Craig L Hanis

Publications of Craig L Hanis

• Single nucleotide polymorphisms in JAZF1 and BCL11A gene are nominally associated with type 2 diabetes in African-American families from the GENNID study.

  Authors: Kurt A Langberg, Lijun Ma, Neeraj K Sharma, Craig L Hanis, Steven C Elbein, Sandra J Hasstedt, Swapan K Das

  Journal of human genetics. 11/2011; 57(1):57-61.

  Prior type 2 diabetes (T2D) genome-wide association studies (GWASs) have generated a list of well-replicated susceptibility loci in populations of European and Asian ancestry. To validate thePrior type 2 diabetes (T2D) genome-wide association studies (GWASs) have generated a list of well-replicated susceptibility loci in populations of European and Asian ancestry. To validate the trans-ethnic contribution of the single-nucleotide polymorphisms (SNPs) involved in these GWASs, we performed a family-based association analysis of 32 selected GWAS SNPs in a cohort of 1496 African-American (AA) subjects from the Genetics of NIDDM (GENNID) study. Functional roles of these SNPs were evaluated by screening cis-eQTLs in transformed lymphoblast cell lines available for a sub-group of Genetics of NIDDM (GENNID) families from Arkansas. Only three of the 32 GWAS-derived SNPs showed nominally significant association with T2D in our AA cohort. Among the replicated SNPs rs864745 in JAZF1 and rs10490072 in BCL11A gene (P=0.006 and 0.03, respectively, after adjustment for body mass index) were within the 1-lod drop support interval of T2D linkage peaks reported in these families. Genotyping of 19 tag SNPs in these two loci revealed no further common SNPs or haplotypes that may be a stronger predictor of T2D susceptibility than the index SNPs. Six T2D GWAS SNPs (rs6698181, rs9472138, rs730497, rs10811661, rs11037909 and rs1153188) were associated with nearby transcript expression in transformed lymphoblast cell lines of GENNID AA subjects. Thus, our study indicates a nominal role for JAZF1 and BCL11A variants in T2D susceptibility in AAs and suggested little overlap in known susceptibility to T2D between European- and African-derived populations when considering GWAS SNPs alone.

• Pleiotropy of type 2 diabetes with obesity.

  Authors: Sandra J Hasstedt, Craig L Hanis, Swapan K Das, Steven C Elbein

  Journal of human genetics. 04/2011; 56(7):491-5.

  The risk of type 2 diabetes (T2D) increases with obesity. One possible explanation is that pleiotropic genes affect risk of both T2D and obesity. To identify pleiotropic genes, we performed bivariateThe risk of type 2 diabetes (T2D) increases with obesity. One possible explanation is that pleiotropic genes affect risk of both T2D and obesity. To identify pleiotropic genes, we performed bivariate analysis of T2D with waist-hip ratio (WHR) and with body mass index (BMI) in the African-American subset of the Genetics of NIDDM (GENNID) sample. Of 12 T2D loci identified through suggestive or higher univariate logarithm of the odds ratio (lod) scores, we inferred pleiotropy with obesity for six (chromosomes 1 at 17-19 Mb, 2 at 237-240 Mb, 7 at 54-73 Mb, 13 at 26-30 Mb, 16 at 26-47 Mb and 20 at 56-59 Mb). These findings provide evidence that at least some of the co-occurrence of obesity with T2D is because of pleiotropic genes. We also inferred four obesity loci through suggestive or higher lod scores for WHR (chromosomes 1 at 24-32 Mb, 2 at 79-88 Mb, 2 at 234-238 Mb and 3 at 148-159 Mb).

• Integrating education, group support, and case management for diabetic Hispanics.

  Authors: Sharon A Brown, Alexandra A García, Mary Winter, Lita Silva, Adama Brown, Craig L Hanis

  Ethnicity & disease. 01/2011; 21(1):20-6.

