Alleles In Children Research Articles

Retrospective Cohort Analysis of Class II Human Leukocyte Antigen (HLA) Alleles in Children With Steroid-Dependent Nephrotic Syndrome Treated With Cyclophosphamide.

Background The role of specific human leukocyte antigen (HLA) alleles as a risk factor for susceptibility, protection, and response to cyclophosphamide (CYC) treatment has been studied in patients with idiopathic nephrotic syndrome (INS). This study investigates the association of class II HLA alleles and the treatment outcome in children with steroid-dependent nephrotic syndrome (SDNS) who were treated with CYC. Methods A total of 77 children who were diagnosed with SDNS and had received CYC at least a year before were enrolled. After obtaining informed consent from the parents, blood samples were collected to type the HLA class II locus (DR and DQ) using sequence-specific primers (SSP). An equal number of adult healthy controls (AHC) were included. Results The median age of the study participants at disease onset was five (IQ: 3-7) years with a male-to-female ratio of 1.48:1.The common HLA alleles found in the study cohort and controls were DRB1*7 45 (29%), DRB1*15 30 (19.5%), and DQB1*2 57 (37%), and DRB1*15 31(20%), DRB1*17 36 (23%), DQB1*6 42 (27%), and DQB1*2 38 (25%), respectively. Identification of a particular allele to predict a good or poor response was not statistically significant (p-value >0.05). Conclusion The study demonstrates the common HLA alleles in the cohort. However, a specific allele that can predict a good and poor response to CYP was not identified. Further large-scale, prospective multicenter studies are needed to identify such alleles to decide the use of CYC in the SDNS population judiciously.

Does HLA explain the high incidence of childhood-onset type 1 diabetes in the Canary Islands? The role of Asp57 DQB1 molecules

The Canary Islands inhabitants, a recently admixed population with significant North African genetic influence, has the highest incidence of childhood-onset type 1 diabetes (T1D) in Spain and one of the highest in Europe. HLA accounts for half of the genetic risk of T1D.AimsTo characterize the classical HLA-DRB1 and HLA-DQB1 alleles in children from Gran Canaria with and without T1D.MethodsWe analyzed classic HLA-DRB1 and HLA-DQB1 alleles in childhood-onset T1D patients (n = 309) and control children without T1D (n = 222) from the island of Gran Canaria. We also analyzed the presence or absence of aspartic acid at position 57 in the HLA-DQB1 gene and arginine at position 52 in the HLA-DQA1 gene. Genotyping of classical HLA-DQB1 and HLA-DRB1 alleles was performed at two-digit resolution using Luminex technology. The chi-square test (or Fisher's exact test) and odds ratio (OR) were computed to assess differences in allele and genotype frequencies between patients and controls. Logistic regression analysis was also used.ResultsMean age at diagnosis of T1D was 7.4 ± 3.6 years (46% female). Mean age of the controls was 7.6 ± 1.1 years (55% female). DRB1*03 (OR = 4.2; p = 2.13–13), DRB1*04 (OR = 6.6; p ≤ 2.00–16), DRB1* 07 (OR = 0.37; p = 9.73–06), DRB1*11 (OR = 0.17; p = 6.72–09), DRB1*12, DRB1*13 (OR = 0.38; p = 1.21–05), DRB1*14 (OR = 0.0; p = 0.0024), DRB1*15 (OR = 0.13; p = 7.78–07) and DRB1*16 (OR = 0.21; p = 0.003) exhibited significant differences in frequency between groups. Among the DQB1* alleles, DQB1*02 (OR: 2.3; p = 5.13–06), DQB1*03 (OR = 1.7; p = 1.89–03), DQB1*05 (OR = 0.64; p = 0.027) and DQB1*06 (OR = 0.19; p = 6.25–14) exhibited significant differences. A total of 58% of the studied HLA-DQB1 genes in our control population lacked aspartic acid at position 57.ConclusionsIn this population, the overall distributions of the HLA-DRB1 and HLA-DQB1 alleles are similar to those in other European populations. However, the frequency of the non-Asp-57 HLA-DQB1 molecules is greater than that in other populations with a lower incidence of T1D. Based on genetic, historical and epidemiological data, we propose that a common genetic background might help explain the elevated pediatric T1D incidence in the Canary Islands, North-Africa and middle eastern countries.

