Biomedical subjects

J A Kelly

Publications and source records attributed to J A Kelly.

At least 19 recordsLinked to original sources

PubMed2006

Meta-analysis of genome-wide linkage studies of systemic lupus erythematosus.

A genetic contribution to the development of systemic lupus erythematosus (SLE) is well established. Several genome-wide linkage scans have identified a number of putative susceptibility loci for SLE, some of which have been replicated in independent samples. This study aimed to identify the regions showing the most consistent evidence for linkage by applying the genome scan meta-analysis (GSMA) method. The study identified two genome-wide suggestive regions on 6p21.1-q15 and 20p11-q13.13 (P-value=0.0056 and P-value=0.0044, respectively) and a region with P-value<0.01 on 16p13-q12.2. The region on chromosome 6 contains the human leukocyte antigen cluster, and the chromosome 16 and 20 regions have been replicated in several cohorts. The potential importance of the identified genomic regions are also highlighted. These results, in conjunction with data emerging from dense single nucleotide polymorphism typing of specific regions or future genome-wide association studies will help guide efforts to identify the actual predisposing genetic variation contributing to this complex genetic disease.

Chromosomes, Human, Pair 16↗

PubMed2006

Familial aggregation and linkage analysis of autoantibody traits in pedigrees multiplex for systemic lupus erythematosus.

Autoantibodies are clinically relevant biomarkers for numerous autoimmune disorders. The genetic basis of autoantibody production in systemic lupus erythematosus (SLE) and other autoimmune diseases is poorly understood. In this study, we characterized autoantibody profiles in 1,506 individuals from 229 multiplex SLE pedigrees. There was strong familial aggregation of antinuclear antibodies (ANAs), anti-double-stranded DNA (dsDNA), anti-La/SSB, anti-Ro/SSA, anti-Sm, anti-nRNP (nuclear ribonucleoprotein), IgM antiphospholipid (aPL) antibodies (Abs) and rheumatoid factor (RF) across these families enriched for lupus. We performed genome-wide linkage analyses in an effort to map genes that contribute to the production of the following autoantibodies: Ro/SSA, La/SSB, nRNP, Sm, dsDNA, RF, nuclear and phospholipids. Using an approach to minimize false positives and adjust for multiple comparisons, evidence for linkage was found to anti-La/SSB Abs on chromosome 3q21 (adjusted P=1.9 x 10(-6)), to anti-nRNP and/or anti-Sm Abs on chromosome 3q27 (adjusted P=3.5 x 10(-6)), to anti-Ro/SSA and/or anti-La/SSB Abs on chromosome 4q34-q35 (adjusted P=3.4 x 10(-4)) and to anti-IgM aPL Abs on chromosome 13q14 (adjusted P=2.3 x 10(-4)). These results support the hypothesis that autoantibody production is a genetically complex trait. Identification of the causative alleles will advance our understanding of critical molecular mechanisms that underlie SLE and perhaps other autoimmune diseases.

Black or African American↗

PubMed2006

Programmes, resources, and needs of HIV-prevention nongovernmental organizations (NGOs) in Africa, Central/Eastern Europe and Central Asia, Latin America and the Caribbean.

This study assessed the programmes, resources, and needs of HIV-prevention nongovernmental organizations (NGOs) in 75 countries in Africa, Central/Eastern Europe and Central Asia, Latin America and the Caribbean. Multiple databases and expert recommendations were used to identify one major HIV-prevention NGO in the capital or a large city in each country, and in-depth interviews were conducted with each NGO Director. Most NGOs are carrying out their programmes with minimal funding and few regularly employed personnel. Most are highly dependent on international donors, but reliance on small grants with short funding periods limits programme development capacity. HIV-prevention activities varied by region, with African NGOs most likely to use peer education and community awareness events; Eastern European NGOs most likely to offer needle exchange; Latin American NGOs to have resource centres and offer risk reduction programmes; and Caribbean organizations to use mass education approaches. Across regions, NGOs most often targeted the general public and youth, although specialized at-risk groups were the additional focus of attention in some regions. Limited funding, governmental indifference or opposition, AIDS stigma, and social discomfort discussing sex were often cited as barriers to new HIV-prevention programmes. NGOs are critical service providers. However, their funding, programmes, and resource capacities must be strengthened if NGOs are to realize their full potential in HIV prevention.