  Culturally tailored diabetes self-management education (DSME) improves glycemic control and other health outcomes in Mexican Americans but sociocultural barriers to health improvements remain. ThisCulturally tailored diabetes self-management education (DSME) improves glycemic control and other health outcomes in Mexican Americans but sociocultural barriers to health improvements remain. This study explored the feasibility of adding a nurse case manager (NCM) to DSME to foster DSME attendance and increase utilization of other available health care services. The setting was a rural community on the Texas-Mexico border in one of the poorest counties in the United States. Using a repeated measures pretest, post-test control group design, we enrolled 165 Mexican American adults into: 1) an experimental group that received a DSME intervention plus access to a NCM; or 2) a control group that received DSME only. Both experimental and control groups received the DSME intervention, reported positive changes in diet and physical activity, and showed improved clinical outcomes; there were no significant group differences. A statistically significant reduction in body mass index was seen in women compared to men, regardless of group or number of NCM contacts. For individuals having the most NCM contacts, DSME attendance rates were greater. Participants expressed acceptance of the NCM; they preferred face-to-face contact rather than by telephone. Our previously tested, culturally tailored DSME continues to be an effective strategy for improving glycemic control in Mexican Americans. This feasibility study provided partial support for the NCM model for underserved border communities, but additional research is needed on resource utilization and the nature of NCM contacts.

• Univariate and bivariate linkage analysis identifies pleiotropic loci underlying lipid levels and type 2 diabetes risk.

  Authors: Sandra J Hasstedt, Craig L Hanis, Steven C Elbein

  Annals of human genetics. 07/2010; 74(4):308-15.

  Dyslipidemia frequently co-occurs with type 2 diabetes (T2D) and with obesity. To investigate whether the co-occurrence is due to pleiotropic genes, we performed univariate linkage analysis of lipidDyslipidemia frequently co-occurs with type 2 diabetes (T2D) and with obesity. To investigate whether the co-occurrence is due to pleiotropic genes, we performed univariate linkage analysis of lipid levels and bivariate linkage analysis of pairs of lipid levels and of lipid levels paired with T2D, body mass index (BMI), and waist-hip ratio (WHR) in the African American subset of the Genetics of NIDDM (GENNID) sample. We obtained significant evidence for a pleiotropic low density lipoprotein cholesterol (LDL-C)-T2D locus on chromosome 1 at 16-19 megabases (MB) (bivariate lod = 4.41), as well as a non-pleiotropic triglyceride (TG) locus on chromosome 20 at 28-34 MB (univariate lod = 3.57). In addition, near-significant evidence supported TG-T2D loci on chromosome 2 at 81-101 MB (bivariate lod = 4.23) and 232-239 MB (bivariate lod = 4.27) and on chromosome 7 at 147-151 MB (univariate lod = 3.08 for TG with P = 0.041 supporting pleiotropy with T2D), as well as an LDL-C-BMI locus on chromosome 3 at 137-147 MB (bivariate lod score = 4.25). These findings provide evidence that at least some of the co-occurrence of dyslipidemia with T2D and obesity is due to common underlying genes.

• Identification of Diabetic Retinopathy Genes through a Genome-Wide Association Study among Mexican-Americans from Starr County, Texas.

  Authors: Yi-Ping Fu, D Michael Hallman, Victor H Gonzalez, Barbara E K Klein, Ronald Klein, M Geoffrey Hayes, Nancy J Cox, Graeme I Bell, Craig L Hanis

  Journal of ophthalmology. 01/2010; 2010.

  To identify genetic loci for severe diabetic retinopathy, 286 Mexican-Americans with type 2 diabetes from Starr County, Texas, completed physical examinations including fundus photography forTo identify genetic loci for severe diabetic retinopathy, 286 Mexican-Americans with type 2 diabetes from Starr County, Texas, completed physical examinations including fundus photography for diabetic retinopathy grading. Individuals with moderate-to-severe non-proliferative and proliferative diabetic retinopathy were defined as cases. Direct genotyping was performed using the Affymetrix GeneChip Human Mapping 100 K Set, and SNPs passing quality control criteria were used to impute markers available in HapMap Phase III Mexican population (MXL) in Los Angeles, California. Two directly genotyped markers were associated with severe diabetic retinopathy at a P-value less than .0001: SNP rs2300782 (P = 6.04 × 10(-5)) mapped to an intron region of CAMK4 (calcium/calmodulin-dependent protein kinase IV) on chromosome 5, and SNP rs10519765 (P = 6.21 × 10(-5)) on chromosomal 15q13 in the FMN1 (formin 1) gene. Using well-imputed markers based on the HapMap III Mexican population, we identified an additional 32 SNPs located in 11 chromosomal regions with nominal association with severe diabetic retinopathy at P-value less than .0001. None of these markers were located in traditional candidate genes for diabetic retinopathy or diabetes itself. However, these signals implicate genes involved in inflammation, oxidative stress and cell adhesion for the development and progression of diabetic retinopathy.