Genetic polymorphisms of the folate cycle and hyperhomocysteinemia in children from areas bordering the Chоrnobyl exclusion zone

The aim of the work is to establish a relationship between polymorphisms of the FC and the state of hyperhomocysteinemia in children living in areas bordering the ChEZ). Research methods: laboratory, genetic, mathematical-statistical. Results: The levels of homocysteine (Hcy) in blood and genetic polymorphisms of the folate cycle (FC) were determined in 690 children (322 boys and 368 girls) aged 8-17 years old living near the ChEZ. It was found that 97.8% of the children had genotypes with risk alleles of FC polymorphisms. The most common combinations of 2 and 3 polymorphic variants. The proportion of hyperhomocysteinemia cases was recorded in 62.5% of those examined and did not generally depend on the number of FC polymorphisms with risk alleles. Unlike their mothers, there was no correlation between blood Hcy concentration and the number of FC polymorphisms with risk alleles in children. The frequency of hyperhomocysteinemia cases in boys was likely higher than in girls. Hyperhomocysteinemia was detected in 40% of cases among children with no risk alleles for FC genetic polymorphisms. Genotypes with allele variants of one FC polymorphism were found in 15% of cases. High frequency of hyperhomocysteinemia was recorded both in the subgroup with T/T MTHFR:677 genotype and in most genetic subgroups. A high frequency of hyperhomocysteinemia, with four polymorphisms with risk alleles, was associated with compound heterozygotes A/CMTHFR:1298 and C/TMTHFR:677 in combination with A/G MTR genotypes: A2756G and G/G A66G. The homozygous variant of the neutral allele A of the MTRR:A66G genetic polymorphism, which controls methionine synthase reductase, contributed to the improvement of Hcy methylation processes in risk allele variants of three FC polymorphisms. Conclusions: The conducted studies indicate that in children of the second Chоrnobyl generation, who have been living in conditions of constant radiation exposure in areas affected by the Chоrnobyl accident since birth, the occurrence of hyperhomocysteinemia is not associated with a specific genotype and the number of FC polymorphisms with risk alleles. The results obtained indicate the participation of genetic and environmental factors in the occurrence of hyperhomocysteinemia in the population of children living in areas located near the ChEZ.

Association of HLA class II DR/DQ alleles in children and adolescents with rheumatic heart disease from a tertiary care centre in North India

IntroductionRheumatic fever and RHD constitutes an important public health problem in India. The relatively low attack rate of RF, the high concordance rate for RF in monozygotic twins (19%) compared to dizygotic twins (2.5%), and the high familial incidence of RF suggest the involvement of host genetic factors in susceptibility to RF with consequential progression to RHD. ObjectiveTo study the association of HLA CLASS II DR/DQ alleles in children and adolescents with RHD from a tertiary care center in North India. Methods30 RHD patients and 30 age and sex-matched controls were included in our study and blood samples for HLA typing were processed through LAB Type™ reverse SSO DNA typing method. The assignment of the HLA typing was based on a comparison with already published HLA gene sequences. ResultsThe mean age of RHD patients and matched control groups were 12.97 ± 2.95 and 11.93 ± 3.23, respectively. In the cases and control group, males accounted for 63.3% and 50% of the patients respectively. A significant difference was found between the cases and controls for HLA DR∗ 15 (p-value 0.002), HLA DR∗ B4 (p-value 0.045), HLA DR∗ B5 (p-value 0.017), and HLA DQB1∗ 02 (p-value 0.005). ConclusionOur study suggests that HLA class II haplotypes may provide insight into the molecular mechanism of RHD and be a useful tool in predicting the clinical outcome in RF patients, thereby affording new means of intervention or vaccine design. Larger studies are needed to address this in our population.

