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Franks, Paul W.
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Publications (10 of 219) Show all publications
Sung, Y. J., Winkler, T. W., de las Fuentes, L., Bentley, A. R., Brown, M. R., Kraja, A. T., . . . Chasman, D. I. (2018). A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. American Journal of Human Genetics, 102(3), 375-400
Open this publication in new window or tab >>A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure
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2018 (English)In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 102, no 3, p. 375-400Article in journal (Refereed) Published
Abstract [en]

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined similar to 18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 x 10(-8)) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 x 10(-8)). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling MSRA, EBF2).

National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-146234 (URN)10.1016/j.ajhg.2018.01.015 (DOI)000426469600011 ()29455858 (PubMedID)
Available from: 2018-04-09 Created: 2018-04-09 Last updated: 2018-06-09Bibliographically approved
Allin, K. H., Tremaroli, V., Caesar, R., Jensen, B. A. H., Damgaard, M. T. F., Bahl, M. I., . . . Pedersen, O. (2018). Aberrant intestinal microbiota in individuals with prediabetes. Diabetologia, 61(4), 810-820
Open this publication in new window or tab >>Aberrant intestinal microbiota in individuals with prediabetes
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2018 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, no 4, p. 810-820Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis: Individuals with type 2 diabetes have aberrant intestinal microbiota. However, recent studies suggest that metformin alters the composition and functional potential of gut microbiota, thereby interfering with the diabetes-related microbial signatures. We tested whether specific gut microbiota profiles are associated with prediabetes (defined as fasting plasma glucose of 6.1-7.0 mmol/l or HbA1c of 42-48 mmol/mol [6.0-6.5%]) and a range of clinical biomarkers of poor metabolic health.

Methods: In the present case-control study, we analysed the gut microbiota of 134 Danish adults with prediabetes, overweight, insulin resistance, dyslipidaemia and low-grade inflammation and 134 age-and sex-matched individuals with normal glucose regulation.

Results: We found that five bacterial genera and 36 operational taxonomic units (OTUs) were differentially abundant between individuals with prediabetes and those with normal glucose regulation. At the genus level, the abundance of Clostridium was decreased (mean log2 fold change -0.64 (SEM 0.23), p adj = 0.0497), whereas the abundances of Dorea, [Ruminococcus], Sutterella and Streptococcus were increased (mean log2 fold change 0.51 (SEM 0.12), p adj = 5 x 10-4; 0.51 (SEM 0.11), p adj = 1 x 10-4; 0.60 (SEM 0.21), p adj = 0.0497; and 0.92 (SEM0.21), p adj = 4 x 10-4, respectively). The two OTUs that differed the most were a member of the order Clostridiales (OTU 146564) and Akkermansia muciniphila, which both displayed lower abundance among individuals with prediabetes (mean log2 fold change -1.74 (SEM0.41), p adj = 2 x 10-3 and -1.65 (SEM0.34), p adj = 4 x 10-4, respectively). Faecal transfer from donors with prediabetes or screen-detected, drug-naive type 2 diabetes to germfree Swiss Webster or conventional C57BL/6 J mice did not induce impaired glucose regulation in recipient mice.

Conclusions/interpretation: Collectively, our data show that individuals with prediabetes have aberrant intestinal microbiota characterised by a decreased abundance of the genus Clostridium and the mucin-degrading bacterium A. muciniphila. Our findings are comparable to observations in overt chronic diseases characterised by low-grade inflammation.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Akkermansia muciniphila, Clostridium, Faecal transfer, Gut microbiota, Hyperglycaemia, Intestinal microbiota, Low-grade inflammation, Prediabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-146199 (URN)10.1007/s00125-018-4550-1 (DOI)000427049100009 ()29379988 (PubMedID)
Available from: 2018-05-14 Created: 2018-05-14 Last updated: 2018-06-09Bibliographically approved
Ahmad, S., Mora, S., Franks, P. W., Orho-Melander, M., Ridker, P. M., Hu, F. B. & Chasman, D. I. (2018). Adiposity and Genetic Factors in Relation to Triglycerides and Triglyceride-Rich Lipoproteins in the Women's Genome Health Study. Clinical Chemistry, 64(1), 231-241
Open this publication in new window or tab >>Adiposity and Genetic Factors in Relation to Triglycerides and Triglyceride-Rich Lipoproteins in the Women's Genome Health Study
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2018 (English)In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 64, no 1, p. 231-241Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Previous results from Scandinavian cohorts have shown that obesity accentuates the effects of common genetic susceptibility variants on increased triglycerides (TG). Whether such interactions are present in the US population and further selective for particular TG-rich lipoprotein subfractions is unknown.

