followed by confirmation using the Sanger sequencing. We found 201 and 8 carriers with either one or two mutations in different genes, respectively, yielding a total carrier frequency of 1 in 15 (6.7%). Of the six AR-MDs, NSHL has the highest carrier frequency followed by WD, CH, CLAH, GSD Ia, and PKU. As carrier screening tests are becoming prevalent and the number of mutations known and tested is rising, a priori data on the carrier frequencies in different ethnic groups is mandatory to plan a population screening program and to estimate its efficiency. In light of this, the present results can be used as a basis to establish a screening policy for common AR-MRs in the Korean population.

Pharmacogenetics of HMG-CoA Reductase Inhibitors: Optimizing the Prevention of Coronary Heart Disease

The statins are the most important group of drugs for lipid-lowering therapy in the prevention of coronary heart disease. Greater reductions in LDL-cholesterol appear to be associated with greater benefits but the clinical efficacy and safety of statin treatment varies considerably from person to person because of a combination of phenotypic and genotypic factors. Pharmacogenetic studies have investigated the relationship between common genetic variants and the lipid responses to statin therapy and adverse events, and some candidate genes related to the pharmacodynamics and pharmacokinetics of different statins have been identified. Some of these genetic variants show a different frequency in different ethnic groups. This field of pharmacogenetic research is receiving considerable attention and many new findings have been reported recently. Pharmacogenetic and pharmacogenomic studies of statin therapy are likely to provide a bet- ter understanding of the effects of these drugs and to help with prediction of the most appropriate drug and dosage for each individual and whether the addition or substitution of other lipid modifying drugs may be necessary to achieve the most safe and effective prevention of coronary heart disease.

Paraoxonase Gene Polymorphism in South-western Korean Population

Paraoxonase (PON) has anti-atherogenic activity. Considering the important role of polymorphism in the genetic susceptibility to cardiovascular disease and the variability of its allele frequencies in different ethnic groups, the distribution of genotypes and allele frequencies of PON1M55L, PON1Q192R, PON2A148G, and PON2S311C polymorphisms was analyzed in a total 988 South-western Koreans and determined their effects on lipid parameters. The genotype distribution of PON1 at position 55 was LL=0.886, LM=0.114; and at position 192 was QQ=0.406, QR=0.594. The frequencies of the PON1 55L allele and the PON1 192R allele were similar to those seen in Chinese populations and Western populations, respectively. The genetic distribution of PON2 at position 148 was AA=0.619, AG=0.345, GG=0.035; and at position 311 was CC=0.035, SC=0.345, SS=0.619. The frequencies of the PON2 148G and 311S alleles were similar to those seen in Chinese populations. The concentrations of LDL and ApoB were significantly different between the PON2A148G (P<0.05) and PON2 S311C polymorphisms (P<0.01). PON polymorphisms and allele frequencies were described in Koreans living south-western part of Korea. These ethnic variations are considered important in the interpretation of diseases associated with PON polymorphisms.

The frequency of transforming growth factor‐β1 gene polymorphisms in a normal southern Iranian population

Several single nucleotide polymorphisms (SNPs) of the transforming growth factor-beta1 gene (TGFB1) have been reported. Determination of TGFB1 SNPs allele frequencies in different ethnic groups is useful for both population genetic analyses and association studies with immunological diseases. In this study, five SNPs of TGFB1 were determined in 325 individuals from a normal southern Iranian population using polymerase chain reaction-restriction fragment length polymorphism method. This population was in Hardy-Weinberg equilibrium for these SNPs. Of the 12 constructed haplotypes, GTCGC and GCTGC were the most frequent in the normal southern Iranian population. Comparison of genotype and allele frequencies of TGFB SNPs between Iranian and other populations (meta-analysis) showed significant differences, and in this case the southern Iranian population seems genetically similar to Caucasoid populations. However, neighbour-joining tree using Nei's genetic distances based on TGF-beta1 allele frequencies showed that southern Iranians are genetically far from people from the USA, Germany, UK, Denmark and the Czech Republic. In conclusion, this is the first report of the distribution of TGFB1 SNPs in an Iranian population and the results of this investigation may provide useful information for both population genetic and disease studies.

