<Emphasis Type="Italic">FMR1</Emphasis> haplotype analyses among Indians: a weak founder effect and other findings

This study on allelic/haplotypic fragile X associations evaluated using STR (DXS548, FRAXAC1, FRAXAC2) and SNP (ATL1) markers flanking the (CGG)(n) locus of FMR1is the first report from the large ethnically complex Indian population. Results have been compared with allele/haplotype distributions reported for other major ethnic groups, including White Caucasians, Africans, and Pacific Asians. Though overall allele frequency distributions at the individual loci are more similar to Western Caucasians compared with others, significant differences are observed in haplotypic associations with the mutated X. The striking findings are: (1) high diversity and heterozygosity of haplotypes among fragile X chromosomes ( n=40) and controls ( n=262), including four haplotypes found exclusively in this study sample; (2) weak association of DXS548-FRAXAC1-FRAXAC2 haplotypes, 2-1-3, 6-3-3+ and 7-4-6+ with the disorder, and absence of White Caucasian fragile X haplotypes 6-4-4 and 6-4-5; (3) weak founder effect for the fragile X expansion mutation in the Indians; (4) lack of a continuum of haplotype-based FMR1 alleles between intermediate (CGG)(n) size ranges and expanded alleles; (5) exclusion of ATL1 as a candidate genetic indicator of FMR1 instability. The high STR-based haplotype diversity observed among fragile X lineages, irrespective of ethnic alliances, strongly suggests the inappropriateness of using STR haplotypes to infer predisposition to instability among ethnically separated fragile X pedigrees and may reiterate the need for identifying newer SNPs from this region to not only determine true founder effects for the fragile X mutation, but also decipher possible mechanisms leading to CGG instability.     

Haplotype study of intermediate-length alleles at the fragile X (FMR1) gene: ATL1, FMRb, and microsatellite haplotypes differ from those found in common-size FMR1 alleles

The CGG repeat within the X-chromosome-linked FMR1 gene, which in hyperexpansion (> 200 copies) results in fragile X syndrome, is highly polymorphic. The mechanism of expansion is not well understood, but CGG repeats called intermediate-length or gray zone alleles (approximately equal 35-60 repeats) are thought to make up the FMR1 alleles showing initial steps in this expansion process. It has been hypothesized that the background haplotype of these alleles plays a role in their susceptibility to expansion. In this study we investigate whether or not the frequencies of alleles and haplotypes at four marker loci in the FMR1 gene region (microsatellites DXS548 and FRAXAC1 and SNPs ATL1 and FMRb) in 84 intermediate-length male chromosomes differ from those in 94 common-size male alleles. The ATL1*G and FMRB*A alleles were more frequent among intermediate-length alleles than among common alleles. In addition, the DXS548-FRAXAC1 T50-T42 and T40-T42 haplotypes were strongly associated with intermediate-length alleles between 41 and 60 CGG repeats (p < 0.001). Two extended haplotypes, DXS548-FRAXAC1-ATL1-FMRb T50-T42-G-A and T40-T42-G-A, are strongly associated (p < 0.001) with intermediate-length alleles between 41 and 60 CGG repeats, and these haplotypes have also been reported as fragile X associated haplotypes in European populations. These data suggest that these haplotypes are among the most susceptible to further expansion among the intermediate-length alleles. T50-T42-G-A was also much more prevalent in males with 35-40 CGG repeats than in males with common-size alleles. ATL1 did not increase discrimination among intermediate-length alleles beyond that detected by DXS548-FRAXAC1 haplotypes, but the FMRb locus did, particularly for the DXS548-FRAXAC1-ATL1 T50-T42-G and T40-T42-G haplotypes. Comparison with fragile X associated haplotypes, from the literature, suggests that repeat hyperexpansion occurs most frequently on chromosomes carrying FMRB*A. Within the intermediate-length allele category, however, there were some significant differences in haplotype frequencies between smaller and larger alleles, and this finding has implications for future studies.     

Predisposition to the fragile X syndrome in Jews of Tunisian descent is due to the absence of AGG interruptions on a rare Mediterranean haplotype.