• Assessment of 193 candidate genes for retinopathy in African Americans with type 1 diabetes.

  Authors: Monique S Roy, D Michael Hallman, Yi-Ping Fu, Mirta Machado, Craig L Hanis

  Archives of ophthalmology. 06/2009; 127(5):605-12.

  OBJECTIVE: To report in African Americans with type 1 diabetes the association of single-nucleotide polymorphisms in 193 candidate genes with diabetic retinopathy (DR) and/or its progression.OBJECTIVE: To report in African Americans with type 1 diabetes the association of single-nucleotide polymorphisms in 193 candidate genes with diabetic retinopathy (DR) and/or its progression. METHODS: A custom panel of 1536 single-nucleotide polymorphisms located on 193 candidate genes for DR was genotyped in 437 African Americans with type 1 diabetes who participated in the New Jersey 725 study. Clinical evaluations at baseline and follow-up examinations included structured clinical interview, ocular examination, 7-field stereoscopic fundus photographs, and blood pressure measurements. Severity of DR was determined via masked grading of fundus photographs. Biological evaluations included blood and urine assays. RESULTS: Single-nucleotide polymorphisms in 13 candidate genes for DR involved in glucose metabolism, angiogenesis, inflammation, neurotransmission, hypertension, and retinal development were significantly associated with the prevalence of severe DR. Three of these genes were also significantly associated with progression of DR. Adjusting for sex, duration of diabetes, glycosylated hemoglobin, systemic hypertension, and total cholesterol did not alter the results. CONCLUSIONS: Our data support the role of genetic factors to account for severity and/or progression of DR in African Americans with type 1 diabetes and to identify several prime genes that likely contribute to the risk of DR.

• Gene by smoking interaction in hypertension: identification of a major quantitative trait locus on chromosome 15q for systolic blood pressure in Mexican-Americans.

  Authors: May E Montasser, Lawrence C Shimmin, Craig L Hanis, Eric Boerwinkle, James E Hixson

  Journal of hypertension. 04/2009; 27(3):491-501.

  OBJECTIVE: Our objective was to investigate the influence of gene by smoking (GxS) interaction on hypertension and blood pressure (BP) using genome-wide linkage analysis in Mexican-Americans,OBJECTIVE: Our objective was to investigate the influence of gene by smoking (GxS) interaction on hypertension and blood pressure (BP) using genome-wide linkage analysis in Mexican-Americans, followed by single nucleotide polymorphism (SNP) fine mapping of candidate genes in the linked chromosomal region. METHODS: We used nonparametric methods to test for linkage of microsatellites with hypertension and BP measures in smokers, nonsmokers, and the combined group. To begin fine mapping of a major quantitative trait locus (QTL) for systolic blood pressure (SBP) on chromosome 15q that showed strong evidence for GxS interaction, we genotyped 55 SNPs in nine candidate genes for association studies using two population-based statistical methods. RESULTS: The strongest evidence for GxS interaction (P = 0.0004) was found for SBP on chromosome 15q, where a major QTL (LOD = 3.36) was identified only in nonsmokers. Follow-up studies identified three SNPs in three genes (ANPEP, IGF1R, and SLCO3A1) that showed associations with SBP only in nonsmokers, cumulatively accounting for a 7 mmHg increase in SBP. However, conditional linkage analyses that accounted for phenotypic effects of these SNPs only slightly reduced the original LOD score. CONCLUSION: The detection of a major QTL on chromosome 15q for SBP in nonsmokers indicates the presence of loci that influence BP via GxS interactions. However, identification of the genes that underlie such QTL effects remains a challenge. Although we found three candidate genes that showed significant associations with SBP in nonsmokers, further studies are required to identify the gene(s) that underlie the chromosome 15q QTL that influences SBP via GxS interactions.

• Adverse association between diabetic retinopathy and cardiac structure and function.

  Authors: David Aguilar, D Michael Hallman, Linda B Piller, Barbara E K Klein, Ronald Klein, Richard B Devereux, Donna K Arnett, Victor H Gonzalez, Craig L Hanis

  American heart journal. 04/2009; 157(3):563-8.

