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SNP43 of CAPN10 and the Risk of Type 2 Diabetes in African-Americans the Atherosclerosis Risk in Communities Study Michael J

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SNP43 of CAPN10 and the Risk of Type 2 Diabetes in African-Americans the Atherosclerosis Risk in Communities Study Michael J SNP43 of CAPN10 and the Risk of Type 2 Diabetes in African-Americans The Atherosclerosis Risk in Communities Study Michael J. Garant,1,2 W.H. Linda Kao,3 Frederick Brancati,3,4 Josef Coresh,3,4 Tejal M. Rami,3 Craig L. Hanis,5 Eric Boerwinkle,5 and Alan R. Shuldiner1,2 Recently, an A-to-G variant in intron 3 (SNP43) of the calcium-activated neutral protease 10 gene (CAPN10) was identified as a possible type 2 diabetes susceptibil- ype 2 diabetes (formerly known as non–insulin- ity gene through positional cloning in Mexican-Ameri- dependent diabetes) is a heterogeneous disorder cans. We conducted cross-sectional and prospective in which both genetic and nongenetic influences studies to evaluate the relation between SNP43 and contribute to disease risk (1). The genetic con- type 2 diabetes and related traits in middle-aged Afri- T tribution is likely to comprise several gene variants, each can-American participants of the Atherosclerosis Risk in Communities Study, a population-based longitudinal with relatively modest effect, which act in combination study. At baseline, 269 prevalent diabetes cases and with each other and with environmental provocations to 1,159 nondiabetic control subjects were studied. Those cause the disease. Genome wide scans have led to the with the G/G genotype were more likely to have diabetes chromosomal localization of susceptibility loci for type 2 than those with the A/G or A/A genotype (odds ratio diabetes in the Pima Indians of North America (2), in In the prospec- African-Americans, Caucasians, and Japanese Americans .(0.05 ؍ OR] 1.41, 95% CI 1.00–1.99, P] tive study, 166 of the control subjects developed inci- from the American Diabetes Association Genetics of dent diabetes over 9 years of follow-up. The incidence of NIDDM (GENNID) Study (3), in Mexican-Americans (3–5), diabetes for individuals with the G/G genotype did not and in Caucasians from Finland (6–9), France (10), Utah differ significantly from those with at least one copy of (U.S.) (11), and the U.K. (12). The first type 2 diabetes ؍ the A allele (23.3 vs. 19.5 per 1,000 person years, P 0.29). Pooling prevalent and incident diabetic cases susceptibility locus, NIDDM1, was discovered in Mexican- together, individuals with the G/G genotype were ϳ40% Americans from Starr County, TX, and was localized to the more likely to have diabetes than those without (OR D2S125-D2S140 region on chromosome two (4). Linkage in Because of the high the region of NIDDM1 has also been observed in French .(0.03 ؍ CI 1.04–1.83, P 95% ,1.38 frequency of the G allele (0.88), ϳ25% of the suscepti- families in some studies (13) but not in other studies bility to type 2 diabetes in African-Americans may be (5,14–16). Through positional cloning, Horikawa et al. (17) attributed to the G/G genotype at SNP43 of CAPN10, recently identified NIDDM1 as calpain 10 (CAPN10). A although most of the subjects with the G/G genotype did common A-to-G single nucleotide polymorphism in intron not develop diabetes over the 9 years of follow-up. We 3 (SNP-43) of CAPN10 was recessively associated with conclude from this large prospective study that the G type 2 diabetes in a Mexican-American population from allele of SNP43 of CAPN10 or another allele or gene that is in linkage disequilibrium with it increases sus- Starr County, TX (17). Calpains, or calcium-activated ceptibility to type 2 diabetes in African-Americans. neutral proteases, are intracellular nonlysosomal cysteine Diabetes 51:231–237, 2002 proteases, which contribute to diverse physiological cell functions (18–21). Despite these diverse functions, cal- pains have not previously been implicated in pathways that regulate glucose homeostasis, and thus, the mecha- nism whereby this variant contributes to diabetes risk is unknown. Furthermore, because SNP43 is in the noncod- ing region of CAPN10, it is not known how this polymor- From the 1Division of Endocrinology, Diabetes and Nutrition, Department of phism affects CAPN10 activity. Given the unclear role of Medicine, University of Maryland, Baltimore, Maryland; the 2Baltimore Veter- ans Administration Geriatric Research and Education Clinical Center, Balti- CAPN10 in diabetes pathogenesis, defining whether more, Maryland; the 3Department of Epidemiology, Johns Hopkins University SNP43 modifies diabetes risk in other populations is of School of Hygiene and Public Health, Baltimore, Maryland; the 4Department of critical importance. Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; and the 5Human Genetics Center, University of Texas Houston Health Science African-Americans are at increased risk for the develop- Center, Houston, Texas. ment of type 2 diabetes (22). However, few studies have Address correspondence and reprint requests to Alan R. Shuldiner, Depart- ment of Medicine, University of Maryland, 660 West Redwood St., Room 494, investigated the genetic underpinnings of type 2 diabetes Baltimore, MD 21201. E-mail. [email protected]. in African-Americans. To define the relevance of SNP43 of Received for publication 17 May 2001 and accepted in revised form 12 CAPN10 in this ethnic group, we examined its relation to October 2001. ARIC, Atherosclerosis Risk in Communities; OR, odds ratio; PAR, popula- type 2 diabetes risk in a large population-based prospec- tion attributable risk. tive study of middle-aged African-American participants of DIABETES, VOL. 51, JANUARY 2002 231 CAPN10 AND TYPE 2 DIABETES IN AFRICAN-AMERICANS ϭ the Atherosclerosis Risk in Communities (ARIC) Study, insulin ln[insulin at V4] – ln[insulin at V1], which becomes ln(insulin at V /insulin at V ). who were characterized with respect to diabetes preva- 4 1 Effect modifications of the association between SNP43 genotype and type lence and incidence. 2 diabetes by physical activity levels (categorized into quartiles) and total energy intake (categorized into quartiles) were assessed by fitting interaction terms into the multiple logistic regression model. In addition, we examined RESEARCH DESIGN AND METHODS potential interactions between diet or physical activity and genotype on the continuous variables, BMI, and glucose using analysis of covariance. Study participants. Subjects of the present analyses were selected from the 4,266 African-American participants of the ARIC Study. The ARIC Study is a prospective epidemiological study that examines clinical and subclinical RESULTS atherosclerotic disease, characteristics of which have been previously re- Allele frequency and genotype distribution by type 2 ported (23). The present analyses were based on information obtained at baseline and after 9 years of follow-up, consisting of a total of four clinic visits diabetes status. At baseline, 269 prevalent diabetes cases (V1 through V4) scheduled 3 years apart. African-American individuals were and 1,159 control subjects were randomly selected from excluded from the sampling frame of the present analyses if they had missing 3,268 African-American ARIC participants to be included demographic, clinical, dietary, or laboratory data at baseline (n ϭ 998), in the present study, with 86% of the participants from resulting in a sampling frame of 3,268 individuals (2,006 women and 1,262 Jackson, MS. The baseline characteristics of the partici- men). Subjects who were excluded because of incomplete data did not differ significantly with respect to demographics. Using sex-stratified random sam- pants were compared between those with and without pling to maintain a female:male ratio of 3:2, as in the original cohort, 1,441 diabetes in Table 1. In the cross-sectional analysis at individuals were selected for the present analyses (sampling fraction 44%). baseline, the allele frequency of the G allele was slightly Study participants were not known to be first-degree relatives of one another. higher in subjects with diabetes (n ϭ 269) than in control Diabetic case subjects were defined as individuals with any one of the ϭ ϭ Ն subjects (n 1,159) (90.0 vs. 87.2%, P 0.08). The following characteristics at V1 through V4 of the study: 1) fasting glucose 7.0 mmol/l (126 mg/dl), 2) nonfasting glucose Ն11.1 mmol/l (200 mg/dl), 3) genotype frequencies were in accordance with Hardy- current use of medication to treat diabetes, or 4) a positive response to the Weinberg equilibrium in both strata, with 2.2% of the question “Has a doctor ever told you that you had diabetes (sugar in the participants homozygous for the A allele (A/A), 77.7% blood)?” homozygous for the G allele (G/G), and 20.1% heterozy- Details of baseline and follow-up examinations of ARIC study subjects have been reported elsewhere. For the purposes of this study, information gous (A/G). Based on studies in Mexican-Americans from included age, sex, race, personal and family history of diabetes, anthropom- Starr County, TX, we assumed a recessive mode of inher- etry (height, weight, waist, hip, and subscapular and triceps skinfolds), and itance in which the more common G allele is the “at risk” fasting blood (glucose, insulin, total cholesterol, HDL cholesterol, and triglyc- allele (17). Participants with the G/G genotype were more erides). Physical activity during leisure time was assessed by a modified likely to have diabetes than those with at least one copy of version of the questionnaire developed by Baecke et al. (24). Dietary intake ϭ was assessed by a modified version of the 61-item food frequency question- the A allele (OR 1.41, 95% CI 1.00–1.99, P 0.05) (Table 2). naire developed by Willett et al. (25). Adjusting the OR for BMI did not change the results, nor Detection of the SNP43 of the CAPN10 gene. A polymerase chain reaction were there any effects of age or sex on the association of was performed (AmpliTaq Gold with GeneAmp; Perkin Elmer Biosystems, the G/G genotype with diabetes.
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