Africa↗

PubMed2005

Functional promoter haplotypes of the human FAS gene are associated with the phenotype of SLE characterized by thrombocytopenia.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies against intracellular antigens and tissue injury. Defective apoptosis of activated immune cells leads to the development of autoantibodies in SLE. FasL initiated apoptosis is central for peripheral tolerance. Fas deficiencies in humans and mice predispose toward systemic autoimmunity. SLE is conferred by many genes. The genetic effects may be concentrated by familial clustering or by stratifying of subphenotypes. We have tested polymorphisms and haplotypes in FAS and FASL for association to SLE or subphenotypes in 126 multiplex American SLE pedigrees and found association of the FAS codon214 AC(C/T) as well as the FAS-670G>A'-codon214 AC(C/T)' haplotype to thrombocytopenia in SLE. Furthermore we have functionally characterized the FAS/FASL promoter polymorphisms associated with SLE in other populations and demonstrate that the activity depends on the allelic variants as well as on the haplotype. The presence of FAS-670G, which affects STAT1 binding, leads to the highest activity. FASL-844C activity is modified by the cis acting -478A and, hence, the haplotype and not the individual variant, determines the promoter activity. We conclude that the FAS/FASL promoter haplotypes are functional and that polymorphisms in FAS may contribute to thrombocytopenia in SLE.

Black or African American↗

PubMed2005

Identifying, recruiting, and assessing social networks at high risk for HIV/AIDS: methodology, practice, and a case study in St Petersburg, Russia.

Population segments at highest risk for HIV are often hidden, marginalized, and hard to reach by conventional prevention programmes. This pattern is especially true in Central and Eastern Europe, where major HIV epidemics have recently appeared, where population members do not perceive themselves as belonging to a community, and where there is little precedence for strong community-based organization service programmes. In these circumstances, naturally existing intact social networks still can be targeted by prevention programmes. HIV prevention interventions undertaken with at-risk social networks can establish new group norms, reduce the risk behaviour of network members, and can reach 'hidden' members of a population known personally to leaders of the social networks. This article illustrates a methodology and a practical description for: (1) accessing high-risk social networks in a community population; (2) identifying and enumerating the membership of the social networks; (3) identifying the social leadership of the networks; and (4) establishing the HIV risk behaviour levels of the recruited networks. To illustrate how social network methods can be applied in the field, the article provides case study reports of HIV prevention fieldwork practice targeting high-risk networks of young men who have sex with men and young heterosexual adults in St Petersburg, Russia. Although there is an extensive conceptual literature on the influence of social networks on risk behaviour, this article describes specific and practical techniques that can be in the development of approaches for social network-based interventions.

Adult↗

PubMed2004

Linkage analysis of SLE susceptibility: confirmation of SLER1 at 5p15.3.

We detected a novel susceptibility gene, SLER1, for systemic lupus erythematosus (SLE) at 5p15.3.(1) This finding was based on a selected subgroup of SLE families, where two or more family members have had alleged rheumatoid arthritis (SLE-RA). The main objective of this study was to replicate the linkage at 5p15.3 based on an independent data set of 88 SLE-RA families. Heterogeneity in the genetic model led us to use a nonparametric allele-sharing method. Since our a priori hypothesis of linkage at 5p15.3 was fixed, we genotyped six markers at the linked region. Our new results replicate the initial linkage at 5p15.3 (Zlr=2.58, P<0.005, LOD=1.45). Moreover, evidence of linkage was sustained when analysis was restricted to the subset of SLE families who had 3 or more individuals with alleged RA (Zlr=3.32, P=0.008, LOD=2.40) The results of our previous findings, together with these new results, confirm the SLER1 linkage at 5p15.3. Our results also demonstrate the utility of clinically defined subgroup analysis for detecting susceptibility loci for complex genetic diseases, such as SLE.