  BACKGROUND: Recent work has demonstrated a link between retinopathy, a marker of microvascular disease, and the development of heart failure, a finding particularly relevant in individuals withBACKGROUND: Recent work has demonstrated a link between retinopathy, a marker of microvascular disease, and the development of heart failure, a finding particularly relevant in individuals with diabetes. Our objective was to assess the relationship between retinopathy and cardiac structure and function in a cohort of individuals with type 2 diabetes mellitus. METHODS: Stereoscopic fundus photography of 7 standard fields was obtained in 531 Mexican American adults with type 2 diabetes mellitus recruited as sibships from Starr County, Texas. Retinopathy was centrally scored and classified as no retinopathy, early nonproliferative diabetic retinopathy, moderate to severe nonproliferative diabetic retinopathy, or proliferative diabetic retinopathy. Echocardiography was used to assess cardiac structure and function. Multilevel mixed models were used to assess associations of clinical and echocardiographic variables with retinopathy while accounting for correlations among siblings. RESULTS: More severe diabetic retinopathy was associated with the presence of hypertension, previous cardiovascular disease, longer duration of diabetes, elevated glycosylated hemoglobin, and greater albuminuria. With worsening severity of diabetic retinopathy, left ventricular (LV) mass and left atrial dimension increased, and LV ejection fraction and LV fractional shortening decreased, independent of potential confounding variables. CONCLUSIONS: More severe diabetic retinopathy was associated with worse cardiac structure and function by echocardiography independent of potential confounding variables. These data suggest a possible microvascular contribution to the development of diabetes-associated cardiac enlargement and dysfunction. Alternatively, common pathways may be leading to both disorders.

• Glucocorticoid receptor gene variant in the 3' untranslated region is associated with multiple measures of blood pressure.

  Authors: Charles C Chung, Lawrence Shimmin, Sivamani Natarajan, Craig L Hanis, Eric Boerwinkle, James E Hixson

  Molecular endocrinology (Baltimore, Md.). 02/2009; 23(1):124-5.

• Genome-Wide Linkage and Admixture Mapping of Type 2 Diabetes in African American Families from the American Diabetes Association GENNID Cohort.

  Authors: Steven C Elbein, Swapan K Das, D Michael Hallman, Craig L Hanis, Sandra J Hasstedt

  Diabetes. 11/2008;

  Objective: We used a single nucleotide polymorphism map in a large cohort of 580 African American families to identify regions linked to type 2 diabetes (T2D), T2D age of diagnosis (AOD), and bodyObjective: We used a single nucleotide polymorphism map in a large cohort of 580 African American families to identify regions linked to type 2 diabetes (T2D), T2D age of diagnosis (AOD), and body mass index (BMI). Research Design and Methods: After removing outliers and problematic samples, we conducted linkage analysis using 5914 SNPs in 1344 individuals from 530 families. Linkage analysis was conducted using variance components for T2D, AOD, and BMI and nonparametric (NPL) analyses. Ordered subset analyses were conducted ranking on AOD, BMI, waist circumference, waist:hip ratio, and amount of European admixture. Admixture mapping was conducted using 4486 markers not in linkage disequilibrium. Results: The strongest signal for T2D (lod 4.53) was a broad peak on chromosome 2, with weaker linkage to AOD (lod 1.82). T2D and AOD were linked to chromosome 13p (3 cM - 22 cM; lod 2.42 and 2.46, respectively). AOD was linked to 18p (66 cM, 2.96). We replicated previous reports on chromosome 7p (79 cM, LOD 2.93). Ordered subset analysis did not overlap with linkage of unselected families. The best admixture score was on chromosome 12 (90 cM; p=0.0003). Conclusions: The linkage regions on chromosomes 7 (27-78 cM) and 18p overlap prior reports, whereas regions on 2p and 13p linkage are novel. Among potential candidate genes implicated are TCF7L1, VAMPs 5 and 8, CKD8, INSIG2, IPF1, PAX8, IL18R1, members of the IL1 and IL1 receptor families, and MAP4K4. These studies provide a complementary approach to genome-wide association scans to identify causative genes for African American diabetes.

• Identification of type 2 diabetes genes in Mexican Americans through genome-wide association studies.

  Authors: M Geoffrey Hayes, Anna Pluzhnikov, Kazuaki Miyake, Ying Sun, Maggie C Y Ng, Cheryl A Roe, Jennifer E Below, Raluca I Nicolae, Anuar Konkashbaev, Graeme I Bell, Nancy J Cox, Craig L Hanis

  Diabetes. 12/2007; 56(12):3033-44.

