IDDM12 (CTLA4) on 2q33 and IDDM13 on 2q34 in genetic susceptibility to type 1 diabetes (insulin-dependent)

Type 1 diabetes (insulin-dependent) is a multifactorial disease with polygenic susceptibility. The major genetic component (IDDM1) resides within the HLA region, but several non-HLA loci have been implicated in the genetic susceptibility. In the present study, we have analysed two such loci, IDDM12 (CTLA4) on 2q33 and IDDM13 on 2q34, in Danish (n = 254) and Spanish (n = 39) type 1 diabetic multiplex families. No significant evidence of linkage of IDDM12 was observed in any of the two studied data sets. However, when the present data were combined with previously published data, they strengthened the evidence of linkage at this locus, p = 0.00002. For the IDDM13 region, we found some positive evidence of linkage of the D2S137-D2S164-D2S1471 markers (p-values 0.007, 0.02, and 0.007, respectively) using transmission disequilibrium testing (TDT) and the Tsp version of the TDT. Importantly, random transmission of all tested alleles was observed in unaffected offspring (p > 0.3). Stratification for HLA (high risk and non-high risk genotypes) in the Danish families did not reveal heterogeneity at IDDM12 or IDDM13. In conclusion, our data on an entirely new family data set did not support the existence of IDDM12 as a type 1 diabetes susceptibility locus in the Danish population. In addition, we found support for evidence of linkage and association of the IDDM13/D2S137-D2S1471 region (approximately 3.5 cM) to type 1 diabetes, however, further studies are needed to substantiate this observation.     

Confirmation of three susceptibility genes to insulin-dependent diabetes mellitus: IDDM4, IDDM5 and IDDM8

Previous genome-wide mapping studies have provided suggestive linkage evidence for several novel susceptibility loci responsible for insulin- dependent diabetes mellitus (IDDM); however, the evidence was not sufficient to confirm the existence of these genes. We analyzed 265 Caucasian families with IDDM and report the first evidence that meets the standard for confirmed linkage for three susceptibility loci. The maximum LOD scores (MLS) were 3.9, 4.5 and 3.6 in our data set, and 5.0, 4.6 and 5.0 for our data combined with non-overlapping data from the literature, for IDDM4 on chromosome 11q13, IDDM5 on 6q25, and IDDM8 on 6q27, respectively. However, we could not confirm linkage for IDDM3 on 15q26 and IDDM7 on 2q31-q33, or linkage disequilibrium between D2S152 and IDDM7.      

Evidence for a type 1 diabetes susceptibility locus (IDDM10) on human chromosome 10p11-q11

A region of linkage to type 1 diabetes has been defined on human chromosome 10p11-q11 (IDDM10; P = 0.0007) using 236 UK and 76 US affected sibpairs and a 1 cM resolution microsatellite marker map. Analysis by the transmission disequilibrium test (TDT) in 1159 families with at least one diabetic child, from the UK, the US, Norway, Sardinia and Italy provided additional support for linkage at D10S193 (P = 0.006, Pc = 0.17). Notably, 5.1 cM distal to D10S193, marker D10S588 also provided positive TDT results (P = 0.009, Pc = 0.25) but the allele under analysis was also preferentially transmitted to nonaffected siblings (P = 0.0008, Pc = 0.02). This allele was positively associated in an independent UK case control study and, importantly, was neutrally transmitted in control CEPH families. These results suggest a type 1 diabetes susceptibility locus on chromosome 10p11-q11 (provisionally designated IDDM10) and demonstrate the necessity of analysis of non affected siblings in disease families, as well as analysis of control families.      

Evidence by allelic association-dependent methods for a type 1 diabetes polygene (IDDM6) on chromosome 18q21

Type 1 diabetes is a common polygenic disease. Fine mapping of polygenes by affected sibpair linkage analysis is not practical and allelic association or linkage disequilibrium mapping will have to be employed to attempt to detect founder chromosomes. Given prior evidence of linkage of the Jk-D18S64 region of chromosome 18q12-q21 to type 1 diabetes, we evaluated the 12 informative microsatellite markers in the region for linkage with disease by the transmission disequilibrium test (TDT) in a UK data set of type 1 diabetic families (n = 195). Increased transmission of allele 4 of marker D18S487 to affected children was detected (P = 0.02). Support for this was extended in a total of 1067 families from four different countries by isolating, and evaluating by the TDT, two novel microsatellites within 70 kb of D18S487. Evidence for linkage and association was P = 5 x 10(-5) and 3 x 10(-4), respectively. There was no evidence for increased transmission of associated alleles to nonaffected siblings. Analysis of an additional 390 families by the TDT did not extend the evidence further, and reduced support in the total 1457 families to P = 0.001 for linkage and P = 0.003 for association. However, evidence for linkage by affected sibpair allele sharing was strong (P = 3.2 x 10(-5)) in the second data set. Heterogeneity in TDT results between data sets was, in part, accounted for by the presence of more than one common disease- associated haplotype (allelic heterogeneity) which confounds the analysis of individual alleles by the TDT. Guidelines for strategies for the mapping of polygenes are suggested with the emphasis on collections of large numbers of families from multiple populations that should be as genetically homogeneous as possible.      