Arthritis, Rheumatoid↗

PubMed2004

Popular opinion leaders and HIV prevention peer education: resolving discrepant findings, and implications for the development of effective community programmes.

A series of community-level trials undertaken in the United States over the past 10 years established the effectiveness of an HIV prevention intervention that systematically identifies, recruits, trains, and engages the popular opinion leaders (POLs) of a population to serve as behaviour change endorsers. Recently, several investigators reported unsuccessful attempts to implement peer education programmes for men who have sex with men in the United Kingdom and raised questions about whether peer-based programmes are effective or feasible. However, POL is a theory-based and very specialized intervention, and the UK peer education programmes did not incorporate many of POL's core or essential elements. Consequently, they were not evaluations of POL. In this article, core elements of the popular opinion leader model are presented; interpretations are made of possible reasons for the discrepant findings of the UK peer education and US POL interventions; and practical issues for applied programme development are discussed.

HIV Infections↗

PubMed2004

Gender roles and HIV sexual risk vulnerability of Roma (Gypsies) men and women in Bulgaria and Hungary: an ethnographic study.

Roma, the largest ethnic minority group in Central and Eastern Europe, have cultures that are traditional, often closed, and autonomous of majority populations. Roma communities are characterized by pervasive social health problems, widespread poverty, limited educational opportunities, and discrimination. Although some evidence suggests high levels of HIV sexual risk behaviour among Roma, little is known about the cultural and social context in which risk behaviour occurs. In-depth interviews were used to elicit detailed information about types of sexual partnerships and sexual risk behaviour practices occurring in them, use and perception of protection, knowledge and beliefs about AIDS and STDs, and sexual communication patterns in a sample of 42 men and women aged 18-52 living in Roma community settlements in Bulgaria and Hungary. Analysis of the interview data revealed that men have great sexual freedom before and during marriage, engage in a wide range of unprotected practices with primary and multiple outside partners, and have much more relationship power and control. In contrast, women are expected to maintain virginity before marriage and then sexual exclusivity to their husbands. Condom use is not normative and is mainly perceived as a form of contraception. Although awareness of AIDS was common, it was generally not perceived as a personal threat. Misconceptions about how HIV is transmitted are widespread, and women - in particular - had very little knowledge about STDs, HIV transmission, and protective steps. There is an urgent need for the development of HIV prevention programs culturally sensitive to Roma populations in Eastern Europe, where HIV rates are rapidly rising.

Adolescent↗

PubMed2004

Drug use and sexual risk behaviours among female Russian IDUs who exchange sex for money or drugs.

Countries of the former Soviet Union are experiencing the steepest increases in annual HIV incidence in the world. Over 80% of registered HIV cases in Russia have occurred among intravenous drug users (IDUs), but current conditions set the stage for a heterosexually-transmitted epidemic. IDUs who also trade sex for money or drugs may serve as a conduit, or 'bridge' group, through which HIV could make inroads into the general Russian population. The present study examined the prevalence of sex trading among female Russian IDUs, and further examined drug use, sexual behaviour, and perceived vulnerability in this group. Female IDUs (n=100) in St Petersburg, Russia participated; 37% reported a history of sex trading. This group reported a mean of 49.5 male sexual partners in the previous month and an average of 15.4 unprotected vaginal intercourse acts in the previous 30 days. A significant minority (44%) also reported sharing injection equipment with others. Mathematical models to calculate risk estimates for HIV seroconversion indicated that participants were at significant risk of contracting HIV and infecting sexual partners. Despite significant rates of risk behaviours, most participants perceived themselves to be at little risk of contracting HIV. Effective HIV prevention programmes targeted at this group are urgently needed and are likely to be a cost-effective step in curtailing the spread of HIV in the region.

Adolescent↗

PubMed2004

HIV prevention nongovernmental organizations in Central and Eastern Europe: programs, resources and challenges.

