The functionally important IL-10 promoter polymorphism (-1082G-->A) is not a major genetic regulator in recurrent spontaneous abortions.

Enhanced secretion of anti-inflammatory Th2 cytokines is a characteristic feature in normal physiological pregnancy. In recurrent spontaneous abortions (RSA), however, defective production of interleukin-10 (IL-10) and other Th2 cytokines has been shown in humans. Association studies have shown that a base exchange polymorphism (guanine-->adenine) at position -1082 of the IL-10 promoter is associated with differential IL-10 production. Since factors contributing to IL-10 production appear to be important in RSA, we studied the IL-10 genotypes of 38 Finnish women with a history of three or more consecutive abortions and 131 ethnically matched healthy controls. No significant differences in the -1082 allele or genotype frequencies were found between the controls and the RSA women. The present study suggests that the IL-10 -1082 (G-->A) polymorphism is not a major genetic regulator in RSA.

Worldwide ethnic distribution of the G protein beta3 subunit 825T allele and its association with obesity in Caucasian, Chinese, and Black African individuals.

Recently, it was demonstrated that one allele (825T) of the gene encoding the G protein beta3 subunit (GNB3) is associated with hypertension in Germans. This study investigates a possible association with obesity in young male Germans, Chinese, and black South Africans with low, intermediate, and high 825T allele frequencies, respectively. In each of these three distinct cohorts, the 825T allele frequency was increased significantly in overweight (body mass index [BMI] > or =25 kg/m2) and obese individuals (BMI >27 kg/m2) compared to those with normal weight. The 825T allele frequencies in these three BMI groups were, respectively, 29.5, 39.3, and 47.7% in Germans, 46.8, 53.9, and 58.6% in Chinese, and 83.1, 87.7, and 90.9% in South Africans. In each of these three distinct groups, the 825T allele was significantly associated with obesity with odds ratios between 2 and 3. More urban than rural black Africans were overweight despite similar 825T allele frequencies in both populations, which underscores the role of both genetic and environmental factors. BP values in young male whites increased significantly with increasing BMI values but were independent of the C825T polymorphism, suggesting that hypertension associated with the 825T allele could be a consequence of obesity. Genotyping of 5254 individuals from 55 native population samples from Africa, the Americas, Europe, Asia, Australia, and New Guinea demonstrated highest 825T allele frequencies in black Africans (82%) and intermediate values in east Asians (47%). It is anticipated that high frequencies of the 825T allele in Africans and Asians may contribute to an obesity and hypertension epidemic if Westernization of lifestyles continues.

HLA-DQA1 alleles and the presence of Helicobacter pylori antibodies.

Recent reports suggest that the HLA-DQA1 gene may be important in determining susceptibility to and outcome of Helicobacter pylori infection. To determine if there is an association between HLA-DQA1 alleles and H. pylori antibodies, DQA1 alleles and H. pylori-specific antibodies were determined in 199 random subjects of Finnish origin (mean age 43 years, range 22-69 years). H. pylori-specific class IgG antibodies were measured using the EIA method (Pyloriset-EIA-G, Orion Diagnostica, Espoo, Finland). HLA-DQA1 typing was carried out using PCR-SSP (PCR with sequence-specific primers). There were 64 subjects with H. pylori-specific class IgG antibodies (ab+) and 135 subjects without H. pylori-specific class IgG antibodies (ab-). Gene and phenotype frequencies of HLA-DQA1 alleles were similar in the ab+ and ab- subjects (P = NS). The data suggest that no single HLA-DQA1 allele is associated with the presence of serum antibodies against H. pylori.

HLA-G polymorphism in Finnish couples with recurrent spontaneous miscarriage.

HLA-G is a class I major histocompatibility complex gene that is expressed in cytotrophoblasts at the materno-fetal interface. It has been suggested that HLA-G could play a key role in materno-fetal immunological interactions during pregnancy. To investigate whether there is an association between HLA-G locus and recurrent spontaneous miscarriage, HLA-G alleles were determined by a PCR-RFLP method in 38 couples with recurrent spontaneous miscarriage and in 26 random control couples. In this series parental HLA-G sharing, extended HLA-G/A haplotypes and the frequencies of the HLA-G alleles were similar in the two groups. Thus, our data suggest that there is no detectable relation between susceptibility to recurrent spontaneous miscarriage and HLA-G locus.

TAP1 and TAP2 genes in nickel allergy.