  OBJECTIVE: The objective of this study was to identify DNA polymorphisms associated with type 2 diabetes in a Mexican-American population. RESEARCH DESIGN AND METHODS: We genotyped 116,204 singleOBJECTIVE: The objective of this study was to identify DNA polymorphisms associated with type 2 diabetes in a Mexican-American population. RESEARCH DESIGN AND METHODS: We genotyped 116,204 single nucleotide polymorphisms (SNPs) in 281 Mexican Americans with type 2 diabetes and 280 random Mexican Americans from Starr County, Texas, using the Affymetrix GeneChip Human Mapping 100K set. Allelic association exact tests were calculated. Our most significant SNPs were compared with results from other type 2 diabetes genome-wide association studies (GWASs). Proportions of African, European, and Asian ancestry were estimated from the HapMap samples using structure for each individual to rule out spurious association due to population substructure. RESULTS: We observed more significant allelic associations than expected genome wide, as empirically assessed by permutation (14 below a P of 1 x 10(-4) [8.7 expected]). No significant differences were observed between the proportion of ancestry estimates in the case and random control sets, suggesting that the association results were not likely confounded by substructure. A query of our top approximately 1% of SNPs (P < 0.01) revealed SNPs in or near four genes that showed evidence for association (P < 0.05) in multiple other GWAS interrogated: rs979752 and rs10500641 near UBQLNL and OR52H1 on chromosome 11, rs2773080 and rs3922812 in or near RALGPS2 on chromosome 1, and rs1509957 near EGR2 on chromosome 10. CONCLUSIONS: We identified several SNPs with suggestive evidence for replicated association with type 2 diabetes that merit further investigation.

• Corticotropin releasing hormone (CRH) gene variation: comprehensive resequencing for variant and molecular haplotype discovery in monosomic hybrid cell lines.

  Authors: Lawrence C Shimmin, Sivamani Natarajan, Heladio Ibarguen, May Montasser, Do-Kyun Kim, Craig L Hanis, Eric Boerwinkle, Pathik D Wadhwa, James E Hixson

  DNA sequence : the journal of DNA sequencing and mapping. 12/2007; 18(6):434-44.

  Candidate gene association studies have met with mixed success due to many reasons including incomplete surveys of genetic variation and differences in patterns of genetic variation among studyCandidate gene association studies have met with mixed success due to many reasons including incomplete surveys of genetic variation and differences in patterns of genetic variation among study populations. We present the results of comprehensive variant discovery for the corticotropin releasing hormone gene (CRH on chromosome 8) encoding a neuropeptide that is central to many physiologic pathways. Mouse-human hybrid cell lines were constructed that are monosomic for human chromosome 8 for resequencing of separated CRH alleles to identify variants and directly determine their chromosomal phase for three major ethnic groups including African Americans (AA), Mexican Americans (MA) and European Americans (EA). We also resequenced diploid individuals to evaluate single nucleotide polymorphism (SNP) discovery in the limited numbers of monosomic hybrid cell lines. Our results show that CRH variation is very different in AA, yielding larger numbers of variants and haplotypes compared to MA and EA. Analysis of LD structure found three haplotype blocks in AA and two blocks in EA. Comparisons between AA and EA groups yielded extremely high measures of genetic differentiation (Wright's F(ST)>0.6), likely reflecting disruptive selection in CRH evolution. Network analysis showed that AA have retained an ancestral CRH haplotype, while the most common EA haplotype is derived from a single recombination event.

• A genome-wide linkage scan for diabetic retinopathy susceptibility genes in Mexican Americans with type 2 diabetes from Starr County, Texas.

  Authors: D Michael Hallman, Eric Boerwinkle, Victor H Gonzalez, Barbara E K Klein, Ronald Klein, Craig L Hanis

  Diabetes. 05/2007; 56(4):1167-73.