Association between MTHFR gene polymorphism and primary hypertension in children

To study the distribution characteristics of methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in children with primary hypertension, and to explore the association between MTHFR C677T gene polymorphism and H-type hypertension in children. A total of 121 children with primary hypertension who were hospitalized in the department of cardiovascular medicine from January to July 2021, newly diagnosed, and untreated were retrospectively selected as the subjects. The children were divided into three groups: CC genotype (19 children), CT genotype (51 children), and TT genotype (51 children). According to the serum homocysteine (Hcy) level, they were divided two groups: H-type hypertension (47 children) and simple hypertension (74 children). The medical data were compared between the groups. The association between MTHFR C677T gene polymorphism and H-type hypertension was evaluated. The mutation frequency of T allele in children with primary hypertension was significantly higher than that in healthy adults in Beijing and Chinese Han adults (P<0.001). The serum Hcy level in the TT genotype group was significantly higher than that in the CC and CT genotype groups (P<0.001). The serum Hcy level in the H-type hypertension group was significantly higher than that in the simple hypertension group (P<0.001), and MTHFR C677T was mostly TT genotype, which was associated with the risk of H-type hypertension (OR=12.71, P<0.001). There was no significant difference in the incidence rate of target organ damage between the H-type hypertension and simple hypertension groups (P>0.05). However, multiple organ involvement was observed in the H-type hypertension group at diagnosis, accounting for 11% (5/47). The mutation rate of MTHFR C677T T allele in children with primary hypertension is high and associated with the serum Hcy level. TT genotype is an independent risk factor for H-type hypertension in children, and it may be related to the severity of early target organ damage.

CYP450 2D6 and 2C19 genotypes in ADHD: not related with treatment resistance but with over-representation of 2C19 ultra-metabolizers.

Cytochrome P450 (CYP450) is a major enzyme system involved in drug metabolism as well as regulation of brain function. Although individual variability in CYP enzymes have been studied in terms of personality traits and treatment effects, no study up to now evaluated CYP polymorphisms in children with attention deficit/hyperactivity disorder (ADHD). We aimed to define the genetic profiles of CYP2D6 and CYP2C19 relevant alleles in children with ADHD according to treatment status and compare the frequencies according to past results. Three hundred and seventeen patients with ADHD-Combined Presentation were enrolled; symptom severity was evaluated by parents and clinicians while adverse effects of previous treatments were evaluated with parent and child reports. Reverse blotting on strip assays was used for genotyping and descriptive and bivariate analyses were conducted. A p-value was set at 0.05 (two-tailed). Children were divided into treatment-naïve (n=194, 61.2%) and treatment-resistant (n=123, 38.8%) groups. Within the whole sample PM, EM and UM status according to 2D6 were 3.8% (n=12), 94.3% (n=299) and 21.9% (n=6); respectively. PM, IM, EM and UM status according to 2C19 were 2.5% (n=8), 19.8% (n=63), 48.6% (n=154) and 29.0% (n=92), respectively. No relationship with treatment resistance, comorbidity or gender could be found. Importantly, CYP2C19 UMs were significantly more frequent in ADHD patients compared to previous studies in the general population. CYPs may be a rewarding avenue of research to elucidate the etiology and treatment of patients with ADHD.

Association of HLA Class II DR/DQ Alleles in Children and Adolescents with Rheumatic Heart Disease from a Tertiary Care Centre in North India

Association of HLA Class II DR/DQ Alleles in Children and Adolescents with Rheumatic Heart Disease from a Tertiary Care Centre in North India

