47 research outputs found
MSJ770019_supplementary_table_1 – Supplemental material for Deconstruction of <i>HLA-DRB1*04:01:01</i> and <i>HLA-DRB1*15:01:01</i> class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis
No full textSupplemental material, MSJ770019_supplementary_table_1 for Deconstruction of HLA-DRB1*04:01:01 and HLA-DRB1*15:01:01 class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis by Lisa E Creary, Kalyan C Mallempati, Sridevi Gangavarapu, Stacy J Caillier, Jorge R Oksenberg and Marcelo A Fernández-Viňa in Multiple Sclerosis Journal</p
MSJ770019_supplementary_table_2 – Supplemental material for Deconstruction of <i>HLA-DRB1*04:01:01</i> and <i>HLA-DRB1*15:01:01</i> class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis
No full textSupplemental material, MSJ770019_supplementary_table_2 for Deconstruction of HLA-DRB1*04:01:01 and HLA-DRB1*15:01:01 class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis by Lisa E Creary, Kalyan C Mallempati, Sridevi Gangavarapu, Stacy J Caillier, Jorge R Oksenberg and Marcelo A Fernández-Viňa in Multiple Sclerosis Journal</p
Genetic variation on chromosone 6 influences F cell levels in healthy individuals of African descent and HbF levels in sickle cell patients
No full textFetal haemoglobin (HbF) is a major ameliorating factor in sickle cell disease. We investigated if a quantitative trait locus on chromosome 6q23 was significantly associated with HbF and F cell levels in individuals of African descent. Single nucleotide polymorphisms (SNPs) in a 24-kb intergenic region, 33-kb upstream of the HBS1L gene and 80-kb upstream of the MYB gene, were typed in 177 healthy Afro-Caribbean subjects (AC) of approximately 7% European admixture, 631 healthy Afro-Germans (AG, a group of African and German descendents located in rural Jamaica with about 20% European admixture), 87 West African and Afro-Caribbean individuals with sickle cell anaemia (HbSS), as well as 75 Northern Europeans, which served as a contrasting population. Association with a tag SNP for the locus was detected in all four groups (AC, P = 0.005, AG, P = 0.002, HbSS patients, P = 0.019, Europeans, P = 1.5 x 10(-7)). The association signal varied across the interval in the African-descended groups, while it is more uniform in Europeans. The 6q QTL for HbF traits is present in populations of African origin and is also acting in sickle cell anaemia patients. We have started to distinguish effects originating from European and African ancestral populations in our admixed study population
Ethnic differences in F cell levels in Jamaica: a potential tool for identifying new genetic locicontrolling fetal haemoglobin
No full textHigh levels of fetal haemoglobin (HbF) are protective in ?-haemoglobinopathies. The proportion of erythrocytes containing HbF (F-cells, FC) was measured in healthy adults of African and Caucasian ancestry to assess the feasibility of localizing genes for the FC trait using admixture mapping. Participants were Afro-Caribbean (AC) blood donors and residents of a rural enclave with a history of recent German admixture (Afro-German, AG) recruited in Jamaica, and Caucasian Europeans recruited in Jamaica and the UK. FC levels were significantly different between groups (P < 0·001); the geometric mean FC level in the AC sample (n = 176) was 3·75% [95% confidence interval (CI) 3·36–4·18], AG sample (n = 631) was 2·77% (95% CI 2·63–2·92), and among Caucasians (n = 1099) was 3·26% (95% CI 3·13–3·39). After adjustment for age, sex, haemoglobin electrophoresis pattern, and HBG2 genotype, FC levels in the AC group remained significantly different (P < 0·001) from those in the Caucasian and the AG group but the difference between the Caucasian and AG groups became non-significant (P = 0·46) despite substantial differences in average ancestry. The data confirm ethnic differences in FC levels and indicate the potential usefulness of these populations for admixture mapping of genes for FC level
Genet Med
No full textPurposeThe lack of an ongoing surveillance system for hemoglobinopathies in the United States impedes the ability of public health organizations to identify individuals with these conditions, monitor their health-care utilization and clinical outcomes, and understand the effect these conditions have on the health-care system. This article describes the results of a pilot program that supported the development of the infrastructure and data collection methods for a state-based surveillance system for selected hemoglobinopathies.MethodsThe system was designed to identify and gather information on all people living with a hemoglobinopathy diagnosis (sickle cell diseases or thalassemias) in the participating states during 2004\u20132008. Novel, three-level case definitions were developed, and multiple data sets were used to collect information.ResultsIn total, 31,144 individuals who had a hemoglobinopathy diagnosis during the study period were identified in California; 39,633 in Florida; 20,815 in Georgia; 12,680 in Michigan; 34,853 in New York, and 8,696 in North Carolina.ConclusionThis approach provides a possible model for the development of state-based hemoglobinopathy surveillance systems.20142016-02-01T00:00:00ZCC999999/Intramural CDC HHS/United StatesDD09-909/DD/NCBDD CDC HHS/United StatesDD10-1017/DD/NCBDD CDC HHS/United States24991875PMC4427044704