The NAD(P)H:Quinone Oxidoreductase (NQO1) C609T Polymorphism Is Found at Variable Frequency in Different Ethnic Groups but Does Not Predispose to De Novo AML in Israel.

Background: The NQO1 gene is located on chromosome 16q22.1. This gene encodes a cytosolic enzyme which is expressed in many tissues including the hematopoietic system. NQO1 has an important role in detoxifying quinones, which are widespread compounds that are present thoughout the body (vitamin K), the diet (proteins, fruits and vegetables) and the environment (solvents, cosmetics, cigarette smoke). A single nucleotide polymorphism (C to T) at position 609 (NQO1*2) produces a proline to serine substitution at codon 187 and results in very reduced enzyme activity (null allele). Wild type genotype individuals have normal NQO1 activity, heterozygotes have reduced activity and homozygotes for the mutation have nearly absent activity. The polymorphism is present at varying frequencies in different ethnic groups throughout the world. Several reports have shown an association of this polymorphism and susceptibility to nonhematological malignancies such as lung cancer in smokers. Other reports have found that it is associated with de novo adult AML, therapy-related AML, infant leukemia with MLL rearrangements and benzene-induced hematotoxicity/leukemia.Aims: To determine the frequency of the NQO1*2 allele in Israeli ethnic groups and to determine if the allele predisposes to de novo adult AML in Israeli patients.Methods: We used PCR to analyze for the presence of the NQO1*2 allele, utilizing the methodology of MT Smith (Blood 2001) with nested PCR and digestion with Hinf1. We studied adult AML patients of different ethnic origins (156 Jews and 106 Arabs) and normal controls of three major ethnic groups in Israel (270 Caucasian Jews, 250 Arabs and 168 Ethiopian Jews). Too few Ethiopian adult AML patients were identified to be included in the analysis.Results: In the control Arab group, the distribution of the alleles was: homozygous normal (CC) 54%, heterozygotes (CT) 38.5%, and homozygous mutant (TT) 7.5%, which was virtually identical to the distribution in Arab AML patients (CC 52.8%, CT 41.5% and TT 5.7%). Similarly, the distribution in Caucasian Jewish controls was: CC 60.8%, CT 37.2%, and TT 2%, virtually identical to CC 61.1%, CT 35% and TT 3.9% in Caucasian AML patients. Ethiopian controls had a very different allelic distribution: CC 72.6%, CT 26.2% and TT 1.1 %. While the differences among the various ethnic groups was highly statistically significant, there were no statistically significant differences in allelic frequencies of patients as compared to ethnic matched controls.Conclusions: In Israel there are significant differences in allelic distribution of NQO1 among various ethnic groups. However, the null allele was not present at a higher frequency in patients, suggesting that the null allele did not predispose to the development of de novo adult AML in Israel. The reason for the discrepancy between our data and other published studies may relate to underlying genetic differences in our population, for example, in CYP2E1, which participates in the same metabolic pathways as NQO1. Alternatively, it is possible that NQO1 protects against de novo AML only under specific environmental conditions, which may not exist in Israel. Our findings emphasize the importance of cross-cultural validation of pharmacogenetic studies, in order to assure the reliability of the findings.

Molecular analysis of HLA allele frequencies and haplotypes in Baloch of Iran compared with related populations of Pakistan

The extreme polymorphism in different loci of the human leukocyte antigen (HLA) system has been used as an invaluable tool for anthropological studies. Determination of HLA allele and haplotype frequencies in different ethnic groups is useful for population genetic analyses and the study of genetic relationships among them. In the present study, molecular analysis of HLA-A, -B, -C, -DQA1, -DQB1, and -DRB1 genes has been used to assign HLA allele and haplotype frequencies in 100 unrelated healthy individuals from the Baloch ethnic group of Iran. The results were compared with Baloch and other ethnic groups in the neighboring Pakistan. The results of this study showed that the most frequent HLA class I alleles were A*02011 (20.2%), B*4006 (11.1%), and C*04011 (28.6%). The most common HLA class II alleles were DQA1*0101/2 (42.5%), DQB1*0201 (32%), and DRB1*0301 (29%). Three-locus haplotype analysis revealed that A*11011-B*4006-C*15021 (5.8%) and DQA1*0501-DQB1*0201-DRB1*0301 (22.1%) were the most common HLA class I and II haplotypes, respectively, in this population. Neighbor-joining tree based on DA genetic distances and correspondence analysis according to HLA-A, -B, -DQB1, and -DRB1 allele frequencies showed that Baloch of Iran are genetically very close to Baloch and Brahui of Pakistan. This may reflect an admixture of Brahui and Baloch ethnic groups of Pakistan in the Balochistan province of Iran.