HIV incidence is rising more rapidly in some areas of Central and Eastern Europe than anywhere else in the world. Carrying out effective HIV prevention programs requires the presence of "bridges" that can reach community populations most vulnerable to the disease. Nongovernmental organizations (NGOs) are in a natural role to conduct HIV prevention programs. The Directors of 29 HIV prevention NGOs representing almost all countries in Central and Eastern Europe participated in in-depth interviews by telephone. The broad topics of these interviews included descriptions of the three largest programs conducted by each NGO during the past six months, at-risk target populations served, major barriers faced, and funding sources that sponsored HIV prevention activities. NGO programs most often targeted injection drug users (IDUs); other stigmatized groups were less frequently served by NGOs in the sample. The most common types of prevention activities were needle exchange, HIV prevention peer education, and delivering AIDS presentations and distributing educational materials. Among the major barriers that hampered effective conduct of HIV prevention programs were a shortage of available financial resources, governmental indifference or opposition, and AIDS-related stigma. National governments rarely provided substantial funds for NGO programs, and most funding came from United Nations agencies or private foundations. The information sources reported to be most helpful in assisting NGOs in program development were sharing ideas with other NGOs, participating in conferences, and accessing information from the Internet. A number of programs reported by the NGO Directors were innovative, outstanding, and comprehensive. Five such exemplary programs are described in this article. HIV epidemics in the region are still potentially controllable. NGOs need immediate support so that they can carry out their community-based activities on a larger scale.

Communicable Disease Control↗

PubMed2002

Anticytokine therapy--new approach to the treatment of autoimmune and cytokine-disturbance diseases.

We pioneered the theory (Nature, 1974) that hyperproduced interferons (cytokines) can bring autoimmune diseases (AD) and neutralizing these cytokines can be therapeutic. In 1975 we first performed successful anticytokine therapy using anti-IFN-alpha antibodies in patients with rheumatoid arthritis (RA). In 1989 we proposed also treating AD including AIDS by removing TNF-alpha and IFN-alpha. Our theory has been widely confirmed: injections of IFN-alpha and -gamma can exacerbate AD, while antibodies to IFN-alpha and -gamma and TNF-alpha can be therapeutic. Anti-IFN-gamma may be a universal treatment for Th1 AD. We had good results using anti-IFN-gamma to treat RA, multiple sclerosis (MS), transplant rejection, alopecia areata, vitiligo, psoriatic arthritis, psoriasis and others. For Th1/Th2 diseases, antagonists to cortisol could prevent the Th1-Th2 shift and allow treatment as a Th1 disease. Anticytokine therapy can also be therapeutic in many neuropsychiatric diseases. Every disturbance of homeostasis may lead to cytokine disturbance. IL-10 may restore homeostasis by inhibiting the production of certain Th1 cytokines and could be used to treat some embryonic disturbances and AD including MS.

Autoimmune Diseases↗

PubMed2002

A genome screen of systemic lupus erythematosus using affected-relative-pair linkage analysis with covariates demonstrates genetic heterogeneity.

Systemic lupus erythematosus (SLE) appears to be the consequence of complex genetics and of only partly understood environmental contributions. Previous work by ourselves and by others has established genetic effects on 1q, 2q, 4p, 6p, and 16p using SLE as the phenotype. However, individual SLE affecteds are extraordinarily different from one another by clinical and laboratory measures. This variation may have a genetic basis; if so, it is advantageous to incorporate measures of between-family clinical variability as covariates in a genetic linkage analysis of affected relative pairs (ARPs) to allow for locus heterogeneity. This approach was applied to genome scan marker data from 160 pedigrees multiplex for SLE and containing 202 ARPs. Because the number of potential covariates was large, we used both ad hoc methods and formal principal components analysis to construct four composite covariates using the SLE classification criteria plus age of onset, ethnicity, and sex. Linkage analysis without covariates has detected evidence for linkage at 1q22-24, 2q37, 4p16, 12p12-11, and 17p13. Linkage analysis with these covariates uncovered linkage at 13p11, 17q11-25, and 20q12 and greatly improved evidence for linkage at 1q22-24, 2q37, 12p12-11, and 17p13. Follow-up analysis identified the original variables contributing to locus heterogeneity in each of these locations. In conclusion, allowing for locus heterogeneity through the incorporation of covariates in linkage analysis is a useful way to dissect the genetic contributions to SLE and uncover new genetic effects.