We have studied the ethnic distribution of the fragile X syndrome in Israel and have found that 36/136 (26.5%) of apparently unrelated pedigrees were of Tunisian Jewish descent. The Tunisian Jews, however, constitute only 2%-3% of the general Israeli population, identifying the first ethnic group significantly (P < .001) predisposed to the development of this disease. Associated with this increase in disease prevalence, we have found an unusually high incidence of FMR1 CGG repeats devoid of AGG interruptions among the normal Tunisian Jewish population (30/150, or 20.0%). Furthermore, the proportion of these alleles beyond the FMR1 CGG repeat instability threshold (>35 repeats) (8/150, or 5.3%) was significantly greater (P < .04) than that proportion found among non-Tunisian Jewish controls in Israel (1/136). Haplotype analysis has indicated that these large uninterrupted CGG repeat alleles are present on a previously unreported (DXS548-FRAXAC1-FRAXAC2) haplotype that accounts for all observed cases of disease among Tunisian Jewish X chromosomes. The high prevalence of disease among Tunisian Jews, we suggest, is due to a founder effect of this rare haplotype, which is completely devoid of AGG interruptions in the Jewish population of Tunisia.     

The BTNL2 gene and sarcoidosis susceptibility in African Americans and Whites

The BTNL2 gene is a member of the B7 receptor family that probably functions as a T-cell costimulatory molecule. It resides in the class II major histocompatibility complex (MHC) region of chromosome 6p and has recently been associated with sarcoidosis susceptibility in a white German population. We sought to replicate the BTNL2 association in an African American family-based study population (n=219 nuclear families) and two case-control populations--one African American (n=295 pairs) and one white (n=366 pairs). Ten SNPs were detected within a 490-bp region spanning exon/intron 5 of BTNL2. Haplotype variation within this region was significantly associated with sarcoidosis in all three study populations but more so in whites (P=.0006) than in the African American case-control (P=.02) or family-based (P=.03) samples. The previously reported BTNL2 SNP with the strongest sarcoidosis association, rs2076530, was also the SNP with the strongest association in our white population (P<.0001). The A allele of rs2076530 results in a premature exon-splice site and increases risk for sarcoidosis (odds ratio=2.03; 95% confidence interval 1.32-3.12). Although rs2076530 was not associated with sarcoidosis in either African American sample, a three-locus haplotype that included rs2076530 was associated with sarcoidosis across all three study samples. Multivariable logistic regression analyses showed that BTNL2 effects are independent of human leukocyte antigen class II genes in whites but may interact antagonistically in African Americans. Our results underscore the complexity of genetic risk for sarcoidosis emanating from the MHC region.     

Data on the CGG repeat at the fragile X site in the non-retarded Japanese population and family suggest the presence of a subgroup of normal alleles predisposing to mutate

The fragile X mutation is the result of amplification in the repeat number of p(CGG) _n in FMR-1; alleles with more than 52 repeats have been shown to be so unstable as to mutate in the repeat number in almost every transmission. To improve our understanding of mutations in normal alleles of FMR-1, the following studies were carried out in the Japanese population: a study on length variation in the repeat to determine the allele distribution of the repeat length in a non-retarded population, family studies to observe new mutations in normal allele, and haplotype analyses with microsatellite markers flanking the repeat to confirm estimated mutation rates and founder chromosomes in the fragile X syndrome. Analysis of the p(CGG) _n in 370 unrelated males detected 24 distinct alleles with repeats of 18–44. A comparison with previously reported data suggests the presence of racial/ethnic differences in the allele distribution. No premutation allele was found in 824 unrelated X chromosomes examined by the polymerase chain reaction and Southern blot analysis. Family studies detected one new mutation in a total of 303 meioses. However, the mutation rate was not in accordance with the expected or observed heterozygosities in the population or with linkage disequilibrium observed between the repeat numbers and the haplotypes of the markers flanking the CGG. The haplotype in the chromosome in which the new mutation was found was the same as that frequently found in the Japanese fragile X chromosomes, and the variance in the CGG repeat number was wider in chromosomes with the haplotypes frequently found in the fragile X chromosome than in those with the other haplotypes. These observations suggest that a subgroup is present in normal alleles and that this subgroup is more liable to mutate than others.     

The fragile X syndrome in Finland: demonstration of a founder effect by analysis of microsatellite haplotypes

Microsatellite markers RS46 (DXS548) and FRAXAC2 flanking the fragile X mutation, an expansion of a (CGG)_n repeat within the FMR-1 gene, were typed in 60 unrelated northern and eastern Finnish fragile X families and in a control population from the same geographical region. A significant difference was found in allelic and haplotypic distributions between the normal X and fragile X chromosomes. Evidence for a strong founder effect was detected, with the haplotype 196-153 being present on 80% of the fragile X chromosomes, but on only 8% of the normal X chromosomes. In addition to this major haplotype, four minor haplotypes were found on the fragile X chromosomes. These results suggest that the majority of present-day fragile X mutations in Finland may have a common initial ancestor, probably from the 16th century.     