The study was undertaken to see whether TAP1 and TAP2 (transporter associated with antigen processing) genes are involved in susceptibility to nickel allergy. The products of these genes are important in antigen transport and processing, making them candidates for disease susceptibility. Fifty-five nickel-sensitive and 54 non-sensitive subjects were TAP1- and TAP2-typed by amplification refractory mutation system - polymerase chain reaction. The allele and phenotype frequencies of TAP2B were significantly (p = 0.019 and 0.012, respectively) increased in nickel-sensitive subjects versus controls. Relative risk (RR) for TAP2B was 2.7 and etiological factor (EF) = 0.46. The allele frequency of TAP2C was decreased among the nickel-sensitive subjects versus controls (p = 0.016). RR for TAP2C was 0.18. In conclusion, TAP2B increases the risk for nickel allergy, the results suggesting a considerably high EF.

HLA markers in a community-based rheumatoid arthritis series.

We wanted to investigate whether rheumatoid arthritis (RA) patients, defined by the American College of Rheumatology (ACR) 1987 criteria and selected from one community by the help of the official Finnish data registers, share the common HLA susceptibility genes. The HLA frequencies of 88 RA patients representing 85% of the prevalent cases of RA in the community were compared with those of 188 healthy controls. Fifty-four per cent of the index cases with RA had DR4 compared with 30% of the healthy controls (P <0.001). The 'RA susceptibility sequence' was found in 75% of the DRB1 genes in the index cases, but it did not correlate with the severity of the disease. The frequency of DR3 was not increased in RA patients but it was associated with features of severe disease, that is, with a high erythrocyte sedimentation rate (P<0.05), extra-articular disease (P<0.01) and prostheses in large joints (P<0.05). According to our results community-based RA patients satisfying the new ACR criteria show the common DR4 association. DR3 was the only HLA allele which showed some disease-modifying effect correlating with the severity of RA.

The frequency of QAP2.1 is increased in psoriasis vulgaris patients but no unusual linkage between QAP/DQA1 or QBP/DQB1.

Psoriasis vulgaris is a chronic skin disease with a genetic and immunological background. We have previously defined the two most frequent risk haplotypes in Finns: A2,B13,Cw6,DR7,DQA1*0201 and A1,B17,Cw6,DR7,DQA1*0201. The aim of this study was to further examine whether the flanking regions, URRs of DQ (QAP and QBP) and TAP1 and TAP2 genes are involved in susceptibility to psoriasis. The frequency of QAP2.1 was increased in psoriatics as compared with controls (Pc = 3.6 x 10(-2), RR = 5.0), and the frequency of QAP4.1 was decreased in psoriasis patients (Pc = 4.2 x 10(-2)). The frequency of the phenotype combination Val/Ile at position 379 of TAP2 was decreased in patients (Pc = 1 x 10(-2)). The allele and phenotype frequencies of TAP1 and TAP2 genes were not different between these groups. Haplotypes A2, B13,Cw6,DR7,DQA1*0201,QAP2.1 and A1,B17,Cw6, DR7,DQA1*0201,QAP2.1 are the two most frequent HLA marker haplotypes for psoriasis vulgaris in Finns, Cw6, DR7, DQA1*0201 and QAP2.1 being the most important single alleles for the risk of this disease.

HLA five-locus haplotypes in Finns.

The extreme polymorphism of HLA genes makes them a powerful tool for distinguishing between different genetic populations. Five-locus HLA haplotypes of Finns (from Oulu, Northern Finland) are described here in order to characterize further the migration pathways of the population to Finland after the Ice Age. From random families, 364 haplotypes were obtained. The most frequent Finnish haplotype A3,Cw4,B35,DR1,DQ1 (7.7%) is a Caucasoid ancestral haplotype and is shared with Italians of Celtic and non-Celtic origin. The haplotype A1,Cw7,B8,DR3,DQ2, which occurs in 4.7% of Finns, is the most frequent haplotype in Caucasoids. The haplotypes A3,Cw7,B7,DR2,DQ1 (3.6%) and A2,Cw7,B7,DR2,DQ1 (2.5%) are shared with several Caucasoid populations and the latter also with Jamaican blacks. A2,Cw5,B44,DR5,DQ3 (0.8%) is shared with Italians of Celtic and non-Celtic origin, A2,Cw6,B13,DR7,DQ2 (1.1%) with Caucasoids in the USA and A9,Cw4,B35,DR1,DQ1 (0.8%) with Mongoloids. The haplotypes A2,CW3,B62,DR4,DQ3 (3.0%), A2,Cw2,B27,DR8,DQ4 (1.7%), A2,Cw3,B62,DR6,DQ1 (1.4%) and A2,Cw1,B27,DR4,DQ3 (1.4%) were also found to be among the most frequent in the Finnish population. The most frequent HLA haplotypes are consistent with the postulated ancient migration of populations from southern Scandinavia and Germany to Finland, the most frequent haplotype suggesting a common Celtic origin and one less frequent haplotype suggesting an influence from the east.