  We conducted a genome-wide linkage scan for genes contributing to retinopathy risk using 794 diabetes case subjects from 393 Mexican-American families from Starr County, Texas, having at least twoWe conducted a genome-wide linkage scan for genes contributing to retinopathy risk using 794 diabetes case subjects from 393 Mexican-American families from Starr County, Texas, having at least two diabetic siblings. The sample included 567 retinopathy case subjects comprising 282 affected sibling pairs. Retinopathy was classified as none, early nonproliferative, moderate-to-severe nonproliferative, or proliferative. Using 360 polymorphic markers (average spacing 9.4 cM), we conducted nonparametric linkage analysis followed by ordered-subset analysis (OSA) ranking families by average age of diabetes diagnosis. For any retinopathy, the highest LOD scores including all families were on chromosomes 3 (2.41 at 117 cM) and 12 (2.47 at 15.5). OSA logarithm of odds (LOD) scores >2 for any retinopathy occurred on chromosomes 12 (4.47 at 13.2 cM), 15 (3.65 at 100.6), and 20 (2.67 at 54.1). Scores >2 for either moderate-to-severe nonproliferative or proliferative retinopathy occurred on chromosomes 5 (2.53 at 11.2 cM), 6 (2.28 at 30.6), and 19 (2.21 at 100.6). Thus, unconditional linkage analysis revealed suggestive evidence of linkage with retinopathy on two chromosomes, whereas OSA revealed strong evidence of linkage on two chromosomes, and suggestive evidence on four. Candidate genes were identified in most implicated regions.

• Racial admixture and its impact on BMI and blood pressure in African and Mexican Americans.

  Authors: Hua Tang, Eric Jorgenson, Maya Gadde, Sharon L R Kardia, D C Rao, Xiaofeng Zhu, Nicholas J Schork, Craig L Hanis, Neil Risch

  Human genetics. 08/2006; 119(6):624-33.

  Admixed populations such as African Americans and Hispanic Americans present both challenges and opportunities in genetic epidemiologic research. Because of variation in admixture levels amongAdmixed populations such as African Americans and Hispanic Americans present both challenges and opportunities in genetic epidemiologic research. Because of variation in admixture levels among individuals, case-control association studies may be subject to stratification bias. On the other hand, admixed populations also present special opportunities both for examining the role of genetic and environmental factors for observed racial/ethnic differences, and for possibly mapping alleles that contribute to such differences. Here we examined the distribution and relationship of individual admixture (IA) estimates with BMI and three measures of blood pressure in two admixed populations in the NHLBI Family Blood Pressure Program (FBPP): African Americans and Mexican Americans. For the African Americans, we observed modest but significant differences in average African IA among four recruitment sites. We observed a slight excess of African IA among hypertensives compared to normotensives, and a positive (non-significant) regression of African IA on blood pressure in untreated participants. Within Mexican Americans, we found no difference in average IA between hypertensives and normotensives, but a positive (marginally significant) regression of African IA on diastolic blood pressure. We also observed a significant positive regression of Caucasian IA (and negative regression of Native American IA) on BMI. Our results are suggestive of genetic differences between Africans and non-Africans that influence blood pressure, but such effects are likely to be modest compared to environmental ones. Excess obesity among Native Americans compared to whites is not consistent with a simple genetic explanation.

• Genetics of diabetic retinopathy.

  Authors: Craig L Hanis, D Hallman

  Current diabetes reports. 05/2006; 6(2):155-61.

  Diabetes is rapidly increasing in frequency with an attendant toll of complications, including diabetic retinopathy. Although the underlying mechanisms remain elusive, genetic susceptibility is keyDiabetes is rapidly increasing in frequency with an attendant toll of complications, including diabetic retinopathy. Although the underlying mechanisms remain elusive, genetic susceptibility is key to both types 1 and 2 diabetes and is increasingly recognized for its contribution to diabetic complications. In this article we review the evidence connecting genetic susceptibility to diabetic retinopathy. Elucidating the susceptibility genes and pathways should permit strategies to slow and reverse the troubling trends for the population, families, and individuals.

• Patterns of linkage disequilibrium in the type 2 diabetes gene calpain-10.

  Authors: M Geoffrey Hayes, Laura Del Bosque-Plata, Takafumi Tsuchiya, Craig L Hanis, Graeme I Bell, Nancy J Cox

  Diabetes. 01/2006; 54(12):3573-6.

  We investigated the patterns and extent of linkage disequilibrium (LD) in the vicinity of the type 2 diabetes gene calapin-10 (CAPN10) in Mexican Americans, European Americans, African Americans, andWe investigated the patterns and extent of linkage disequilibrium (LD) in the vicinity of the type 2 diabetes gene calapin-10 (CAPN10) in Mexican Americans, European Americans, African Americans, and Chinese Americans. We found that CAPN10 occurs within a single block of high LD and that LD decays rapidly outside of the gene. This reduces the likelihood that associations between CAPN10 polymorphisms and type 2 diabetes could be attributed to variation at some distance from CAPN10. We also consistently observed that cases have more extensive LD than control subjects and that cases from families with evidence for linkage have more extensive LD than cases from families without evidence for linkage. These observations further suggest that there are one or more relatively common alleles increasing risk of type 2 diabetes in this local region.