The FMR1 CGG repeat and linked microsatellite markers in two Basque valleys

Fragile X syndrome is associated with an unstable CGG repeat sequence in the 5' untranslated region of the first exon of the FMR1 gene. The present study involved the evaluation of factors implicated in CGG repeat stability in a normal sample from two Basque valleys (Markina and Arratia), to discover whether the Basque population shows allelic diversity and to identify factors involved, by using the data in conjunction with previous findings. The study was based on a sample of 204 and 58 X chromosomes from the Markina and Arratia valleys, respectively. The CGG repeat, the AGG interspersion and two flanking microsatellite markers, FRAXAC1 and DXS548, were examined. In the Markina valley, gray zone alleles (> or =35 CGG repeats) were associated with anchoring AGGs, with the longest 3' pure CGG repeats of the valley (=15), with the 5' instability structure 9+n and with one principal fragile X FRAXAC1-DXS548 haplotype 42-50. In the Arratia valley, gray zone alleles (> or =35 CGG repeats) showed the highest frequency among the Basque samples analyzed, and were associated with anchoring AGGs, with the longest 3' pure repeats (> or =20), with the 5' instability structure 9+n and with one "normal" FRAXAC1-DXS548 haplotype 38-40 (these data from Arratia suggest the existence of a "protective" haplotype). The results showed, on the one hand, differences between Markina and Arratia in factors implicated in CGG repeat instability and, on the other hand, a great similarity between the general Basque sample from Biscay and the Markina valley.     

Secondary structure and dynamics of the r(CGG) repeat in the mRNA of the fragile X mental retardation 1 (FMR1) gene.

The CGG triplet repeat found within the 5'UTR of the FMR1 gene is involved in the pathogenesis of both fragile X syndrome and fragile X-associated tremor/ataxia syndrome (FXTAS). The repeat has been shown to form both hairpins and tetraplexes in DNA; however, the secondary structure of CGG-repeat RNA has not been well defined. To this end, we have performed NMR spectroscopy on in vitro transcribed CGG-repeat RNAs and see clear evidence of intramolecular hairpins, with no evidence of tetraplex structures. Both C*G and G*G base pairs form in the hairpin stem, though in a dynamic equilibrium of conformations. In addition, we investigated the effect of an AGG repeat interruption on hairpin stability; such interruptions are often interspersed within the CGG repeat element and are thought to modulate secondary structure of the RNA. While the AGG repeat lowers the Tm of the hairpin at low Mg2+ concentrations, this difference disappears at physiological Mg2+ levels.     

Recurrence of the R408W Mutation in the Phenylalanine Hydroxylase Locus in Europeans

The relative frequency of the common phenylalanine hydroxylase (PAH) mutation R408W and its associations with polymorphic RFLP, VNTR, and short-tandem-repeat (STR) sites in the PAH gene were examined in many European populations and one representative North American population of defined European descent. This mutation was found to cluster in two regions: in northwest Europe among Irish and Scottish peoples, and in eastern Europe, including the Commonwealth of Independent States. This allele was significantly less frequent in intervening populations. In eastern European populations, the R408W mutation is strongly associated with RFLP haplotype 2, the three-copy VNTR allele (VNTR 3), and the 240-bp STR allele. In northwestern European populations, it is strongly associated with RFLP haplotype 1, the VNTR allele containing eight repeats (VNTR 8), and the 244-bp STR allele. An examination of the linkage between the R408W mutation and highly polymorphic RFLP, VNTR, and STR haplotypes suggests that recurrence is the most likely mechanism to account for the two different major haplotype associations of R408W in Europe.     

FMR1 in global populations.

Fragile X syndrome, a frequent form of inherited mental retardation, results from the unstable expansion of a cryptic CGG repeat within the 5' UTR region of the FMR1 gene. The CGG repeat is normally polymorphic in length, and the content is frequently interrupted by AGG triplets. These interruptions are believed to stabilize the repeat, and their absence, leading to long tracts of perfect CGG repeats, may give rise to predisposed alleles. In order to examine the stability of normal FMR1 alleles, the repeat length of 345 chromosomes from nine global populations was examined with the content also determined from 114 chromosomes as assessed by automated DNA sequencing. The FMR1 alleles, defined by the CGG repeat, as well as by the haplotypes of nearby polymorphic loci, were very heterogeneous, although the level of variation correlated with the age and/or genetic history of a particular population. Native American alleles, interrupted by three AGG repeats, exhibited marked stability over 7,000 years. However, in older African populations, parsimony analysis predicts the occasional loss of an AGG, leading to more perfect CGG repeats. These data therefore support the suggestion that AGG interruptions enhance the stability of the FMR1 repeat and indicate that the rare loss of these interruptions leads to alleles with longer perfect CGG-repeat tracts.     