Typing of pentanucleotide STR polymorphisms

Pentanucleotide tandem repeat markers are of interest for forensic science because they may present less stutter in electrophoretic patterns. We focused on the analysis of the DNA sequence for each allele at two pentanucleotide STR loci, D6S957 and D10S2325, in order to understand their structures in the human genome and to construct allelic ladders, necessary for forensic DNA typing. In order to evaluate the forensic applicability of both pentanucleotide tandem repeat loci and to construct a preliminary database, the genotype distributions and allele frequencies in different ethnic groups were investigated. The population samples included Caucasians (Germans) and Asians (Chinese). The Amp-FLP technique was employed for DNA typing. An example of each allele and new alleles were sequenced. Allele determination for each pentanucleotide STR locus was carried out by comparison with a sequenced allelic ladder made in-house. Both pentanucleotide STR markers provided easily interpretable results. No evidence of deviation from Hardy–Weinberg equilibrium was observed. In 64 confirmed father/mother/child trios, no mutation event was observed. Using a maximum likelihood method, the mutation rate at both STR loci was indirectly estimated as 2.5×10 −5, suggesting both pentanucleotide STR markers would be useful for forensic casework and paternity analysis.

Ethnic variation in the HER-2 codon 655 genetic polymorphism previously associated with breast cancer.

HER-2, a protooncogene located on chromosome 17q21, encodes a transmembrane glycoprotein (p185) with tyrosine kinase activity. Alterations of the HER-2 gene have been implicated in the carcinogenesis and prognosis of breast cancer and other solid tumors. It is also a cancer-therapeutic target for antibody-based therapy against the HER-2 protein. A single-nucleotide polymorphism (SNP) at codon 655, resulting in a G-to-A transition (Ile655Val) in the transmembrane domain-coding region of this gene has been associated with an increased risk of breast cancer, particularly among younger women. To understand the importance of this finding throughout the world, we evaluated this polymorphism in Ghanaian, Kenyan, Sudanese, Caucasian, African-American, Saudi, and Filipino subjects using a polymerase chain reaction-restriction fragment length polymorphism assay. The frequency of the Val allele, which is associated with increased breast cancer risk, was highly variable between populations (0%-24%). Continental African populations had a lower frequency of the Val allele than did Saudi, Chinese, Filipino, Caucasian, and African-American subjects. The data suggest that this SNP has variable frequency in different ethnic groups. The findings in this study correspond with the lower incidence and lower risk of breast cancer in African women compared with Caucasian and African-American women.

BCR-ABL rearrangement frequencies in chronic myeloid leukemia and acute lymphoblastic leukemia in Ecuador, South America

Different BCR-ABL transcript variants occur more or less frequently, according to the leukemia type. We report the frequencies of BCR-ABL transcript variants studied in chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) patients in the Ecuadorian population. The frequencies found for CML patients in this study were 94.6% for the b2/a2 rearrangement and 5.4% for the b3/a2 rearrangement; whereas in ALL, all cases (100%) that presented the BCR-ABL rearrangement had the e1/a2 junction. Since our results differ from the frequencies previously reported, we suggest that this may be due to a different genetic background in the population involved in this study when compared to the populations analyzed in prior studies. Furthermore, we recommend a survey of the BCR-ABL transcript variants and their frequencies in different ethnic groups.