HLA risk haplotype Cw6,DR7,DQA1*0201 and HLA-Cw6 with reference to the clinical picture of psoriasis vulgaris.

Psoriasis vulgaris has HLA associations. We have previously defined HLA-Cw6,DR7,DQA1*0201 as the central element of the risk haplotypes for psoriasis. On the other hand, Cw6 as a single gene has the strongest association with psoriasis. The aim of this study was to determine whether the risk haplotype and Cw6 correlate with the clinical parameters of the disease. The series consisted of 64 patients and the clinical parameters were age at onset, family history of psoriasis, arthritis and the frequency of inpatient treatment. The HLA risk haplotype Cw6,DR7,DQA1*0201 had previously been found in 30% and Cw6 alone in 54% of the patients. The presence of Cw6 correlated with early age at onset (Pc = 0.01). The presence of the risk haplotype correlated with a positive family history of psoriasis among the first-degree relatives (Pc = 0.02) and an overall positive family history (Pc = 0.04), but Cw6 had a stronger correlation with an overall positive family history (Pc = 0.01). There were no positive correlations with arthritis or the number of inpatient treatment periods. Only type I psoriasis was associated with Cw6 (Pc = 0.0006). In conclusion, Cw6 and the haplotype Cw6,DR7,DQA1*0201 are important in the heredity of psoriasis vulgaris, but the presence of Cw6 alone is sufficient to indicate a clinically significant risk for psoriasis.

HLA-G polymorphism and allelic association with HLA-A in a Finnish population.

The polymorphism of the HLA-G gene can be identified by PCR-RFLP analysis. This short communication describes the PCR-RFLP analysis of HLA-G polymorphisms in exons 2 and 3 and the association of different HLA-G and HLA-A alleles in 26 healthy Finnish families.

Immunogenetic profile of psoriasis vulgaris: association with haplotypes A2,B13,Cw6,DR7,DQA1*0201 and A1,B17,Cw6,DR7,DQA1*0201.

Psoriasis vulgaris is a skin disease with an immunological and genetic background present in 1-3% of the population. We studied the genetic susceptibility to psoriasis vulgaris in Finns with serological HLA typing and genomic HLA class II typing of the DQ and DP loci to evaluate the risk of developing psoriasis. The haplotypes most frequently distinguishing between psoriatics and controls were those that carried Cw6 (P < 10(-8)), DQA1*0201 (P = 9.3 x 10(-6)) and DR7 (P = 3.9 x 10(-5)). The two most frequent marker haplotypes were A2,B13,Cw6,DR7, DQA1*0201 and A1,B17,Cw6,DR7,DQA1*0201, which were not found among the control subjects. A deficit of haplotype B8,DR3,DQ2 (2 out of 124 in the patients versus 15 out of 106 in the controls, P = 1.5 x 10(-4)) was found, and this was in accordance with a slightly decreased frequency of DQA1*0501 (P = 3.1 x 10(-2)), which was usually linked with this haplotype. These results stimulate the research for a genetic resistance factor in psoriasis. Thus, this report sheds further light on the immunogenetic background of psoriasis in Finland. We conclude that the inheritance of psoriasis has a polygenic mode, in which the Cw6,DR7,DQA1*0201 combination seems to be important (P = 7.5 x 10(-7), relative risk 24.4, aetiological factor 0.29).

Chronic sclerosing osteomyelitis of the mandible in monozygotic twins.

Identical female twins with chronic sclerosing osteomyelitis of the mandible are presented. The diagnoses of both at the age of 12 years were based on typical history, and on clinical, radiographic, and histologic findings. High concentrations of IgA and IgG were detected in the serum of both patients, but deviations were not observed in other immunologic variables. The normally commensal organism, Propionibacterium acnes grew from a bone biopsy specimen from the mandible of one twin. No oral focus of the disease was confirmed in either case. We suggest that hereditary factors must have played a role in the pathogenesis of these cases of chronic osteomyelitis.