Analysis of Variance↗

PubMed2002

The genetics of systemic lupus erythematosus: putting the pieces together.

With lambda(s) estimates of 10 to 20 and other evidence of familial aggregation, as well as a monozygotic twin concordance rate >20, systemic lupus erythematosus (SLE) would appear to be a very promising phenotype using modern genetic approaches. Indeed, genetic associations are already known at numerous candidate loci including various HLA alleles, complement component genes, Fcgamma receptors, and others, and murine genetic studies of lupus models have provided additional candidate genes and potential syntenic linkages to evaluate in man. The completed genetic linkage studies performed on various collections of pedigrees multiplex for SLE have identified 60 susceptibility loci with varying degrees of evidence for linkage in man. Seven of these meet or exceed the threshold for significant linkage (LOD > or = 3.3 or P < or = 0.00005) at 1q22-23, 1q41, 2q37, 4p16, 6p21-11, 16q13 and 17p13. In addition, these linkages usually dominate in one ethnicity or another, suggesting that the responsible polymorphisms, once identified, will also vary by ethnicity. Evidence that these linkages can be reproduced range from outright independent confirmation (1q41, 4p16 and 6p21) to additional suggestive evidence in the genomic region of the purported linkage (1q22-23 and 2q37). The results now available suggest that human lupus genetics are robust and that gene identification should be possible using existing genetic approaches and technologies.

Animals↗

PubMed2002

A genetic marker within the CD44 gene confirms linkage at 11p13 in African-American families with lupus stratified by thrombocytopenia, but genetic association with CD44 is not present.

Systemic lupus erythematosus (SLE) is complicated from both a clinical and genetic standpoint. We have stratified SLE families by the presence of thrombocytopenia, which is associated with increased mortality among SLE patients, and found genetic linkage at chromosome 11p13 in African-American families. In the present study we have evaluated CD44, a gene very close (0.5 cM) to the peak LOD score marker, as a candidate gene. Using a newly identified short DNA repeat within the CD44 gene, we find a LOD score of 2.7, which confirms linkage within this genetic interval. However, using a panel of four single nucleotide markers spanning the CD44 gene, we find no genetic association with SLE. Therefore, these data further suggest an SLE susceptibility gene at 11p13, but also imply that an ancestral mutation in the CD44 gene does not account for the linkage.

Black People↗

PubMed2002

The genetics of systemic lupus erythematosus stratified by renal disease: linkage at 10q22.3 (SLEN1), 2q34-35 (SLEN2), and 11p15.6 (SLEN3).

Renal disease occurs in 40-75% of systemic lupus erythematosus (SLE) patients and significantly contributes to morbidity and mortality. We used two pedigree stratification strategies to explore the impact of the ACR renal criterion for SLE classification upon genetic linkage with SLE. In both we used SLE as the phenotype. First, we evaluated genome scan data from >300 microsatellite markers in the 75 pedigrees that had at least one SLE affected with the SLE renal criterion. A maximum-likelihood parametric model approach produced a maximum screening LOD score of 3.16 at 10q22.3 in the European-American (EA) pedigrees. The African-American (AA) pedigrees obtained a maximum screening LOD score of 2.58 at 11p15.6. A multipoint sib-pair regression analysis produced P = 0.0000008 in EA at 10q22.3 (SLEN1) and P = 0.000001 in AA at 2q34-35 (SLEN2). A second stratification strategy explored the renal criterion in 35 pedigrees with two or more SLE patients with renal disease and produced a LOD score of 3.34 at 11p15.6 in AA (SLEN3). Sib-pair analysis in these 35 pedigrees revealed P = 0.00003 at 4q13.1 in EA, P = 0.00003 at 11p13 and 0.00007 at 3q23 in AA. Thus, multiple genetic linkages are related to the renal criterion in SLE. Of the significant genetic linkages with SLE described herein, those at 10q22.3 in the EA pedigrees (SLEN1) and at 2q34-35 in the AA pedigrees (SLEN2) have not been previously described.

Black People↗

PubMed2002

Genetic linkage of systemic lupus erythematosus with chromosome 11q14 (SLEH1) in African-American families stratified by a nucleolar antinuclear antibody pattern.

