High frequency of HLA DQA1*0301 in Yakuts: no correlation with IDDM incidence

Diabetologia, Jun 1995

O. V. Evgrafov

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High frequency of HLA DQA1*0301 in Yakuts: no correlation with IDDM incidence

Table 1, H L A class II susceptibility to IDDM in Japanese patients Total IDDM (n= 0 0 T. Awata , R. Hagura, T. Urakami, Y. Kanazawa 4. Vandewalle CL, Decraene T, Schuit FC, De LI, Pipeleers DG, Gorus FK (1993) Insulin autoantibodies and high titre islet cell antibodies are preferentially associated with the HLA DQAI*0301-DQBI*0302 haplotype at clinical type 1 (insulin-dependent) diabetes mellitus before age 10 years, but not at onset between age 10 and 40 years. The Belgian Diabetes Registry. Diabetologia 36:1155-1162 5. Awata T, Kuzuya T, Matsuda A, Iwamoto Y, Kanazawa Y (1992) Genetic analysis of H L A class II alleles and susceptibility to type 1 (insulin-dependent) diabetes mellitus in Japanese subjects. Diabetologia 35:419-424 6. Awata T, Kanazawa Y (1994) Genetic markers for insulindependent diabetes mellitus in Japanese. Diabetes Res Clin Pract 24 [Suppl]: S 83-S 87 7. Awata T, Matsumoto C, Urakami T, Hagnra R, Amemiya S, Kanazawa Y (1994) Association of polymorphism in the interferon y gene with IDDM. Diabetologia 37:1159-1162 8. National Diabetes Data Group (1979) Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 28:103%1057 9. Kobayashi T, Tamemoto K, Nakanishi K et al. (1993) Immunogenetic and clinical characterization of slowly progressive IDDM. Diabetes Care 16:780-788 - 53.42 21.3b 11.8 3.4 5.6 43.3 Fast progressive IDDM Onset < 15 year (n =52) 15-30 year (n = 39) > 30 year (n = 39) Frequencies (%) of alleles or haplotypes are presented, apc < 0.002, bpc < 0.05 Slowly progressive IDDM (n = 48) Control (n = 279) betes, since it was not significantly increased in patients with slowly progressing disease (Table 1) [9]. Interactions between this haplotype and later age-specific environmental factors, or later-age operative genetic factors, may be involved in the disease development, but obviously further studies are necessary to confirm and clarify this observation. High frequency of HLA DQAI*0301 in Yakuts: no correlation with IDDM incidence Dear Sir, Products of H L A DQA1 and H L A DQB1 genes are considered to directly participate in the development of insulin-dependent diabetes mellitus (IDDM). HLA DQA1 Arg52 alleles (mainly 0301 allele) and non-Asp-57 alleles of the H L A DQB1 gene are associated with IDDM in different populations [ 1 ]. Moreover, incidence of the disease correlates with the frequency of "diabetogenic" alleles of the DQB1 gene in different populations [ 2 ]. The DQA1 gene has not been investigated as frequently from this point of view. Products of HLA DQB1 and DQA1 genes (DQfi and DQc~ chains, respectively) form a heterodimer molecule and it could be assumed that both genes are important for development of IDDM, and that frequency of HLA DQAI*0301 should also correlate with IDDM incidence. We compared HLA DQA1 allele frequencies in Russian (IDDM incidence is 6.3 [ 3 ]) and Yakut populations with a low Frequency Yakuts No. subjects Russians No. subjects IDDM incidence (Table 1). The incidence IDDM in Saha Republic (Yakutia) calculated from the data of Ministry of Health and demographic data [ 4 ] is 2.7. A vast majority of the diabetic subjects are patients of Slavonic or Jewish origin, thus I D D M frequency in Yakuts should actually be considerably lower. This small-scale investigation shows an unexpectedly high frequency of the 0301 allele of the HLA DQA1 gene in Yakuts that does not correlate with a low IDDM incidence. We determined alleles of H L A D Q A 1 locus by the amplification/restriction procedure described previously [ 5 ] with some modifications. This method allowed us to distinguish seven alleles or allele sets (Table 1). The most "diabetogenic" DQAI*0301 allele is more frequent in Yakuts (18 from 50 chromosomes) than in Russians (14 from 114 chromosomes). Investigation of Yakut patients with Viliuisk encephalomyelitis uncovered even greater frequency of this allele. Our unpublished investigations together with other data support the idea that presence of D Q A I * 0 3 0 1 allele in one of the homologous chromosomes is sufficient for diabetes susceptibility. Thus, comparison of "diabetogenic" allele carrier numbers is probably m o r e informative than comparison of allele frequencies (Table 1). The difference between frequencies of D Q A I * 0 3 0 1 allele carriers in Yakuts and Russians is reliable (p < 0.05 after correction for multiple comparisons) and the data are in accordance with investigations of H L A D Q A 1 alleles in Japanese and Chinese, who also have a high frequency of the H L A DQAI*0301 allele and a low incidence of I D D M [ 6, 7 ]. It is possible that role of the D Q a chain is less than is proposed here. H o w e v e r there is no reason to reject the