中国人群16号染色体q12区存在系统性红斑狼疮易感基因

目的：明确16号染色体与中国人系统性红斑狼疮（systemic lupus erythematosus,SLE)相关性，并对其进行易感基因定位以期发现疾病侯选基因。方法：以16号染色体遗传距离57．79－65．1cM的5对微卫星标记，对157个SLE患者家系DNA进行扩增，产物经377DNA测序仪电泳，所得数据由Genescan软件收集，并以ETDT及Genehunter软件进行统计处理。在阳性位点处寻找疾病侯选基因以实时PCR进行基因表达研究。结果：D16S409及D16S517与SLE存在传递不平衡，其中尤以D16S517最为显著（P＜0．0001）。D16S517中，271bp等位基因优先传递给患病子代，277bp等位基因则优先传递给正常子代。对侯选基因的研究显示OAZ（OLF1／EBF－associated zinc finger protein)基因表达显著高于正常对照。结论：中国人群16q12区（58．46cM)与SLE发病相关联，OAZ是该区域可能的疾病基因，其疾病机理有待进一步研究。     

Further evidence for linkage of Gilles de la Tourette syndrome (GTS) susceptibility loci on chromosomes 2p11, 8q22 and 11q23-24 in South African Afrikaners

Utilizing DNA samples from 91 Afrikaner nuclear families with one or more affected children, five genomic regions on chromosomes 2p, 8q, 11q, 20q, and 21q that gave evidence for association with GTS in previous case-control association studies were investigated for linkage and association with GTS. Highly polymorphic markers with mean heterozygosity of 0.77 were typed and resulting genotypes evaluated using single marker transmission disequilibrium (TDT), single marker haplotype relative risk (HRR), and multi-marker "extended" TDT and HRR methods. Single marker TDT analysis showed evidence for linkage or association, with p-values near 0.05, for markers D2S139, GATA28F12, and D11S1377 on chromosomes 2p11, 8q22 and 11q23-24, respectively. Extended, two-locus TDT and HRR analysis provided further evidence for linkage or association on chromosome 2 with p-values of 0.007 and 0.025, and chromosome 8 with p-values of 0.059 and 0.013, respectively. These results provide important additional evidence for the location of GTS susceptibility loci.     

LetterEvidence of Association between FKBP1B and Thyroid Autoimmune Disorders in a Large Tunisian Family

FKBP1B belongs to immunophilins superfamily and functions as a cytosolic receptor protein of FK506. The role of FKBP1B in the immunosuppressive pathway of FK506 is well established. Previously, we reported a strong evidence of linkage between D2S171 microsatellite marker (located in vicinity of FKBP1B gene) and susceptibility to autoimmune thyroid diseases (AITDs). In this study, we report linkage disequilibrium between the dimorphism (C/T) in the 3′ untranslated region (3′ UTR) of FKBP1B gene and susceptibility to AITDs.

DNAs were extracted from a large Tunisian family affected with Graves' disease (GD) and Hashimoto's thyroiditis (HT) and analysed by PCR–RFLP using DraIII restriction enzyme. Our results showed an excess of transmission of the allele C from heterozygous parents to affected offspring (transmission disequilibrium test (TDT)=4.76; p=0.012). This suggests a linkage disequilibrium of 3′ UTR (C/T) SNP with AITDs. Moreover, The FBAT analysis gives a significant association with the C allele under the recessive model (χ²=5.50; p=0.018). These results support the involvement of FKBP1B gene in the genetic susceptibility to the AITDs development in the studied family.     