Clinical manifestations of NF1 in African-Americans and Caucasians

Most of the clinical manifestations of NF1 are thought to occur in similar frequencies in different ethnic groups. One exception to this assumption may be optic glioma, which has been reported to be less common in African-Americans. We have compared the manifestations of NF1 in a retrospective analysis of 55 individuals with NF1, including 39 Caucasians and 16 African-Americans in the first part of the study. All patients met the NIH consensus criteria for NF1. The diagnosis of NF1 was established at the mean age of 11.1 years in African-Americans and 8.3 years in Caucasians (±SD 6.9 years for African-Americans and 12.3 years for Caucasians; p<0.01). The results revealed that most of the findings were seen in similar frequencies in African-Americans and Caucasians. However, the following manifestations were found to be different: 3 of 16 African-Americans and 3 of 39 Caucasians were noted to have plexiform neuroma. None of the African-Americans were found to develop renal artery stenosis, although it was noted in 2 Caucasians. Three patients from the African-American group were found to develop intracranial tumors other than optic glioma, although none of the Caucasians were noted to have similar tumors in our sample. One explanation for these differences would be that African-Americans might be getting medical attention only if they have significant problems such as plexiform neuroma or intracranial tumors. To better evaluate the previously reported difference on the frequency of optic glioma, we are collecting a larger sample currently including 84 African-Americans and 880 Caucasians. Thus far optic glioma has been diagnosed in 4 of the 84 (4.8%) patients whose both parents were African-Americans and in 144 of the 880 (16.4%) Caucasians (further analysis is continuing). Our results thus far suggest that the manifestations of NF-1 are somewhat different in African-Americans, a lower frequency of optic glioma being the most significant difference. Better understanding of clinical differences in patients with NF-1 from different ethnic groups will help to identify modifying genetic factors and to establish appropriate individualized diagnostic and management plans.

2 The immunogenetics of the seronegative spondyloarthropathies

In none of the rheumatic diseases has the genetic contribution to pathogenesis been so well characterized as in the seronegative spondyloarthropathies. Most important has been the elucidation of the structure and effect on disease expression of HLA-B27, where 11 subtypes have been distinguished to date. These vary in frequency in different ethnic groups and seem to show differential disease associations. The high frequency of this gene in patients with the seronegative spondyloarthropathies, especially ankylosing spondylitis (AS) and Reiter's syndrome (RS)/reactive arthritis (ReA), has emerged as probably the best example of a disease association with a hereditary marker. Other HLA genes, in addition to HLA-B27, have been implicated in psoriasis and psoriatic arthritis. These include those from the HLA-C locus and from HLA-DR. In addition, recent family studies have implicated other genes outside the MHC that further enhance the susceptibility to AS.

Ribosomal P autoantibodies in systemic lupus erythematosus. Frequencies in different ethnic groups and clinical and immunogenetic associations

To determine the frequencies and clinical associations of antiribosomal P antibodies (anti-P) in a large multiethnic cohort of patients with systemic lupus erythematosus (SLE), and to assess whether anti-P was associated with any major histocompatibility complex (MHC) class II alleles or shared amino acid sequences. Sera from 394 SLE patients were studied for anti-P using an enzyme-linked immunosorbent assay, and MHC class II alleles (HLA-DRB1, DQA1, and DQB1) were determined by DNA oligotyping. Anti-P antibodies were found in 13-20% of patients in the majority of ethnic groups, but were perhaps more frequent in Chinese patients (36%) and less common in Bulgarian patients (6%). Neuropsychiatric lupus (psychosis and/or depression) was significantly associated with anti-P. The HLA-DR2, DQ6 haplotypes DRB1*1501 or *1503, DQA1*0102, and DQB1*0602 were increased in anti-P-positive whites, blacks, and Mexican Americans. The HLA-DQB1*0602 allele showed the strongest association with anti-P when these 3 ethnic groups were combined and compared with both race-matched anti-P-negative SLE patients and normal controls. The HLA-DQ8 specificity (DQB1*0302) was increased both in whites and in Mexican-Americans with anti-P who were negative for HLA-DQB1*0602, and perhaps also increased in Greeks, but not in blacks, in whom HLA-DQB1*0301 was increased. A shared amino acid sequence in HLA-DQB1 (at position 26 of leucine and position 30 of tyrosine) was strongly associated with anti-P positivity (70%) versus anti-P negativity (42%) across ethnic lines. The anti-P response in SLE patients, occurring in approximately 15% of patients, was strongly influenced by certain MHC class II alleles and was correlated with diffuse neuropsychiatric dysfunction.

Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms.

Thiopurine S-methyltransferase (TPMT) catalyses the S-methylation of thiopurines such as mercaptopurine and thioguanine. TPMT activity exhibits genetic polymorphism, with about 1 in 300 inheriting TPMT-deficiency as an autosomal recessive trait. If treated with standard dosages of thiopurines. TPMT-deficient patients accumulate excessive thioguanine nucleotides (TGN) in hematopoietic tissues, leading to severe hematopoietic toxicity that can be fatal. However, TPMT-deficient patients can be successfully treated with a 10-15-fold lower dosage of these medications. The human gene encoding polymorphic TPMT has been cloned and characterized, and two mutant alleles have recently been isolated from TPMT-deficient and heterozygous patients (TPMT*2, TPMT*3), permitting development of PCR-based methods to identify TPMT-deficient and heterozygous patients prior to therapy. TPMT*3 is the predominant mutant allele in American whites, accounting for about 75% of mutations in this population. Ongoing studies aim to better define the influence of TPMT activity on thiopurine efficacy, to identify additional mutant alleles and determine their frequency in different ethnic groups, to elucidate the mechanism(s) for loss of function of mutant proteins, to identify potential endogenous substrates and to define the molecular mechanisms of TPMT regulation. Together, these advances bold the promise of improving the safety and efficacy of thiopurine therapy.

Molecular genetics of systemic sclerosis.

Much recent work has focused on associations of progressive systemic sclerosis with genetic factors, particularly those of the major histocompatibility complex. Increased frequencies of a variety of major histocompatibility complex genes have been inconsistent and variable from center to center. Progressive systemic sclerosis, however, is a clinically and serologically heterogeneous disease, with autoantibody subsets that occur in differing frequencies in different ethnic groups, and previous variability in the major histocompatibility complex associations may reflect ethnic differences between the groups studied. Recent data suggest that progressive systemic sclerosis is a composite disease of HLA class II-associated autoantibody responses. Moreover, amino acid residues at specific positions in HLA class II molecules have been implicated in promoting these responses, especially in HLA-DQ beta outermost domains. The role of other genetic factors is less well defined and needs further study.

Lactose Intolerance in Singapore

Primary lactose intolerance has been described with varying frequency in different ethnic groups. A high incidence was described in Chinese students resident in Australia. A study was therefore undertaken on an indigenous Asian population in Singapore to establish the incidence and age of onset of lactose intolerance together with its relationship to lactose intake. Ninety-eight subjects ranging in age from 1 to 42 years were studied with lactose and glucose tolerance tests. Intestinal mucosal biopsies were assayed for lactase, sucrase, and maltase activity and examined by dissecting and light microscopy. Barium-lactose meals and xylose absorption tests also were performed. A detailed history of milk intake from birth was taken to relate the appearance or nonappearance of lactose intolerance to continued milk intake after weaning. Lactose intolerance was found to be universal after the age of 10 years. Before this there was increasing incidence of intolerance with increasing age, particularly after the age of 4 years. A secondary cause for lactase deficiency was excluded in all except 6 subjects by finding normal jejunal mucosa on dissecting and light microscopy, normal xylose absorption, and normal glucose tolerance tests. The correlation of barium-lactose meals with lactose tolerance tests and intestinal lactase activity was reasonable in adults but poor in children. It was shown that, of the tolerant children, 75% were milk drinkers and 25% were non-milk drinkers. Sixty-one per cent of the lactoseintolerant children were non-milk drinkers while 39% were milk drinkers. Intolerance appeared at an earlier age in non-milk drinkers. There is controversy on whether primary lactose intolerance is due to a genetic deficiency of intestinal lactase or whether the enzyme deficiency is adaptive. The relationship of lactose tolerance to continued milk intake after weaning found in this study would support a theory of adaptation.