MO1026MICROALBUMIN LEVEL IN URINE DEPENDING ON ACE GENE POLYMORPHISM IN PATIENTS WITH VUR

Abstract Background and Aims reflux nephropathy (RN) is the most serious complication of vesicoureteral reflux (VUR). The aim of the study was to assess the urinary level of MA (microalbumin) as an expression of tubulointerstitial damage depending of ACE genotype polymorphisms in children with VUR. Method 94 patients, with VUR at the age from 3 year to 16 years (average age of 6.72 ± 0.68 years), including 65 girls (69,1%) were enrolled. As a control population to compare the distribution of genotypes and alleles of ACE gene used a sample of 100 healthy children (82girls), indigenous ethnic groups, mean age of 11.3 ± 5.4 years. To determine the gene polymorphism of ACE we used the method of polymerase chain reaction. Renal scar in DMSA scan was performed at least six months after urine tract infection (UTI). According to DMSA scan results, children were divided into 2 groups: gr. 1 - 12p. (VUR without RN), gr. 2 – 82 p. (VUR with RN). Urinary excretion of MA was measured by ELISA method. Results In gr. 1 is the frequency of genotype I/I amounted to 58%, I/D is 42% and D/D – is not detected. In the scar group (gr.2) frequency of genotype I/I is 12% (p1,2&amp;lt;0,05), I/D is 63% and (p&amp;gt;0.05), and D/D is 25% (p&amp;lt;0.05), respectively. In the distribution of I and D allele in children with VUR (71,3% of children with RN has got D allele). In RN groups with genotype D/D, the level of MA/Cr in the urine was 1,5 times higher than in children with genotype I/D (p&amp;lt;0.05) and 3-3,5 times higher than in patients with genotype I/I (р=0.0001). Significant difference in urinary levels of MA/Cr in the non scar group with genotype I/I and I/D is not revealed. Conclusion D/D-genotype of ACE may be a genetic susceptibility factor contributing to adverse renal prognosis – reflux nephropathy and presenting as risk factor for scar formation. A high urinary level of MA/Cr and positive correlation with genotype D/D is a significant and sensible marker of tubulointerstitial damage

Spinocerebellar ataxia type 2 from an evolutionary perspective: Systematic review and meta-analysis.

Dominant diseases due to expanded CAG repeat tracts, such as spinocerebellar ataxia type 2 (SCA2), are prone to anticipation and worsening of clinical picture in subsequent generations. There is insufficient data about selective forces acting on the maintenance of these diseases in populations. We made a systematic review and meta-analysis on the effect of the CAG length over age at onset, instability of transmissions, anticipation, de novo or sporadic cases, fitness, segregation of alleles, and ancestral haplotypes. The correlation between CAG expanded and age at onset was r2 =0.577, and transmission of the mutant allele was associated with an increase of 2.42 CAG repeats in the next generation and an anticipation of 14.62 years per generation, on average. One de novo and 18 sporadic cases were detected. Affected SCA2 individuals seem to have more children than controls. The expanded allele was less segregated than the 22-repeat allele in children of SCA2 subjects. Several ancestral SCA2 haplotypes were published. Data suggest that SCA2 lineages may tend to disappear eventually, due to strong anticipation phenomena. Whether or not the novel cases come from common haplotypes associated with a predisposition to further expansions is a question that needs to be addressed by future studies.

Combination of HLA-DRB1 alleles as a factor causing risks of sporadic congenital heart defects and congenital malformations without chromosome diseases

Congenital heart defects are anomalies that are becoming more and more frequent every year. Their specific weight is the highest among all the defects and malformations in fetus. Besides, children with sporadic congenital heart defects and malformations are still born rather frequently. We made an assumption that congenital heart defects (CHD) and congenital malformations (CM) were formed due to inflammatory process decompensation within «mother – fetus» system occurring in case of a conflict as per HLA between a semi-allogenic fetus and its mother’s microenvironment. A risk of such a conflict might be associated with certain HLA combinations in parents’ genotypes. Our research goal was to reveal peculiarities of HLA-DRB1 alleles combinations in married couples who had children with sporadic CHD and CM without any chromosome diseases and to determine whether such peculiarities could cause risks of congenital anomalies. We determined frequency of 14 alleles in HLA-DRB1 gene in all people who took part in the research. Our research allowed establishing that parents whose children suffered from CHD more frequently had common HLA-DRB104, female HLA-DRB107 with male HLA-DRB113, HLA-DRB117 and female HLA-DRB113 with male HLA-DRB114. Children who suffered from CM more frequently had parents who were homologous as per HLA-DRB112, as well as with female HLA-DRB112 and male HLA-DRB101, HLA-DRB104, HLA-DRB113, and HLA-DRB115; this greater frequency was statistically significant. We also detected an authentic increase in frequency of HLA-DRB112 allele in children against their parents. Children with CM also had HLA-DRB112 allele statistically significantly more frequently than healthy children. Peculiarities related to HLA-DRB1 alleles combination are genetic predictors of CHD and CM occurrence; their determination will allow minimizing risks of such disorders due to early diagnostics and timely prevention.