• Two major QTLs and several others relate to factors of metabolic syndrome in the family blood pressure program.

  Authors: Aldi T Kraja, Dabeeru C Rao, Alan B Weder, Richard Cooper, J David Curb, Craig L Hanis, Stephen T Turner, Mariza de Andrade, Chao Agnes Hsiung, Thomas Quertermous, Xiaofeng Zhu, Michael A Province

  Hypertension. 10/2005; 46(4):751-7.

  Genome-wide variance components linkage analysis was performed on 4 latent factors underlying metabolic syndrome derived from 10 risk factors. The latent factors represent obesity and insulin, bloodGenome-wide variance components linkage analysis was performed on 4 latent factors underlying metabolic syndrome derived from 10 risk factors. The latent factors represent obesity and insulin, blood pressure, lipids and insulin, and central obesity. The metabolic syndrome factor scores were derived in 4 ethnic groups recruited in 3 Networks of the Family Blood Pressure Program: GENOA (blacks, Hispanics, and whites), HyperGEN (blacks and whites), SAPPHIRe (Asians). Heritabilities of metabolic syndrome factors ranged from 66% for obesity and insulin to 11% for blood pressure factor. We observed higher heritabilities for obesity and insulin, and lipids and insulin, whereas those for blood pressure and central obesity were smaller. Linkage analysis detected two major quantitative trait loci. One of them linked to the obesity and insulin factor with a lod score of 3.94 (P=0.00001, marker GATA11A06, D18S53, 41.24 cM) at marker positions linkage (lod 4.71, at 46.84 cM at 1-cM-apart distances linkage), located on chromosome 18p11.21 in GENOA black. The other linked to the blood pressure factor with a lod score of 3.22 (P=0.000059, marker GATA49C09, D17S1290, 82 cM) at marker positions linkage (lod 3.56, at 84.63 cM for 1 cM apart distances linkage) located on chromosome 17q23.1 in Hispanics. These quantitative trait loci, together with 4 additional ones with lod scores >2.5, and 30 additional ones with lod score >1.7, offer hope for dissecting the genetic architecture of metabolic syndrome with beneficial implications for molecular diagnosis, prognosis, and in potential medical intervention.

• Haplotype structure and phylogenetic shadowing of a hypervariable region in the CAPN10 gene.

  Authors: Vanessa J Clark, Nancy J Cox, Molly Hammond, Craig L Hanis, Anna Di Rienzo

  Human genetics. 08/2005; 117(2-3):258-66.

  It has been proposed that variation in calpain 10 (CAPN10) contributes to the risk of type 2 diabetes (T2D). A previous survey of CAPN10 in ethnically diverse populations revealed an intronic regionIt has been proposed that variation in calpain 10 (CAPN10) contributes to the risk of type 2 diabetes (T2D). A previous survey of CAPN10 in ethnically diverse populations revealed an intronic region with a significant excess of polymorphism levels relative to inter-species sequence divergence, suggesting that this region was the target of long-standing balancing selection. Based on the thrifty genotype hypothesis, variation that increases risk to T2D in contemporary humans at one time conferred a survival advantage in ancestral populations. Thus, the signature of positive natural selection in a T2D candidate gene could identify a genomic region containing variation that influences disease susceptibility. Here, we investigate this hypothesis by re-sequencing the CAPN10 region with unusual polymorphism levels in T2D cases and controls (n=91) from a Mexican American (MA) population, and by using networks to infer the evolutionary relationships between the major haplotypes. Haplotype tag SNPs (htSNPs) were then selected in each population sample and in MA cases and controls. By placing the htSNPs on the haplotype network, we investigate how cross-population differences in CAPN10 genetic architecture may affect the detection of the disease association. Interestingly, despite the small scale of our case-control study, we observe a nearly significant signal of association between T2D and variation in the putative target of balancing selection. Finally, we use phylogenetic shadowing across 10 primate species to search for conserved non-coding elements that may affect the expression and function of CAPN10. These elements are postulated to be the targets of long-standing balancing selection.

• Familial aggregation of severity of diabetic retinopathy in Mexican Americans from Starr County, Texas.

  Authors: D Michael Hallman, J Charles Huber, Victor H Gonzalez, Barbara E K Klein, Ronald Klein, Craig L Hanis

  Diabetes care. 06/2005; 28(5):1163-8.