Prevalence and phenotype consequence of FRAXA and FRAXE alleles in a large,ethnically diverse,special education-needs population.

We conducted a large population-based survey of fragile X (FRAXA) syndrome in ethnically diverse metropolitan Atlanta. The eligible study population consisted of public school children, aged 7-10 years, in special education-needs (SEN) classes. The purpose of the study was to estimate the prevalence among whites and, for the first time, African Americans, among a non-clinically referred population. At present, 5 males with FRAXA syndrome (4 whites and 1 African American), among 1,979 tested males, and no females, among 872 tested females, were identified. All males with FRAXA syndrome were mentally retarded and had been diagnosed previously. The prevalence for FRAXA syndrome was estimated to be 1/3,460 (confidence interval [CI] 1/7,143-1/1,742) for the general white male population and 1/4, 048 (CI 1/16,260-1/1,244) for the general African American male population. We also compared the frequency of intermediate and premutation FRAXA alleles (41-199 repeats) and fragile XE syndrome alleles (31-199 repeats) in the SEN population with that in a control population, to determine if there was a possible phenotype consequence of such high-repeat alleles, as has been reported previously. No difference was observed between our case and control populations, and no difference was observed between populations when the probands were grouped by a rough estimate of IQ based on class placement. These results suggest that there is no phenotype consequence of larger alleles that would cause carriers to be placed in an SEN class.     

Prevalence of carriers of premutation-size alleles of the FMRI gene--and implications for the population genetics of the fragile X syndrome.

The fragile X syndrome is the second leading cause of mental retardation after Down syndrome. Fragile X premutations are not associated with any clinical phenotype but are at high risk of expanding to full mutations causing the disease when they are transmitted by a carrier woman. There is no reliable estimate of the prevalence of women who are carriers of fragile X premutations. We have screened 10,624 unselected women by Southern blot for the presence of FMR1 premutation alleles and have confirmed their size by PCR analysis. We found 41 carriers of alleles with 55-101 CGG repeats, a prevalence of 1/259 women (95% confidence interval 1/373-1/198). Thirty percent of these alleles carry an inferred haplotype that corresponds to the most frequent haplotype found in fragile X males and may indeed constitute premutations associated with a significant risk of expansion on transmission by carrier women. We identified another inferred haplotype that is rare in both normal and fragile X chromosomes but that is present on 13 (57%) of 23 chromosomes carrying FMR1 alleles with 53-64 CGG repeats. This suggests either (1) that this haplotype may be stable or (2) that the associated premutation-size alleles have not yet reached equilibrium in this population and that the incidence of fragile X syndrome may increase in the future.     

Testing for population subdivision and association in four case-control studies

Population structure has been presumed to cause many of the unreplicated disease-marker associations reported in the literature, yet few actual case-control studies have been evaluated for the presence of structure. Here, we examine four moderate case-control samples, comprising 3,472 individuals, to determine if detectable population subdivision is present. The four population samples include: 500 U.S. whites and 236 African Americans with hypertension; and 500 U.S. whites and 500 Polish whites with type 2 diabetes, all with matched control subjects. Both diabetes populations were typed for the PPARg Pro12Ala polymorphism, to replicate this well-supported association (Altshuler et al. 2000). In each of the four samples, we tested for structure, using the sum of the case-control allele frequency chi(2) statistics for 9 STR and 35 SNP markers (Pritchard and Rosenberg 1999). We found weak evidence for population structure in the African American sample only, but further refinement of the sample, to include only individuals with U.S.-born parents and grandparents, eliminated the stratification. Our examples provide insight into the factors affecting the replication of association studies and suggest that carefully matched, moderate-sized case-control samples in cosmopolitan U.S. and European populations are unlikely to contain levels of structure that would result in significantly inflated numbers of false-positive associations. We explore the role that extreme differences in power among studies, due to sample size and risk-allele frequency differences, may play in the replication problem.     