Cочетание аллелей HLA-DRB1 как условие реализации риска формирования спорадических врожденных пороков сердца и врожденных пороков развития плода без хромосомных заболеваний

Congenital heart defects are anomalies that are becoming more and more frequent every year. Their specific weight is the highest among all the defects and malformations in fetus. Besides, children with sporadic congenital heart defects and malformations are still born rather frequently. We made an assumption that congenital heart defects (CHD) and congenital malformations (CM) were formed due to inflammatory process decompensation within «mother – fetus» system occurring in case of a conflict as per HLA between a semi-allogenic fetus and its mother’s microenvironment. A risk of such a conflict might be associated with certain HLA combinations in parents’ genotypes. Our research goal was to reveal peculiarities of HLA-DRB1 alleles combinations in married couples who had children with sporadic CHD and CM without any chromosome diseases and to determine whether such peculiarities could cause risks of congenital anomalies. We determined frequency of 14 alleles in HLA-DRB1 gene in all people who took part in the research. Our research allowed establishing that parents whose children suffered from CHD more frequently had common HLA-DRB104, female HLA-DRB107 with male HLA-DRB113, HLA-DRB117 and female HLA-DRB113 with male HLA-DRB114. Children who suffered from CM more frequently had parents who were homologous as per HLA-DRB112, as well as with female HLA-DRB112 and male HLA-DRB101, HLA-DRB104, HLA-DRB113, and HLA-DRB115; this greater frequency was statistically significant. We also detected an authentic increase in frequency of HLA-DRB112 allele in children against their parents. Children with CM also had HLA-DRB112 allele statistically significantly more frequently than healthy children. Peculiarities related to HLA-DRB1 alleles combination are genetic predictors of CHD and CM occurrence; their determination will allow minimizing risks of such disorders due to early diagnostics and timely prevention.

Admixture/fine-mapping in Brazilians reveals a West African associated potential regulatory variant (rs114066381) with a strong female-specific effect on body mass and fat mass indexes.

Admixed populations are a resource to study the global genetic architecture of complex phenotypes, which is critical, considering that non-European populations are severely underrepresented in genomic studies. Here, we study the genetic architecture of BMI in children, young adults, and elderly individuals from the admixed population of Brazil. Leveraging admixture in Brazilians, whose chromosomes are mosaics of fragments of Native American, European, and African origins, we used genome-wide data to perform admixture mapping/fine-mapping of body mass index (BMI) in three Brazilian population-based cohorts from Northeast (Salvador), Southeast (Bambuí), and South (Pelotas). We found significant associations with African-associated alleles in children from Salvador (PALD1 and ZMIZ1 genes), and in young adults from Pelotas (NOD2 and MTUS2 genes). More importantly, in Pelotas, rs114066381, mapped in a potential regulatory region, is significantly associated only in females (p = 2.76e-06). This variant is rare in Europeans but with frequencies of ~3% in West Africa and has a strong female-specific effect (95% CI: 2.32-5.65 kg/m2 per each A allele). We confirmed this sex-specific association and replicated its strong effect for an adjusted fat mass index in the same Pelotas cohort, and for BMI in another Brazilian cohort from São Paulo (Southeast Brazil). A meta-analysis confirmed the significant association. Remarkably, we observed that while the frequency of rs114066381-A allele ranges from 0.8 to 2.1% in the studied populations, it attains ~9% among women with morbid obesity from Pelotas, São Paulo, and Bambuí. The effect size of rs114066381 is at least five times higher than the FTO SNPs rs9939609 and rs1558902, already emblematic for their high effects. We identified six candidate SNPs associated with BMI. rs114066381 stands out for its high effect that was replicated and its high frequency in women with morbid obesity. We demonstrate how admixed populations are a source of new relevant phenotype-associated genetic variants.