Alanine at position 73 of HLA-C is associated with psoriasis vulgaris in Finland.

A close association was found between a specific sequence of HLA-C and psoriasis vulgaris in Finnish patients (chi 2 = 18.4, P = 1.78 x 10(-5)). This sequence codes for alanine at position 73 of the HLA-C molecule in the antigen binding cleft, and alanine may play a role in susceptibility to the disease.

Different distribution of T cell receptor beta-chain haplotypes in mixed connective tissue disease and systemic lupus erythematosus.

Mixed connective tissue disease (MCTD) and systemic lupus erythematosus (SLE) are autoimmune diseases with a genetic background, and it is reasonable to suggest that aberrations in T cell receptor (TCR) genes could contribute to these diseases, as they play an important role in immune regulation. We studied TCR beta-chain gene segments V beta 8, V beta 11 and C beta with restriction fragment length polymorphism (RFLP) in MCTD and SLE patients and controls. Haplotypes could be assigned in individuals who were homozygous for two or three of these three loci, whereupon the haplotype 2/25/10 (V beta 8/V beta 11/C beta) was found to be under-represented in MCTD (P = 0.029). The frequencies of individual alleles in both groups were similar to those of the controls, whereas the number of homozygotes within V beta 8 gene (23/23 kb and 2/2 kb) was increased in MCTD (P = 0.028). It is concluded that the distribution of TCR beta-chain genes could be aberrant in MCTD and could play a role in susceptibility, whereas the TCR beta-chain gene distribution in the SLE patients did not differ from that of the controls.

HLA-DQA1 and DQB1 loci in nickel allergy patients.

Since an association has been reported between nickel allergy and HLA-DQA TaqI restriction fragment length polymorphism, we typed the DQA1 locus by a more precise method to confirm the association and characterize it better. Typing was extended to the DQB1 locus. The loci were typed using polymerase chain reaction and sequence-specific oligonucleotides. The DQA1 allele 0601 was slightly overrepresented among the patients, but the p value was not significant. The frequencies of DQB1 locus alleles did not differ from those of the controls. Thus we were unable to confirm any association between HLA and nickel allergy.

Normal C3b receptor (CR1) genomic polymorphism in patients with insulin-dependent diabetes mellitus (IDDM): is the low erythrocyte CR1 expression an acquired phenomenon?

Expression of the erythrocyte complement receptor (C3bR = CR1 = CD35) and its genomic polymorphism (HindIII RFLP) was studied in a group of 80 patients with IDDM, 31 healthy siblings and 101 healthy blood donors. Defective CR1 expression was found in 26% of the patients with IDDM compared with 9% of the controls (P less than 0.05) and 0% of the siblings. The CR1 gene polymorphism of the IDDM patients did not significantly differ from that of the controls. The presence of a 6.9 kb (L) CR1 gene fragment was associated with a low CR1 expression in the patients (P less than 0.05) and especially in the controls (P less than 0.001). No significant association was found between the presence or absence of the HLA risk antigens for IDDM and CR1 expression. The results confirm that erythrocyte CR1 expression is genetically determined, but the CR1 deficiency associated with IDDM seems to be an acquired rather than a genetic phenomenon.

Differences in HLA antigens between patients with mixed connective tissue disease and systemic lupus erythematosus.

Patients with mixed connective tissue disease (MCTD, n = 32) or systemic lupus erythematosus (SLE, n = 60) were typed for HLA-A, B, C, Dw, and DR antigens. All patients with SLE fulfilled at least four criteria of SLE and the patients with MCTD met the criteria proposed by Alarcon-Segovia (1989). The presence of antibodies to Sm was not considered as an exclusion for MCTD. In the patients with SLE, Dw3, DR3, and the associated B8 and A1 antigens were increased, whereas in the patients with MCTD an increased frequency of Dw4 was found (45 v 18% in controls v 14% in SLE). Of the subtypes of DR4, Dw4 was present in all but one of the DR4 positive patients. The frequency of DR4 in patients with MCTD (52%) differed significantly from that of controls (28%). The strong association of MCTD to one DR4 subtype was further seen in the significantly increased frequency of the B15, DR4 combination. Thus the genetic background seems to be different in patients with MCTD from that in patients with SLE. This could partly explain the clinical differences between these diseases.