Systemic lupus erythematosus (SLE) is an autoimmune disease with complex genetics. We evaluated pedigrees multiplex for SLE that had an affected with antinucleolar antibodies to increase the homogeneity for genetic linkage analysis. We found a significant linkage effect on chromosome 11q14 at marker D11S2002 in African-American Pedigrees. This effect produced a maximum LOD score of 5.62 using a dominant inheritance model with 95% penetrance in males and 99% penetrance in females. The results were supported by multipoint linkage analysis. Fine mapping of the region with two additional markers within 6 cM of D11S2002 further provided evidence of linkage in this region. Linkage at D11S2002, named SLEH1, was previously found in some of these same African-American pedigrees multiplex for SLE, but who were stratified by hemolytic anemia (Kelly et al, submitted). In conclusion, an important SLE susceptibility gene, SLEH1 at 11q14, is identified in African-Americans when stratifying pedigrees by antinucleolar autoantibodies.

Black People↗

PubMed2002

Genome scan stratified by the presence of anti-double-stranded DNA (dsDNA) autoantibody in pedigrees multiplex for systemic lupus erythematosus (SLE) establishes linkages at 19p13.2 (SLED1) and 18q21.1 (SLED2).

Anti-double-stranded DNA (anti-dsDNA) is arguably one of the most specific autoantibodies in systemic lupus erythematosus (SLE). This antibody is associated with more severe SLE and with glomerulonephritis. From 196 pedigrees multiplex for SLE, we selected those that had any SLE affected positive for anti-dsDNA by the Crithidia luciliae kinetoplast imunofluorescence assay. This stratification strategy tested the hypothesis that anti-dsDNA would identify a more genetically homogeneous group of pedigrees, in which previously undetected linkage effects could be established. A genome screen data for linkage to SLE was available at 307 microsatellite markers for this selected group of 71 pedigrees: 37 European-American, 29 African-American, and five others. The most significant results were obtained at 19p13.2 (LOD(max) = 4.93), named SLED1, in the 37 European-American pedigrees using a dominant model with mixed penetrances (92% for females and 49% for males) at 100% homogeneity (theta = 0). A second linkage effect, SLED2, was established in the 29 African-American pedigrees at 18q21.1 (LOD(max) = 3.40) using a recessive model with 100% penetrance (theta = 0.1). Parametric and non-parametric multipoint analyses were performed, which provided further evidence and support of susceptibility genes residing in these regions. In conclusion, two powerful linkages have been detected with SLE based on the presence of anti-dsDNA. These findings show SLE to be a richly complicated disease phenotype that is now ripe for important new discovery through a genetic approach.

Animals↗

PubMed2002

HIV risk characteristics and prevention needs in a community sample of bisexual men in St. Petersburg, Russia.

A new and understudied HIV epidemic is quickly unfolding in the Central and Eastern European countries of the former Soviet Union. Men who have sex with men (MSM) in Russia constitute a population highly vulnerable to sexually-transmitted HIV infection. In a community sample of 434 Russian MSM accessed in gay venues in St. Petersburg, 126 had had both male and female partners in the past three months. In this paper, we report on their risk characteristics. Forty-five per cent of men reported recently engaging in unprotected anal intercourse with their male partners. Respondents had a mean of 3.3 male and 3.4 female partners in the past three months, and most had multiple male and female partners in this time period. There were serious and significant gaps in the AIDS risk knowledge levels of these men, and most believed they had no personal contact with HIV-positive people. Bisexual men were more likely than exclusively gay men to have engaged in commercial sex and tended to have lower AIDS risk knowledge. Although they did not differ in average age, bisexual compared to gay men more recently had their first sex with a man. Multivariate logistic and linear regression analyses showed that condom and safer sex attitudes, perceived norms, AIDS risk knowledge and age at first sex with a man were independent predictors of high-risk behaviour among bisexual men. HIV prevention interventions for bisexual men should address their sexual practices with both male and female partners, correct misconceptions about risk, address behaviour practices rather than gay identity, and recognize risk issues faced by the female partners of bisexual men.

Adult↗