Значение генетических факторов в развитии целиакии у детей узбекской популяции

The results of genetic studies have proven the relationship of celiac disease with class II genes of the major histocompatibility complex (HLA), in particular with the DQ locus. The presence of specific alleles at the HLA-DQ locus is necessary, but insufficient, for the realization of the disease phenotype. In Uzbekistan, the distribution of HLA markers in children with celiac disease has not been studied and these studies are required. Purpose — to establish the peculiarities of the distribution of HLA II class celiac disease alleles in children in the Uzbek population. Materials and methods. We examined 54 children with celiac disease of the Uzbek population, who were registered and receiving inpatient treatment at the Republican Specialized Scientific and Practical Medical Center of Pediatrics. The age of the examined children was from 1 to 14 years old, the average age was 7.3±1.9 years. The control group consisted of 109 unrelated Uzbeks without immune diseases. Molecular typing of HLA II class genes was determined by DNA chain reaction polymerase. Results. As a result of gene typing, 48 (88.8%) out of 54 investigated had DQ2 and DQ8 haplotypes associated with celiac disease. Haplotypes with only DQ2 and DQ8 were found in 19 (39.5%) and 7 (14.5%), respectively. DQ2 from 48 children was found in 18 (37.5%) children in the trans-position, in 2 (4,1%) — as two copies of DQ2 dimers, and in 1 (2%) case in combination with DQ8. Only in one case (2%) was DQ8 found as two copies of DQ8 dimers. The frequency of occurrence of the HLA-DRB1*07 and *13 alleles was significantly higher than in the control group. The maximum value of the relative risk and the criterion of reliability are noted in the DQA1*0501 allele, i.e. it is positively associated with celiac disease (χ2=7.28, RR=2.03). Significance criterion and relative risk were observed in sick children with DQB1*0201 (χ2=6.74, RR=1.97) associated with celiac disease. The number of haplotype (DQA1*0501-DQB1*0201) was 36 (75%). Conclusions. A specific predisposition to celiac disease in children of the Uzbek population is associated with the genes HLA-DQA1*0501, HLA-DQB1*0201, HLA-DRB1*07 and *13. Alleles such as DRB1*15, DQA1*0102, DQB1*0303 and *0502, have a protective effect in the development of celiac disease in children of the Uzbek population. A high frequency of carriage of the DRB1*13 — HLA-DQА1*0501 and DQB1*0201 (DQ2 type) haplotype in Uzbeks (75%) was found, which requires a more thorough population genetic study of the Uzbek population for the HLA II class DRB1-DQA1-DQB1 genes. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of these Institutes. The informed consent of the patient was obtained for conducting the studies. No conflict of interest was declared by the authors. Key words: celiac disease, children, genetics, HLA class II.

Analysis OF C677T polymorphism in methylene tetrahydrofolate reductase (MTHFR) gene as a risk factor for congenital talipes equino varus (CTEV)

BackgroundClubfoot is a common congenital foot deformity. Low folate status in mothers has been associated with CTEV. Folate metabolism might be affected by Methylene Tetrahydrofolate Reductase (MTHFR) gene polymorphism. The present study was aimed to investigate MTHFR C677T polymorphism and its association with CTEV. MethodsThis is a Case-mother-Dyad study with 30 pairs of cases and controls. Single Nucleotide Polymorphism (SNP) analysis of the MTHFR gene was done in this hospital-based study by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). ResultsIn this study, we observed less relative risk of CTEV in presence of C allele as compared to T allele in children, with Relative Risk- 0.6281 and likelihood ratio of 0.5714. While analysing the correlation of genotype variation in cases (CC = 8(26.66%) and CT = 22(73.33%)) with there biological mother (CC = 13(43.33%) and CT = 17(56.66%)), no significant correlation (p = 0.3110) was found between cases and their biological mother genotype. ConclusionAmong the enrolled cases, there was a significant association of increased CTEV risk with 677T variant allele of MTHFR gene. Also, maternal MTHFR genotype was not found to influence CTEV risk of offspring.

Increased Burden of Common Risk Alleles in Children With a Significant Fracture History.