Evidence of Genetic Interaction between the β-Globin Complex and Chromosome 8q in the Expression of Fetal Hemoglobin
No full textDuring human development, the switch from fetal to adult hemoglobin (Hb) is not complete with the residual γ-globin expression being restricted to a subset of erythrocytes termed “F cells” (FC). Statistical analyses have shown the FC trait to be influenced by a common sequence variant (C→T) at position −158 upstream of the Gγ-globin gene, termed the “XmnI-Gγ polymorphism.” The XmnI-Gγ site is believed to be involved in the expression of the Gγ-globin gene through interaction with transcription factors, and polymorphisms in the transcription factors could be influencing fetal Hb expression, conditional on the XmnI-Gγ site. Using a two-locus model, in which the second locus was the known quantitative-trait locus (QTL) at the XmnI-Gγ site, we showed suggestive linkage to chromosome 8q. A maximum single-point LOD score of 4.33 and a multipoint LOD score of 4.75 were found in a 15–20 cM region of chromosome 8q. A single-locus analysis failed to show linkage of FC to the region when the XmnI-Gγ site was accounted for by removing its effects from the data or including it as a covariate. Results of the single-locus analysis were significant when the effects of the XmnI-Gγ site were not accounted for in any way. The results of analysis in a large Indian kindred indicate that there is an interaction between the XmnI-Gγ site and a QTL on chromosome 8q that is influencing the production of fetal Hb
Deconstruction of <i>HLA-DRB1*04:01:01</i> and <i>HLA-DRB1*15:01:01</i> class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis
No full textBackground: The association between HLA-DRB1*15:01 with multiple sclerosis (MS) susceptibility is well established, but the contribution of the tightly associated HLA-DRB5*01:01 allele has not yet been completely ascertained. Similarly, the effects of HLA-DRB1*04:01 alleles and haplotypes, defined at the full-gene resolution level with MS risk remains to be elucidated. Objectives: To characterize the molecular architecture of class II HLA-DR15 and HLA-DR4 haplotypes associated with MS. Methods: Next-generation sequencing was used to determine HLA-DQB1, HLA-DQA1, and HLA-DRB1/4/5 alleles in 1403 unrelated European-American patients and 1425 healthy unrelated controls. Effect sizes of HLA alleles and haplotypes on MS risk were measured by odds ratio (OR) with 95% confidence intervals. Results: HLA-DRB1*15:01:01:01SG (OR = 3.20, p < 2.2E–16), HLA-DRB5*01:01:01 (OR = 2.96, p < 2.2E–16), and HLA-DRB5*01:01:01v1_STR1 (OR = 8.18, p = 4.3E–05) alleles all occurred at significantly higher frequencies in MS patients compared to controls. The most significant predis-posing haplotypes were HLA-DQB1*06:02:01~ HLA-DQA1*01:02:01:01SG~HLA-DRB1*15:01:01:01SG~HLA-DRB5*01:01:01 and HLA-DQB1*06:02:01~HLA-DQA1*01:02:01:01SG~HLA-DRB1*15:01:01:01SG~HLA-DRB5*01:01:01v1_STR1 (OR = 3.19, p < 2.2E–16; OR = 9.30, p = 9.7E–05, respectively). Analyses of the HLA-DRB1*04 cohort in the absence of HLA-DRB1*15:01 haplotypes revealed that the HLA-DQB1*03:01:01:01~HLA-DQA1*03:03:01:01~HLA-DRB1*04:01:01:01SG~HLA-DRB4*01:03:01:01 haplotype was protective (OR = 0.64, p = 0.028), whereas the HLA-DQB1*03:02:01~HLA-DQA1*03:01:01~HLA-DRB1*04:01:01:01SG~HLA-DRB4*01:03:01:01 haplotype was associated with MS susceptibility (OR = 1.66, p = 4.9E–03). Conclusion: HLA-DR15 haplotypes, including genomic variants of HLA-DRB5, and HLA-DR4 haplotypes affect MS risk. </jats:sec
Usability of NewSTEPs Data for Assessing the Characteristics of Infants with Newborn Screening Disorders
No full textMost state newborn screening programs in the U.S. currently contribute case data to the Newborn Screening Technical Assistance and Evaluation Program (NewSTEPs). To assess the usability of these data for research, we examined the completeness of key variables, particularly race and ethnicity. Data included 24,129 cases of 34 newborn screening disorders from 45 states available in NewSTEPs as of 31 August 2020. Birth years of cases ranged between 2006 and 2020. Rates of missing data for sex, gestational age, birth weight, and race/ethnicity were 3.8%, 31.7%, 7.0%, and 39.7%, respectively. After excluding 21 states for which ≥50% of cases had missing data on race and/or ethnicity, 16,010 cases from 24 states remained. The disorders with the highest proportions in which cases were recorded as Hispanic ethnicity/any race were methylmalonic acidemia (48.7%) and maple syrup urine disease (45.7%). Analyses indicated that sex and birth weight data in NewSTEPs are reasonably complete, but missing data are common for gestational age and race/ethnicity. Despite this, our analyses revealed several novel associations between race/ethnicity and newborn screening disorders, such as the high burden of maple syrup urine disease among Hispanic patients. This demonstrates the potential usefulness of NewSTEPs for research if investments in higher-quality data are made
