P. Teisberg

The locus for apolipoprotein E (apoE) is linked to the complement component C3 (C3) locus on chromosome 19 in man

SummaryBy two-dimensional electrophoresis of human serum a genetically determined polymorphism of apolipoprotein E (apoE) can be demonstrated. Three alleles occur with appreciable frequency in Caucasian populations. In the present study the segregation of apoE and complement component C3 (C3) types in material from Norwegian families has been studied. Linkage has convincingly been demonstrated between the two loci with a lod score of 3.00 in males at a recombination fraction of 13%. As it is known that the C3 locus is situated on chromosome 19 in man, apoE can be located to this specific chromosome. Positive linkage data do not, to our knowledge, at present exist with regard to other apolipoproteins.

The Bf locus in the HLA region of chromosome 6: linkage and association studies.

SummaryBf allele frequencies in a material of 172 unrelated Norwegians are given. Bf/HLA linkage relations in 49 informative matings with 178 children, and Bf/HLA association data of a material of 212 Bf-HLA haplotypes are presented. Of 171 informative meioses, there were no Bf-HLA-B recombinations, while 3 out of 158 Bf-HLA-A informative meioses showed recombination. There is significant association between the BfF and the HLA-BW 35 allele.It is concluded that the Bf locus is situated on the HLA-B side of HLA-A within the HLA region, in very close proximity to HLA-B.

Genetics of LCAT (lecithin: cholesterol acyltransferase) deficiency.

Since 1967 a syndrome characterized by renal disease, normochromic anaemia and corneal opacities has been described in 7 members of 3 different Norweigan families. The patients have low levels of esterified cholesterol and lack LCAT (lecithin: cholesterol acyltransferase) activity in plasma. The genetic basis of the disorder seems to be the presence of a LCAT deficiency gene in double dose. This gene is probably the result of a single mutational event. Linkage studies revealed non-random assortment between LCTA deficiency and serum haptoglobin (Hp) types. After Hp subtyping a combined lod score of 3-41 at a recombination fraction of 0-00 was obtained. Association was revealed between the LCAT deficiency gene and the Hp-1S gene. We propose that the LCAT gene is situated close to the alpha-haptoglobin locus on chromosome no. 16.

The two apolipoprotein loci apoA-I and apoA-IV are closely linked in man

SummaryIn man the closely linked genes for the apolipoproteins A-I and C-III have been assigned to chromosome 11. Linkage studies performed in a Norwegian family with a mutant apoA-I gene established a close linkage between the loci for apoA-I and apoA-IV. For both sexes combined, the peak lod score was 3.01 at a recombination fraction of θ=0.00. Thus this study adds the locus of apoA-IV to the previously reported apolipoprotein gene cluster on chromosome 11. The previously unidentified polymorphic serum protein, USP1, is by immunochemical and electrophoretical methods identified as apoA-IV. ApoA-IV typing should be a valuable tool in elucidating the genomic organization of chromosome 11.

Electrophoretic polymorphism of human C4 is due to charge differences in the alpha chain, presumably in the C4d fragment.

Various common C4 gene products were isolated from serum by immunoprecipitation. After reduction the C4 α‐, β‐, and γ‐polypeptide chains were studied by two‐dimensional electrophoresis. Isoelectrofocusing was performed in the first dimension and sodium dodecyl sulphate polyacrylamide gradient gel electrophoresis in the second. The charge differences behind the electrophoretic C4 polymorphism were shown to reside in the 95,000‐u(atmic mass units) α‐chain. Charge variation closely mirroring the α‐chain differences were also found in a 49,000‐u fragment of the α‐chain, most probably C4d. The basic β‐chain could not be studied in detail, but no differences were observed with regard to molecular weight or charge of the γ‐chains of the different C4 gene products.

C3 polymorphism: Genetic linkage relations

Twenty‐one linkage relations of the C3 locus have been analyzed in Norwegian family material by means of the computer program MOSM. No suggestion of linkage was found. Excluding linkage intervals for which our data have reduced the probability of linkage by more than 95 %, it appears that in males, PGM1, Rh and ACP1 are not linked to C3 closer than TH –.40; Fy and HL‐A not closer than. 35; ABO and Hp not closer than. 30; Gm not closer than. 25; MNSs and K not closer than. 20; PGM3 and Inv not closer than. 15; Do, Gc and Tf not closer than. 10; and Pi not closer than. 05. In females, PTC is not closer to C3 than. 20; Le(Se) not closer than. 15; Jk and P not closer than. 10; and Lu not closer than. 02. Low exclusion levels reflect low information except for C3‐Gc. But if the trend found for this relation should reflect a loose linkage, a very large amount of information would be necessary to establish it.