Extreme presentations of common disease in children are often presumed to be of Mendelian etiology, but their polygenic basis has not been fully explored. We tested whether children with significant fracture history and no osteogenesis imperfecta (OI) are at increased polygenic risk for fracture. A childhood significant fracture history was defined as the presence of low-trauma vertebral fractures or multiple long bone fractures. We generated a polygenic score of heel ultrasound-derived speed of sound, termed "gSOS," which predicts risk of osteoporotic fracture. We tested if individuals from three cohorts with significant childhood fracture history had lower gSOS. A Canadian cohort included 94 children with suspected Mendelian osteoporosis, of which 68 had negative OI gene panel. Two Finnish cohorts included 59 children with significant fracture history and 22 with suspected Mendelian osteoporosis, among which 18 had no OI. After excluding individuals with OI and ancestral outliers, we generated gSOS estimates and compared their mean to that of a UK Biobank subset, representing the general population. The average gSOS across all three cohorts (n = 131) was -0.47 SD lower than that in UK Biobank (n = 80,027, p = 1.1 × 10-5 ). The gSOS of 78 individuals with suspected Mendelian osteoporosis was even lower (-0.76 SD, p = 5.3 × 10-10 ). Among the 131 individuals with a significant fracture history, we observed 8 individuals with gSOS below minus 2 SD from the mean; their mean lumbar spine DXA-derived bone mineral density Z-score was -1.7 (SD 0.8). In summary, children with significant fracture history but no OI have an increased burden of common risk alleles. This suggests that a polygenic contribution to disease should be considered in children with extreme presentations of fracture. © 2020 American Society for Bone and Mineral Research.

Inherited genetic susceptibility to acute lymphoblastic leukemia in Down syndrome

AbstractChildren with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) and distinct somatic features, including CRLF2 rearrangement in ∼50% of cases; however, the role of inherited genetic variation in DS-ALL susceptibility is unknown. We report the first genome-wide association study of DS-ALL, comprising a meta-analysis of 4 independent studies, with 542 DS-ALL cases and 1192 DS controls. We identified 4 susceptibility loci at genome-wide significance: rs58923657 near IKZF1 (odds ratio [OR], 2.02; Pmeta = 5.32 × 10−15), rs3731249 in CDKN2A (OR, 3.63; Pmeta = 3.91 × 10−10), rs7090445 in ARID5B (OR, 1.60; Pmeta = 8.44 × 10−9), and rs3781093 in GATA3 (OR, 1.73; Pmeta = 2.89 × 10−8). We performed DS-ALL vs non-DS ALL case-case analyses, comparing risk allele frequencies at these and other established susceptibility loci (BMI1, PIP4K2A, and CEBPE) and found significant association with DS status for CDKN2A (OR, 1.58; Pmeta = 4.1 × 10−4). This association was maintained in separate regression models, both adjusting for and stratifying on CRLF2 overexpression and other molecular subgroups, indicating an increased penetrance of CDKN2A risk alleles in children with DS. Finally, we investigated functional significance of the IKZF1 risk locus, and demonstrated mapping to a B-cell super-enhancer, and risk allele association with decreased enhancer activity and differential protein binding. IKZF1 knockdown resulted in significantly higher proliferation in DS than non-DS lymphoblastoid cell lines. Our findings demonstrate a higher penetrance of the CDKN2A risk locus in DS and serve as a basis for further biological insights into DS-ALL etiology.

HLA-DRB1 allele distribution among children with rheumatic heart disease in Haji Adam Malik Hospital Medan, Indonesia.

Rheumatic heart disease (RHD) is influenced by genetic factor, microorganism's virulence, and environmental factor. The aim of this study was to determine human leukocyte (HLA)-DRB1 allele among children with RHD in Medan, Indonesia. Methods An observational study was conducted at the Department of Child Health, Haji Adam Malik Hospital Medan from April to June 2017. Inclusion criteria were children aged 5-18 years diagnosed with RHD. Children with concomitant congenital heart disease were excluded. HLA-DRB1 alleles were analyzed using the PCR sequence-specific priming (SSP) technique. Statistical analysis was done using computer software. Results A total of 62 children were enrolled. The mean age of children was 12.6 (SD 3.44) years; 33 (53.2%) were male. The most dominant allele was HLA-DRB1*12, followed by HLADRB1*15. Conclusion It is proven in this research that RHD is influenced by genetic factor with HLA-DRB1*12 allele found to be the most common allele in children with RHD in Medan, Indonesia.

HLA-DQB1*02 allele in children with celiac disease: Potential usefulness for screening strategies.

