Cucca, F. et al. A male-female bias in type 1 diabetes and linkage to chromosome Xp in MHC HLA-DR3-positive patients. Nature Genet. 19, 301-302

University of Oxford, Oxford, England, United Kingdom
Nature Genetics (Impact Factor: 29.35). 06/1998; 19(3):301-302. DOI: 10.1038/995


It is generally assumed that the male:female (M:F) ratio in patients
with type 1 (insulin-dependent) diabetes mellitus (IDDM) is 1. A recent survey,
however, revealed that high incidence countries (mainly European) have a high
M:F ratio and low incidence ones (Asian and African) have a low M:F ratio1. We have now analysed the M:F ratio according to genotype at the
major locus, the major histocompatibility complex (MHC; IDDM1). There
are two main IDDM1 susceptibility haplotypes, HLA-DR3 and -DR4, which
are present in 95% of Caucasian cases2,
4. We report here
that in medium/high incidence Caucasian populations from the United States
of America, United Kingdom and Sardinia (1307 cases), the bias in male incidence
is largely restricted to the DR3/X category of patients (X DR4) with
a M:F ratio of 1.7 (P = 9.3 10−7), compared
with a ratio of 1.0 in the DR4/Y category (Y DR3). This is additional
evidence for significant heterogeneity between the aetiology of 'DR4-associated'
and 'DR3-associated' diabetes5,
We analysed linkage of type 1 diabetes to chromosome X, and as expected, most
of the linkage to Xp13−p11 was in the DR3/X affected sibpair families
(n = 97; peak multipoint MLS at DXS1068 = 3.5, P = 2.7
10−4; single point MLS = 4.5, P = 2.7
10−5). This is evidence for aetiological heterogeneity
at the IDDM1/MHC locus and, therefore, in the search for non-MHC loci
in type 1 diabetes, conditioning of linkage data by HLA type is advised.

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Available from: Francesco Cucca, May 14, 2014
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    • "Although the global incidence of T1D seems not to differ between male and female, countries with a high incidence of T1D have a high male to female ratio and those of low incidence have a low ratio [27]. The increased number of females in T1D group is consistent with findings of higher T1D prevalence among females in Brazil [9]. "
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    ABSTRACT: CD226 rs763361 variant increases susceptibility to type 1 diabetes (T1D) in Caucasians. There is no data about CD226 variants in the very heterogeneous Brazilian population bearing a wide degree of admixture. We investigated its association with T1D susceptibility, clinical phenotypes, and autoimmune manifestations (islet and extrapancreatic autoantibodies). Casuistry. 532 T1D patients and 594 controls in a case-control study. Initially, CD226 coding regions and boundaries were sequenced in a subset of 106 T1D patients and 102 controls. In a second step, two CD226 variants, rs763361 (exon 7) and rs727088 (3' UTR region), involved with CD226 regulation, were genotyped in the entire cohort. C-peptide and autoantibody levels were determined. No new polymorphic variant was found. The variants rs763361 and rs727088 were in strong linkage disequilibrium. The TT genotype of rs763361 was associated with TID risk (OR = 1.503; 95% CI = 1.135-1.991; P = 0.0044), mainly in females (P = 0.0012), greater frequency of anti-GAD autoantibody (31.9% × 24.5%; OR = 1.57; CI = 1.136-2.194; P = 0.0081), and lower C-peptide levels when compared to those with TC + CC genotypes (0.41 ± 0.30 ng/dL versus 0.70 ± 0.53 ng/dL P = 0.0218). Conclusions. The rs763361 variant of CD226 gene (TT genotype) was associated with susceptibility to T1D and with the degree of aggressiveness of the disease in T1D patients from Brazil. Ancestry had no effect.
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    • "Two whole genome scans for linkage in GD have shown evidence for linkage at putative X-chromosome loci, Xq21 [68], and Xp11 [69], and these loci have also been identified in localized linkage scans of the X-chromosome, Xq21 [68] and Xp11 [70], although one of the two genome wide screen increased their numbers and performed an enlarged genome wide screen and no evidence for Xp21 as a region of linkage to GD [71]. In terms of broader relevancy to autoimmunity in general, Xp11 has also been linked to other autoimmune disorders, T1D, multiple sclerosis, and RA, thus suggesting the presence of common susceptibility polymorphism(s) [72–74]. The FOXP3 gene is located at Xp11.23 within this area of autoimmune disease linkage and is therefore an excellent positional candidate gene for autoimmunity at this locus. "
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    ABSTRACT: Autoimmune thyroid diseases (AITDs), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are caused by immune response to self-thyroid antigens and affect approximately 2-5% of the general population. Genetic susceptibility in combination with external factors, such as smoking, viral/bacterial infection, and chemicals, is believed to initiate the autoimmune response against thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITDs. Various techniques have been employed to identify genes contributing to the etiology of AITDs, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions) that are linked to AITDs, and, in some of these loci, putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to GD and HT and some are common to both diseases, indicating that there is a shared genetic susceptibility to GD and HT. Known AITD-susceptibility genes are classified into three groups: HLA genes, non-HLA immune-regulatory genes (e.g., CTLA-4, PTPN22, and CD40), and thyroid-specific genes (e.g., TSHR and Tg). In this paper, we will summarize the latest findings on AITD susceptibility genes in Japanese.
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    • "Indeed, it suggests that males are more susceptible to environmental agents. Male excess has previously been reported and was largely restricted to those patients carrying the HLA-DR3/nonDR4 genotype [43]. Results of another study do not support a significant involvement of the Y chromosome in DR3/nonDR4 type 1 diabetic cases in early-onset type 1 diabetes as a whole [44]. "
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    ABSTRACT: The aim of this prospective study was to determine the incidence of type 1 diabetes mellitus in 15-34-year-aged Lithuanian males and females during 1991 - 2008 A contact system with general practitioners covering 100% of the 15-34-year-aged Lithuanian population was the primary data source. Reports from regional endocrinologists and statistical note-marks of State patient insurance fund served as secondary sources for case ascertainment. The average age-standardized incidence rate was 8.30 per 100,000 persons per year (95% Poisson distribution confidence interval [CI] 7.90-8.71) during 1991 - 2008 and was statistically significantly higher among males (10.44 per 100,000 persons per year, 95% CI 9.82-11.10) in comparison with females (6.10 per 100,000, 95% CI 5.62-6.62). Male/female rate ratio was 1.71 (95% CI 1.63-1.80). Results of the linear 1991 - 2008 regression model showed that the incidence of Type 1 diabetes in 15-34-year-aged males and females decreased slightly over the time (r = -0.215, p > 0.05). Our data demonstrated the male predominance in primary incidence of type 1 diabetes mellitus in 15-34-year-aged population in Lithuania. The incidence of type 1 diabetes mellitus in 15-34-year-aged males and females decreased slightly during 1991-2008.
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