  OBJECTIVE: Diabetic retinopathy is a major cause of blindness. To determine whether retinopathy itself or only its severity aggregates in families, we examined the occurrence and severity of diabeticOBJECTIVE: Diabetic retinopathy is a major cause of blindness. To determine whether retinopathy itself or only its severity aggregates in families, we examined the occurrence and severity of diabetic retinopathy in Mexican-American siblings with type 2 diabetes. RESEARCH DESIGN AND METHODS: Using stereoscopic fundus photography of seven standard fields, we measured retinopathy in 656 type 2 diabetic patients from 282 Mexican-American families from Starr County, Texas. Retinopathy severity was scored using the Early Treatment of Diabetic Retinopathy Study system and classified as no retinopathy, early nonproliferative diabetic retinopathy (NPDR-E), moderate-to-severe nonproliferative diabetic retinopathy (NPDR-S), or proliferative diabetic retinopathy (PDR). RESULTS: Of 249 siblings of randomly selected probands with retinopathy, 169 (67.9%) had retinopathy, compared with 95 of 125 siblings of unaffected probands (76.0%; P = 0.11). Proband retinopathy class was associated (P = 0.03) with sibling retinopathy class, with significant odds ratios (ORs) for NPDR-E versus no retinopathy (OR 0.57 [95% CI 0.35-0.93]) and PDR versus NPDR-E (2.02 [1.13-3.63]); the contrast of NPDR-S versus NPDR-E approached significance (1.78 [0.99-3.20]). With the more severe classes (PDR and NPDR-S) combined in one group and the less severe ones (none and NPDR-E) in another, more severe proband retinopathy was associated with more severe sibling retinopathy (1.72 [1.03-2.88]). CONCLUSIONS: More severe diabetic retinopathy showed evidence of familial aggregation, but the occurrence of diabetic retinopathy per se did not. The factors involved in the onset of diabetic retinopathy may differ from those involved in its progression to more severe forms.

• Genome-wide linkage scans for fasting glucose, insulin, and insulin resistance in the National Heart, Lung, and Blood Institute Family Blood Pressure Program: evidence of linkages to chromosome 7q36 and 19q13 from meta-analysis.

  Authors: Ping An, Barry I Freedman, Craig L Hanis, Yii-Der I Chen, Alan B Weder, Nicholas J Schork, Eric Boerwinkle, Michael A Province, Chao Agnes Hsiung, Xiaodong Wu, Thomas Quertermous, D C Rao

  Diabetes. 04/2005; 54(3):909-14.

  Genome-wide linkage analyses were performed using a multipoint variance components method in eight study groups from four multicenter networks (whites and blacks in GenNet; whites, blacks, andGenome-wide linkage analyses were performed using a multipoint variance components method in eight study groups from four multicenter networks (whites and blacks in GenNet; whites, blacks, and Mexican Americans in GENOA; whites and blacks in HyperGEN; and Asians in SAPPHIRe) that comprise the National Heart, Lung, and Blood Institute Family Blood Pressure Program (FBPP), in order to identify quantitative trait loci (QTLs) influencing fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR). These study populations were enriched with subjects who had elevated blood pressure. Participants fasting <8 h, those with a history of type 2 diabetes, or those on antidiabetic medications were excluded from the current investigation. These three phenotypes were suitably transformed to approximate normal distributions. Each phenotype was adjusted for the effects of age, BMI, and field center separately by sex within each of the eight network ethnicity groups before genetic analysis. A total of 8,664 subjects comprising 5,923 sibpairs from 4,043 families with 365 markers were available for conducting a meta-analysis using a modified Fisher's method of combining the P values from each of the eight scans. Evidence of linkages was found on chromosome 7q36 at 163 cM, with a logarithm of odds (LOD) score of 3.21 for HOMA-IR, and on chromosome 19q13 at 88 cM, with a LOD score of 3.33 for fasting glucose. We also found suggestive linkages (LOD score >/=2.2) on chromosome 7q36 at 163 cM, with LOD scores of 2.31 for fasting glucose and 2.26 for fasting insulin (versus the LOD score of 3.21 for HOMA-IR at this locus). In conclusion, QTLs were identified on chromosomes 7q36 and 19q13 for fasting glucose, insulin, and insulin resistance in large and multiple-ethnicity populations in the FBPP with good replications across several other independent studies for relevant traits. Follow-up dense mapping and association studies are warranted.