Through a retrospective analysis of a real-life cohort of children with celiac disease(CD), who underwent HLA-DQ genotyping, we supported our previous findings indicating the presence of HLA-DQB1*02 allele in at least 90%-95% of pediatric patients. In the present study, reporting the HLA-DQ analysis from 184 children (age range: 1-16years) diagnosed with CD in a single centre, we found that 97.29% of all these CD children (n=179 out of 184 genotyped patients) resulted to be carriers of at least one copy of HLA-DQB1*02 allele. If a widened screening for CD should result tobeappropriate in the pediatric population afterfurther clinical research,this observation might be potentially exploited to consider a two-step screening strategy, starting with the HLA-DQB1*02 targeted analysisfollowed by the specific serology for CD in these predisposed patients only. However, additional and larger studies are needed to support our findings.

Relapsing periodic arthritis, palindromic rheumatism and MEFV gene-related variants alleles in children

BackgroundRelapsing periodic arthritis is a general term used for a group of diseases with recurring and periodic nature, in which the joints are intermittently involved. The aim of this study is to evaluation of the possible relationship between MEFV gene mutations in intermittent arthritis of children which has recurring and periodic nature.MethodsIn this cross-sectional study we reviewed medical records of all patients with recurrent and periodic arthritis referred to pediatric rheumatology clinic from 2003 to 2019.We excluded all patients with suspicious anamnesis and/or positive history of FMF, JIA, gout, psoriasis, IBD and SLE. The peripheral blood of these patients was screened for the 12 common pathogenic MEFV gene variants (FMF Strip Assay, Vienna lab, Vienna, Austria) according to manufacturer’s instructions.ResultsAmong 195 recorded files, 11 patients were identified with idiopathic recurrent and periodic feature. 3 patients suffering from recurrent transient synovitis hip (RSH) and 8 patients were fully compatible with the Pasero and Barbieri modified criteria of palindromic rheumatism (PR). Their mean age at diagnosis was 6.5 and 4.6 years and the average follow-up was 2.6 and 6.6 years in PR and RSH patients, respectively. The most frequently involved joints were knees and ankles in PR patients. The mean duration of attacks was 3.3 days in RSH patients and with various courses in PR. The median number of attacks was 4.75 in PR and 3 in RSH patients per year. In PR group 7 patients showed no mutations and all patients of RSH had these mutations; V726A, R761H, A744S as in heterozygote pattern.ConclusionAn idiopathic relapsing periodic arthritis in children with exclusively hip involvement is a MEFV gene related arthropathy; whereas with various joint attacks it could be considered as childhood PR.

HLA-B*14 allele predicts HIV-1 mother-to-child-transmission, in Salvador, Brazil

BackgroundClass I human leukocyte antigens, especially the molecules encoded at the B locus (HLA-B), are associated with AIDS progression risk. Different groups of HLA-B alleles have been associated to a protective effect or increasing susceptibility to HIV infection and are expressed from the earliest stages of gestation. ObjectiveThe aim of this study was to evaluate which variants of HLA-B are associated with the risk of HIV vertical transmission in infected pregnant women and in their offspring, in a referral center in Salvador Bahia. MethodsWe performed HLA-B genotyping in 52 HIV-infected mothers and their children exposed to HIV-1 during pregnancy (N=65) in Salvador, Brazil. We compared the HLA-B alleles frequency in mothers, uninfected and infected children, according to the use of antiretroviral prophylaxis. ResultsAbsence of antiretroviral antenatal and postnatal prophylaxis was significantly associated with vertical transmission of HIV-1 (p=<0.01, and p=<0.01 respectively). Frequency of HLA-B*14 (29.2%, p=0.002), HLA-B*18 (16.7%, p=0.04) or HLA-B*14:1 (20.8%, p=0.01) alleles subgroups were significantly higher in HIV-1 infected children and persisted (HLA-B*14, p=0.04) even after adjusting for use of antiretroviral prophylaxis. No significant difference in expression of HLA-B alleles was observed among mothers who transmitted the virus compared to those who did not. ConclusionsExpression of HLA-B*14 allele in children exposed to HIV-1 is predictive of vertical transmission and reinforces the important role of genetics in mother-to-child transmission.