Psoriasis susceptibility locus in chromosome region 3q21 identified in patients from southwest Sweden

We have performed a pair-wise linkage study in the search for psoriasis susceptibility regions. A preliminary scan was performed on 20 families. In this set we obtained indications of linkage on chromosome 3q21. This region was further investigated using material from a total of 104 families (set 1B) resulting in a non-parametric linkage (NPL) of 1.77. The material was stratified in families whose parental origin is in southwest Sweden (set 1C). A maximum NPL value of 2.77 was obtained in this group. A transmission disequilibrium test (TDT) was performed on the stratified material (set 1C) and a significant P value of 0.005 was obtained, at marker D3S1269. The locus was confirmed with TDT in replicate material consisting of 148 families in which a single member was affected (P value 0.0007) at marker D3S1551. Thus, we have observed a significant P value using TDT in the vicinity of markers D3S1269/D3S1551, suggesting a novel psoriasis susceptibility region.     

Evidence for a type 1 diabetes susceptibility locus (IDDM10) on chromosome 10p11-q11 in a Russian population

Around 20 susceptibility loci for type 1 diabetes mellitus (T1DM) have been mapped. One of these loci, IDDM10, was found on chromosome 10p11-q11. Here, we investigated whether the IDDM10 locus contributes in the susceptibility to T1DM in a Russian family dataset. One hundred and fourteen simplex Russian families, each containing two siblings (one affected with T1DM diagnosed and one nondiabetic sibling), and 97 multiplex families, containing 106 affected full sibling pairs, were studied. Genomic DNA from the venous blood of the patients was genotyped by PCR using 12 microsatellites (D10S193, D10S548, D10S565, D10S586, D10S588, D10S675, D10S1243, D10S1426, D10S1733, D10S1772, D10S1780 and D10S1783) located on chromosome 10p11-q11. Using the multipoint linkage analysis, the region of suggestive linkage, with a multipoint logarithm of odds (LOD) ratio (MLS) value of more than 2.2, was found between markers D10S1733 and D10S1780, an area of 9.0 cM on the genetic map. The maximum linkage peak (MLS = 2.85 and nonparametric logarithm = 2.68) was observed between markers D11S565 and D11S1243. Using the transmission disequilibrium test, an association of these markers, D10S565 (P overall = 0.0082) and D10S1243 (P overall = 0.017), with T1DM was shown. These results suggest the evidence for the IDDM10 susceptibility locus on chromosome 10p11-q11.     

Analysis of chromosome 6q in Basque families with type 1 diabetes. GEPV-N. Basque-Navarre Endocrinology and Paediatric Group

Over the last few years several studies of linkage between non-HLA loci and type 1 diabetes mellitus have mapped several putative susceptibility genes on chromosome 6q; in fact, positive evidence of linkage and/or association of IDDM5 (6q25), IDDM8 (6q27) and IDDM15 (6q21) with type 1 diabetes has been reported. We have studied these loci in diabetic families of Basque origin, a genetically homogeneous population, to avoid artifactual association results due to admixture within the sample analysed. Statistical analyses of linkage were performed using a transmission disequilibrium test (TDT). We could not confirm linkage for IDDM5, IDDM8 and IDDM15 in our population, possibly due to population-specific differences in genetic susceptibility and/or environmental triggering factors to type 1 diabetes.     

Evidence of association between FKBP1B and thyroid autoimmune disorders in a large Tunisian family

FKBP1B belongs to immunophilins superfamily and functions as a cytosolic receptor protein of FK506. The role of FKBP1B in the immunosuppressive pathway of FK506 is well established. Previously, we reported a strong evidence of linkage between D2S171 microsatellite marker (located in vicinity of FKBP1B gene) and susceptibility to autoimmune thyroid diseases (AITDs). In this study, we report linkage disequilibrium between the dimorphism (C/T) in the 3' untranslated region (3' UTR) of FKBP1B gene and susceptibility to AITDs. DNAs were extracted from a large Tunisian family affected with Graves' disease (GD) and Hashimoto's thyroiditis (HT) and analysed by PCR-RFLP using DraIII restriction enzyme. Our results showed an excess of transmission of the allele C from heterozygous parents to affected offspring (transmission disequilibrium test (TDT) = 4.76; p = 0.012). This suggests a linkage disequilibrium of 3' UTR (C/T) SNP with AITDs. Moreover, The FBAT analysis gives a significant association with the C allele under the recessive model (chi2 = 5.50; p = 0.018). These results support the involvement of FKBP1B gene in the genetic susceptibility to the AITDs development in the studied family.     

Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups

Linkage disequilibrium (association) analysis was used to evaluate a candidate region near the CTLA4/CD28 genes using a multi-ethnic collection of families with one or more children affected by IDDM. In the data set unique to this study (Spanish, French, Mexican-American, Chinese and Korean), the transmission/disequilibrium test (TDT) revealed a highly significant deviation for transmission of alleles at the (AT)n microsatellite marker in the 3' untranslated region (P = 0.002) and the A/G polymorphism in the first exon (P = 0.00002) of the CTLA4 gene. The overall evidence for transmission deviation of the CTLA4 A/G alleles is also highly significant (P = 0.00005) in the combined data set (669 multiplex and 357 simplex families) from this study and a previous report on families from USA, Italy, UK, Spain and Sardinia. Significant heterogeneity was observed in these data sets. The British, Sardinian and Chinese data sets did not show any deviation for the A/G polymorphism, while the Caucasian-American data set showed a weak transmission deviation. Strong deviation for transmission was seen in the three Mediterranean-European populations (Italian, Spanish and French) (P = 10(-5)), the Mexican-American population (P = 0.002) and the Korean population (P = 0.03). These results suggest that a true IDDM susceptibility locus (designated IDDM12) is located near CTLA4.      

家族性热性惊厥的染色单体型相对风险和传递不平衡分析

目的　确认家族性热性惊厥是否与染色体６ｑ 或８ｑ 连锁。方法　对核心家系为主的５０ 个家族性热性惊厥家系的热休克蛋白（ ｈｅａｔ ｓｈｏｃｋ ｐｒｏｔｅｉｎ , Ｈ Ｓ Ｐ）７０ 编码区 Ｐｓｔ Ⅰ位点、 Ｈ Ｓ Ｐ７０１ ５′非翻译区、 Ｈ Ｓ Ｐ７０２ ３′非翻译区、微卫星 Ｄ８ Ｓ８４ 和 Ｄ８ Ｓ８５ 等５ 个遗传标志的分型结果,用计算机群体与家系遗传分析系统 Ｐ Ｐ Ａ Ｐ 进行单体型相对风险（ｇｅｎｏｔｙｐｅｂａｓｅｄ ｈａｐｌｏｔｙｐｅ ｒｅｌａｔｉｖｅ ｒｉｓｋ , Ｇ Ｈ Ｒ Ｒ） 和传递不平衡（ｔｒａｎｓｍｉｓｓｉｏｎｄｉｓｅｑｕｉｌｉｂｒｉｕ ｍ ｔｅｓｔ , Ｔ Ｄ Ｔ） 分析。结果　 Ｇ Ｈ Ｒ Ｒ 显示标志 Ｄ８ Ｓ８５ 、 Ｔ Ｄ Ｔ 分析显示 Ｄ８ Ｓ８４ 与家族性热性惊厥有一定关联或存在连锁不平衡。结论　提示家族性热性惊厥可能与染色体８ｑ 连锁。     

Evidence for linkage by transmission disequilibrium test analysis of a chromosome 22 microsatellite marker D22S278 and bipolar disorder in a Palestinian Arab population

A number of linkage studies suggest a schizophrenia susceptibility locus on chromosome 22, particularly with microsatellite marker D22S278 (22q12). In addition to some evidence for linkage to schizophrenia in this region, linkage to bipolar disorder using this marker has also been reported. We tested a group of 60 Bipolar I triads and an expanded group of 79 Bipolar I and Bipolar II triads recruited from a Palestinian Arab population for linkage with the D22S278 marker. Significant linkage was observed using the extended transmission disequilibrium test for multiallelic markers (ETDT) for both Bipolar I (P = 0.031) and the expanded group of Bipolar I and Bipolar II (P = 0.041). These weakly positive results are at least consistent with the hypothesis that this region of chromosome 22 might harbor a susceptibility locus for both major psychoses and should be considered for more intensive study. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:836-838, 2000.     

NO LINKAGE OR ASSOCIATION OF TELOMERIC AND CENTROMERIC T-CELL RECEPTOR β-CHAIN MARKERS WITH SUSCEPTIBILITY TO TYPE 1 INSULIN-DEPENDENT DIABETES IN HLA-DR4 MULTIPLEX FAMILIES

The T-cell receptor β locus (TCRB) on chromosome 7q35 was studied as a candidate region for genetic susceptibility to type 1 insulin-dependent diabetes (IDDM). A highly polymorphic microsatellite marker mapping to the TCRBV6.7 gene and a TCRB C-region RFLP were used to genotype the members of a total of 21 multiplex IDDM families from two different geographical areas. There was no evidence to support linkage to either of these markers with IDDM, and conventional two-point analysis excluded linkage to the telomeric end of the TCRB complex, in the region of the highly informative TCRBV6.7 marker. There was significant linkage of IDDM to the class II HLA-D locus with significant lod scores >3.0 obtained for the HLA-DRB1 and HLA-DQB1 genes. Affected sib-pair (ASP) and transmission disequilibrium (TDT) association tests confirmed these findings.     