hypothesis of a functional role for D Q loci in diabetes susceptibility. Moreover, there is an association of I D D M with the DQAI*0301 allele in Japanese subjects. More important are exclusions from the correlation between I D D M incidence and non-Asp57 allele frequency of D Q B 1 in different populations [ 6, 8 ]. I D D M is a multifactorial disease, and another genetic or environmental factor could play a key role in its resistance in Yakut and other populations. Unusual data concerning the role of D Q genes in diabetes susceptibility are mainly derived from investigations of Mongoloid populations living in a quite different environment. It appears that another race-specific genetic factor is responsible for incidence of I D D M in different populations. In any case further population study of I D D M susceptiHLA-A alleles and susceptibility to IDDM D e a r Sir, We were interested to read " A gene in the H L A class I region contributes to susceptibility to I D D M in the Finnish population?" [ 1 ]. D a t a from such a large, well-characterized population are extremely valuable in the study of the contribution of H L A genes to insulin-dependent diabetes mellitus (IDDM). We believe, however, that considerable caution should be exercised in the interpretation of the results. The authors show that of the four Cwl, B56, DR4, D Q 8 haplotypes identified, only the A2-associated haplotype was significantly associated with I D D M (82 of 1492 diabetic haplotypes were A2, Cwl, B56, DR4, D Q 8 compared with 14 of 1254 control haplotypes). This finding is taken as evidence that the H L A class I region contributes to diabetes susceptibility. It should be noted, however, that the three non-A2, Cwl, B56, DR4, D Q 8 haplotypes are very uncommon, together constituting only 7 of 1492 diabetic haplotypes and 2 of 1254 control haplotypes. This study population, although large, is too small to exclude a disease-predisposing effect of the non-A2 haplotypes. If the distribution of the A2-positive Corresponding author: Dr. D. Jenkins, University of Birmingham, D e p a r t m e n t of Medicine, Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2TH, U K bility genes is important for better understanding of I D D M aetiology. References 82 7 Control haplotypes n = 16 ;g2 = 0.016 (Yates' correction), not significant and A2-negative Cwl, B56, DR4, D Q 8 haplotypes is examined as in Table 1, one finds that the frequency of A2 does not differ significantly between the diabetic and control haplotypes. These data, therefore, do not suggest that the H L A class I region makes a particular contribution to susceptibility to I D D M . The authors also point out that certain Cw3, B62, DR4, D Q 8 haplotypes and certain Cw7, B8, DR3, D Q 2 haplotypes are significantly associated with I D D M but others are not, depending on the allele at the H L A - A locus. It should be noted, however, that those haplotypes which are not associated with diabetes are uncommon, each non-associated haplotype constituting less than 1 % of both the diabetic and control populations. A similar comparison to that m a d e in Table 1 of the distribution between the diabetic and control subjects of the disease-associated Cw3, B62, DR4, D Q 8 haplotypes (A2, A3 and A24) with those which are not (A1, A l l and A28) gives a 1. Deschamps l, Beressi JR Khalil l, R o b e r t JJ , Hors J ( 1991 ) The role of genetic predisposition to type I (insulin-dependent) diabetes mellitus . Ann Med 23 : 427 - 435 2. D o r m a n JS et al . ( 1990 ) Worldwide differencies in the incidence of type I diabetes are associated with amino acid variation at position 57 of the H L A D Q beta chain . Proc Natl Acad Sci U S A 87 : 7370 - 7374 3. Knyazev YuA ( 1991 ) Epidemiology of children's diabetes in the USSR . Pediatrics 2 : 7 - 10 (in Russian) 4. Annual Demographic R e p o r t of the USSR ( 1990 ) Finances and Statistics. Moscow (in Russian) 5. Maeda M, M u r a y a m a N, Ishii H e t al. ( 1989 ) A simple and rapid method for H L A D Q A 1 genotyping by digestion of PCR-amplified D N A with allele specific restriction endonuclease . Tissue Antigens 34 : 290 - 298 6. Penny NA , Jenkins D , Mijovic C H et al. ( 1992 ) Susceptibility to insulin-dependent diabetes mellitus in a Chinese population: role of H L A class II alleles . Diabetes 41 : 914 - 919 7. Todd JA , Mijovic C , Fletcher J e t al. ( 1990 ) The A3 allele of the H L A D Q A 1 locus is associated with susceptibility to type I diabetes in the Japanese . Proc Natl Acad Sci U S A 87 : 1094 - 1098 8. Awata T , Kuzuya T , Matsuda A et al. ( 1990 ) High frequency of aspartic acid at position 57 of H L A - D Q f l chain in Japanese I D D M patients and nondiabetic subjects . Diabetes 39 : 266 - 269

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O. V. Evgrafov. High frequency of HLA DQA1*0301 in Yakuts: no correlation with IDDM incidence, Diabetologia, 1995, 749-750, DOI: 10.1007/BF00401851