FMR1 CGG repeat distribution and linked microsatellite-SNP haplotypes in normal Mexican Mestizo and indigenous populations

The (CGG)n repeat size distribution in the FMR1 gene was studied in healthy individuals: 80 X chromosomes of Mexican Mestizos from Mexico City and 33 X chromosomes of Mexican Amerindians from three indigenous communities (Purepechas, Nahuas, and Tzeltales), along with alleles and haplotypes defined by two microsatellite polymorphic markers (DXS548 and FRAXAC1) and two single nucleotide polymorphisms (FMRA and FMRB). Genetic frequencies of Mestizo and Amerindian subpopulations were statistically similar in almost all cases and thus were considered one population for comparisons with other populations. Sixteen (CGG)n alleles in the 17-38 size range were observed, and the most common were the 25 (38.0%), 26 (28.3%), and 24 (12.3%) repeat alleles. This pattern differs from most other populations reported, but a closer relation to Amerindian, European, and African populations was found, as expected from the historical admixture that gave rise to Mexican Mestizos. The results of the CA repeats analysis at DXS548-FRAXAC1 were restricted to nine haplotypes, of which haplotypes 7-4 (52.2%), 8-4 (23.8%), and 7-3 (11.5%) were predominant. The modal haplotype 7-4, instead of the nearly universal haplotype 7-3, had been reported exclusively in Eastern Asian populations. Likewise, only seven different FRAXAC1-FMRA-FMRB haplotypes were observed, including five novel haplotypes (3TA, 4TA, 3 - A, 4 - A, and 5 - A), compared with Caucasians. Of these, haplotypes - A (78.7%) and 3 - A (13.2%) were the most common in the Mexican population. These data suggest a singular but relatively low genetic diversity at FMR1 in the studied Mexican populations that may be related to the recent origin of Mestizos and the low admixture rate of Amerindians.     

Analysis of the Fragile X Trinucleotide Repeat in Basques: Association of Premutation and Intermediate Sizes,Anchoring AGGs and Linked Microsatellites with Unstable Alleles

Fragile X Syndrome (FXS) is associated with an unstable CGG repeat sequence in the 5’ untranslated region in the first exon of the FMR1 gene which resides at chromosome position Xq27.3 and is coincident with the fragile site FRAXA. The CGG sequence is polymorphic with respect to size and purity of the repeat. Interpopulation variation in the polymorphism of the FMR1 gene and consequently, in the predisposition to FXS due to the prevalence of certain unstable alleles has been observed. Spanish Basque population is distributed among narrow valleys in northeastern Spain with little migration between them until recently. This characteristic may have had an effect on allelic frequency distributions. We had previously reported preliminary data on the existence of FMR1 allele differences between two Basque valleys (Markina and Arratia). In the present work we extended the study to Uribe, Gernika, Durango, Goierri and Larraun, another five isolated valleys enclosing the whole area within the Spanish Basque region. We analyzed the prevalence of FMR1 premutated and intermediate/grey zone alleles. With the aim to complete the previous investigation about the stability of the Fragile X CGG repeat in Basque valleys, we also analyzed the existence of potentially unstable alleles, not only in relation with size and purity of CGG repeat but also in relation with DXS548 and FRAXAC1 haplotypes implicated in repeat instability. The data show that differences in allele frequencies as well as in the distribution of the mutational pathways previously identified are present among Basques. The data also suggest that compared with the analyzed Basque valleys, Gernika had increased frequency of susceptibility to instability alleles, although the prevalence of premutation and intermediate/grey zone alleles in all the analyzed valleys was lower than that reported in Caucasian populations.Key Words: Fragile X syndrome, FMR1 gene, CGG repeat, FRAXAC1, DXS548, basque country.     

Screening for FXTAS in 95 Spanish patients negative for Huntington disease

Fragile X syndrome is the most common form of hereditary mental retardation. The molecular basis of this syndrome is mainly a CGG expansion in the 5' untranslated region of the FMR1 gene. Expansions with more than 200 CGG repeats abolish gene expression causing the classical fragile X phenotype. Premutation carriers (55-200 CGG) have normal cognitive function with increased risk of developing premature ovarian failure and fragile X-associated tremor-ataxia syndrome (FXTAS). Some clinical features associated with FXTAS, such as tremor, gait ataxia, cognitive decline, and generalized brain atrophy, are also seen in other movement disorders. Ninety-five patients referred for HD, who tested negative for the expansion in the IT15 gene, were screened for FMR1 CGG-repeat expansion. One FMR1 premutation male carrier was detected, giving an FXTAS frequency of 1.6%. Our results highlight that FXTAS is still not well diagnosed; therefore, we recommend FMR1 premutation screenings in all patients with late-onset tremor, ataxia, and cognitive dysfunction.     