Further evidence for linkage of Gilles de la Tourette syndrome (GTS) susceptibility loci on chromosomes 2p11, 8q22 and 11q23‐24 in South African Afrikaners

Utilizing DNA samples from 91 Afrikaner nuclear families with one or more affected children, five genomic regions on chromosomes 2p, 8q, 11q, 20q, and 21q that gave evidence for association with GTS in previous case‐control association studies were investigated for linkage and association with GTS. Highly polymorphic markers with mean heterozygosity of 0.77 were typed and resulting genotypes evaluated using single marker transmission disequilibrium (TDT), single marker haplotype relative risk (HRR), and multi‐marker “extended” TDT and HRR methods. Single marker TDT analysis showed evidence for linkage or association, with p‐values near 0.05, for markers D2S139, GATA28F12, and D11S1377 on chromosomes 2p11, 8q22 and 11q23‐24, respectively. Extended, two‐locus TDT and HRR analysis provided further evidence for linkage or association on chromosome 2 with p‐values of 0.007 and 0.025, and chromosome 8 with p‐values of 0.059 and 0.013, respectively. These results provide important additional evidence for the location of GTS susceptibility loci. © 2001 Wiley‐Liss, Inc.     

Transmission of haplotypes of microsatellite markers rather than single marker alleles in the mapping of a putative type 1 diabetes susceptibility gene (IDDM6)

Allelic association methods based on increased transmission of marker alleles will have to be employed for the mapping of complex disease susceptibility genes. However, because the extent of association of single marker alleles with disease is a function of the relative frequency of the allele on disease-associated chromosomes versus non disease-predisposing chromosomes, the most associated marker allele in a region will not necessarily be closest to the disease locus. To overcome this problem we describe a haplotype-based approach developed for mapping of the putative type 1 diabetes susceptibility gene IDDM6. Ten microsatellite markers spanning a 550 kb segment of chromosome 18q21 in the putative IDDM6 region were genotyped in 1708 type 1 diabetic Caucasian families from seven countries. The most likely ancestral diabetogenic chromosome was reconstructed in a stepwise fashion by analysing linkage disequilibrium between a previously defined haplotype of three adjacent markers and the next marker along the chromosome. A plot of transmission from heterozygous parents to affected offspring of single marker alleles present on the ancestral chromosome versus the physical distance between them, was compared with a plot of transmission of haplotypes of groups of three adjacent markers. Analysing transmission of haplotypes largely negated apparent decreases in transmission of single marker alleles. Peak support for association of the D18S487 region with IDDM6 is P = 0.0002 (corrected P = 0.01). The results also demonstrate the utility of polymorphic microsatellite markers to trace and delineate extended and presumably ancient haplotypes in the analysis of common disease and in the search for identical-by-descent chromosome regions that carry an aetiological variant.      

Association between 7q31 markers and Tourette syndrome

Tourette syndrome (TS) is a complex neuropychiatric disorder with a strong genetic basis. Although no specific susceptibility genes have been identified for TS, cytogenetic studies in selected cases suggest the existence of a predisposing gene located in the 7q31 chromosomal region. In order to test the hypothesis of a possible relationship between this region and TS at the population level, we undertook a family based association study in a sample of French Canadian patients from Quebec. For this purpose, markers D7S522, D7S523, and D7S1516 were tested using the extended transmission disequilibrium test (e-TDT). Marker D7S522 showed a biased transmission of alleles from heterozygote parents to their TS offsprings (allele-wise TDT chi(2) = 12.61, 4 df, P = 0.013, genotype-wise TDT chi(2) = 15.49, 7 df, P = 0.030). When the analysis was restricted to patients without ADHD or OCD comorbidity, similar results were observed both allele and genotype-wise (chi(2) = 10.68, 4 df, P = 0.03 and chi(2) = 12.55, 5 df, P = 0.028, respectively). In addition, marker D7S523 was also associated (allele-wise TDT chi(2) = 18.37, 7 df, P = 0.01 and genotype-wise TDT chi(2) = 46.26, 17 df, P = 0.00016), and showed a tendency for association in the comorbidity-free subgroup (genotype-wise TDT chi(2) = 18.7, 10 df, P = 0.044). Finally, marker D7S1516, contained in the inner mitochondrial membrane peptidase 2 like (IMMP2L) gene, also showed a tendency for association (genotype-wise TDT chi(2) = 32.87, 21 df, P = 0.048). These results may reflect the proximity of markers D7S522, D7S523, and possibly D7S1516 to a gene or regulatory region relevant to TS predisposition.