Genetic polymorphism of complement component C8

SummaryExtensive genetic polymorphism of complement component C8 was demonstrated by isoelectric focusing of serum or plasma samples followed by immunoblotting procedures. Using these methods, we could detect both α-γ (C81) and β (C82) chain polymorphisms in the same gel. Two-dimensional (2D) electrophoresis of C8 immunoprecipitates was used to obtain further information of the C8 patterns. Evidence was obtained that the C81 polymorphism resides in the structural gene of the C8 α chain. Both C8 systems show autosomal, chiefly codominant inheritance, and the distribution of phenotypes agrees with the Hardy-Weinberg equilibrium. Our findings suggest at least five different alleles in the C81 system; the gene frequencies of the two most common ones, C81*A and C81*B being 0.59 and 0.39, respectively. In C82 we found evidence for at least three codominant alleles, the gene frequencies for the two most common ones, C82*B and C82*A being 0.94 and 0.05, respectively. In addition, family studies disclosed the existence of a null allele, C82*Q0.

Gene order and gene distances in the HLA region studied by the haplotype method

The present report describes a method to establish gene order and gene distances in chromosomal regions where several genes are located closely together. The method is applied to the study of the complement loci in the HLA complex on chromosome 6 in man.

Studies of HLA, Factor B (Bf), Complement C2 and C4 Haplotypes in Type 1 Diabetic and Control Families from Northern Sweden

The HLA-A,-B,-C,-DR antigens and the complement factors C2, C4 and Bf were determined in 30 insulin-dependent diabetes mellitus (IDDM) patients and 30 healthy controls from northern Sweden. Family studies allowed the deduction of extended haplotypes in the HLA and complement systems. Phenotype studies revealed significant associations between IDDM and HLA-DR4 (p less than 0.001), HLA-DR3 (p less than 0.05), HLA-DR3/4 (p less than 0.025), C4-B3 (p less than 0.001) and Bf-S (p less than 0.025). Haplotype studies showed that the extended haplotype [HLA-B15, C2-1, C4-A3B3, Bf-S, HLA-DR4] had a particularly strong association to IDDM. This haplotype was found in 10 out of 30 IDDM probands but in none of 30 control children and accounts for practically all the C4-B3 allotypes among the 30 IDDM probands. The C4-B3 gene therefore seems to be a valuable marker for IDDM. No haplotype containing HLA-DR3 was increased in frequency among the IDDM probands. The extended haplotype [HLA-B7, C2-1, C4-A3B1, Bf-S, HLA-DR2] present among the controls was absent in the IDDM probands. The frequency of the extended haplotype [HLA-B15, C2-1, C4-A3B3, Bf-S, HLA-DR4] was increased also among the parents to the IDDM probands compared to those of the control parents, whereas the frequency of [HLA-B7, C2-1, C4-A3B1, Bf-S, HLA-DR2] was decreased. The extended haplotype [HLA-B8, C2-1, C4-B1, Bf-S, HLA-DR3] was more common among the males (p less than 0.05) compared to the females in the total material. The family analysis showed that 3 out of 5 affected sibs shared both haplotypes with their IDDM proband. This was the case for only 3 out of 35 unaffected sibs.

Fibrinogen ? chain locus is on chromosome 4 in man

SummaryA molecular fibrinogen variant has been detected by two-dimensional electrophoresis of human plasma samples. Fibrinogen is a complex molecule consisting of three different polypeptide chains Aα, Bβ, and γ. The presently described variation resides in the γ-chain, which in the variant is slightly more basic and heavier than the common form of this chain. In a family material it has been shown that the variant is genetically determined, and the segregation pattern shows autosomal codominant inheritance. The family material has been typed in approximately 30 marker systems, and linkage studies have shown close linkage between the γ-chain locus (FGG) and MNSs. The MNSs loci are known to be located on chromosome 4 in humans and the fibrinogen γ-chain locus is thus on this chromosome. The MNSs/FGG distance is approximately 8 centimorgans. Supplementing data suggest that FGG is distal to MNSs on the long arm of chromosome 4.