Molecular analysis of the (CGG)n expansion in the FMR-1 gene in 59 Spanish fragile X syndrome families

The fragile X mental retardation syndrome is caused by an expansion of a trinucleotide repeat (CGG)_n in the FMR-1 gene. Molecular genetic study of fragile X provides accurate diagnosis and facilitates genetic counseling in families with affected members. We present here the molecular study of 59 Spanish fragile X syndrome families using probe StB 12.3 and the polymerase chain reaction (PCR) of the (CGG)_n repeat sequence of the FMR-1 gene. The results obtained have allowed us to characterize 455 individuals, including eight prenatal diagnoses. The clinical diagnosis of fragile X in 89 affected males was confirmed, 137 female carriers were identified (48 of whom were mentally retarded), 176 individuals at risk were found not to have the expansion, and 12 cases of normal transmitting males (NTM) were detected. In the sample studied, no de novo mutations were detected, nor any mutation different from that described for the (CGG)_n expansion. One nonmentally retarded male was detected as having an unmethylated CpG island for the FMR-1 gene, but with more than 200 CGG repeats (high functioning male). The analysis of the (CGG)_n repeat in 208 normal chromosomes gave an allele distribution similar to that in other Caucasoid population groups, with alleles of 29 and 30 CGG repeats accounting for 46% of the chromosomes. The combination of Southern analysis and PCR of the (CGG)_n repeat is highly efficient for diagnosis, compared with cytogenetic techniques, especially in the detection of female carriers, NTMs, and prenatal diagnosis, enabling accurate genetic counseling to be provided in all cases.     

Polymorphic DNA haplotypes at the LDL receptor locus.

Mutations in the low-density lipoprotein (LDL) receptor gene result in the autosomal dominant disorder familial hypercholesterolemia (FH). Many different LDL receptor mutations have been identified and characterized, demonstrating a high degree of allelic heterogeneity at this locus. The ability to identify mutant LDL receptor genes for prenatal diagnosis of homozygous FH or to study the role of the LDL receptor gene in polygenic hypercholesterolemia requires the use of closely linked RFLPs. In the present study we used 10 different RFLPs, including three newly described polymorphisms, to construct 123 independent haplotypes from 20 Caucasian American pedigrees. Our sample contained 31 different haplotypes varying in frequency from 0.8% to 29.3%; the five most common haplotypes account for 67.5% of the sample. The heterozygosity and PIC of each site were determined, and these values disclosed that eight of the RFLPs were substantially polymorphic. Linkage-disequilibrium analysis of the haplotype data revealed strong nonrandom associations among all 10 RFLPs, especially among those sites clustered in the 3' region of the gene. Evolutionary analysis suggests the occurrence of both mutational and recombinational events in the generation of the observed haplotypes. A strategy for haplotype analysis of the LDL receptor gene in individuals of Caucasian American descent is presented.     

Associations of Fat Distribution and Obesity with Hypertension in a Bi‐ethnic Population: The ARIC Study

Objective: To examine associations of hypertension with obesity and fat distribution among African American and white men and women. Research Methods and Procedures: The analysis sample included 15,063 African American and white men and women between the ages of 45 and 64 years who were participants in the 1987 through 1989 examination of the Atherosclerosis Risk in Communities Study (ARIC). Odds ratios and adjusted prevalences of hypertension were calculated across sexspecific quintiles of body mass index (BMI), waist‐to‐hip ratio (WHR), waist circumference, and waist‐to‐height ratio (waist/height) and adjusted for age, research center, smoking, education, physical activity, alcohol consumption, hormone replacement therapy, and menopausal status. Results: The prevalence of hypertension was higher among African Americans than whites. In the lowest quintile of BMI, 41% of African American women and 43% of African American men had hypertension compared with 14% of white women and 19% of white men. Elevated BMI, WHR, waist circumference, and waist/height were associated with increased odds of hypertension in African American and white men and women. In women, but not in men, there were significant interactions between ethnicity and the anthropometric variables studied here. The direction of the interaction indicated larger odds ratios for hypertension with increasing levels of anthropometric indices in white compared with African American women. Discussion: Obesity and abdominal fat preponderance were associated with increased prevalence of hypertension in African American and white men and women. Associations were similar among African American and white men, but obesity and fat patterning were less strongly associated with hypertension in African American than in white women.