METHODS: We examined these questions using body mass index (BMI) and waist circumference (WC) among women of European ancestry from the Women's Genome Health Study (WGHS) (n = 21840 for BMI; n = 19313 for WC). A weighted genetic risk score (TG-wGRS) based on 40 published TG-associated single-nucleotide polymorphisms was calculated using published effect estimates.

RESULTS: Comparing overweight (BMI ≥ 25 kg/m2) and normal weight (BMI < 25 kg/m2) WGHS women, each unit increase of TG-wGRS was associated with TG increases of 1.013% and 1.011%, respectively, and this differential association was significant (Pinteraction = 0.014). Metaanalyses combining results for WGHS BMI with the 4 Scandinavian cohorts (INTER99, HEALTH2006, GLACIER, MDC) (total n = 40026) yielded a more significant interaction (Pinteraction = 0.001). Similarly, we observed differential association of the TG-wGRS with TG (Pinteraction = 0.006) in strata of WC (<80 cm vs ≥80 cm). Metaanalysis with 2 additional cohorts reporting WC (INTER99 and HEALTH2006) (total n = 27834) was significant with consistent effects (Pinteraction = 0.006). We also observed highly significant interactions of the TG-wGRS across the strata of BMI with very large, medium, and small TG-rich lipoprotein subfractions measured by nuclear magnetic resonance spectroscopy (all Pinteractions < 0.0001). The differential effects were strongest for very large TG-rich lipoprotein.

CONCLUSIONS: Our results support the original findings and suggest that obese individuals may be more susceptible to aggregated genetic risk associated with common TG-raising alleles, with effects accentuated in the large TG-rich lipoprotein subfraction.

National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-144095 (URN)10.1373/clinchem.2017.280545 (DOI)000419121500031 ()29097515 (PubMedID)
Funder
Swedish Heart Lung Foundation, 20150711
Available from: 2018-01-30 Created: 2018-01-30 Last updated: 2018-06-09Bibliographically approved
Ahmad, S., Mora, S., Franks, P. W., Orho-Melander, M., Ridker, P. M., Hu, F. B. & Chasman, D. I. (2018). Adiposity and Genetic Factors in Relation to Triglycerides and Triglyceride-Rich Lipoproteins in the Women's Genome Health Study. Clinical Chemistry, 64(1), 231-241
Open this publication in new window or tab >>Adiposity and Genetic Factors in Relation to Triglycerides and Triglyceride-Rich Lipoproteins in the Women's Genome Health Study
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2018 (English)In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 64, no 1, p. 231-241Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Previous results from Scandinavian cohorts have shown that obesity accentuates the effects of common genetic susceptibility variants on increased triglycerides (TG). Whether such interactions are present in the US population and further selective for particular TG-rich lipoprotein subfractions is unknown.

METHODS: We examined these questions using body mass index (BMI) and waist circumference (WC) among women of European ancestry from the Women's Genome Health Study (WGHS) (n = 21840 for BMI; n = 19313 for WC). A weighted genetic risk score (TG-wGRS) based on 40 published TG-associated single-nucleotide polymorphisms was calculated using published effect estimates.

RESULTS: Comparing overweight (BMI ≥ 25 kg/m2) and normal weight (BMI < 25 kg/m2) WGHS women, each unit increase of TG-wGRS was associated with TG increases of 1.013% and 1.011%, respectively, and this differential association was significant (Pinteraction = 0.014). Metaanalyses combining results for WGHS BMI with the 4 Scandinavian cohorts (INTER99, HEALTH2006, GLACIER, MDC) (total n = 40026) yielded a more significant interaction (Pinteraction = 0.001). Similarly, we observed differential association of the TG-wGRS with TG (Pinteraction = 0.006) in strata of WC (<80 cm vs ≥80 cm). Metaanalysis with 2 additional cohorts reporting WC (INTER99 and HEALTH2006) (total n = 27834) was significant with consistent effects (Pinteraction = 0.006). We also observed highly significant interactions of the TG-wGRS across the strata of BMI with very large, medium, and small TG-rich lipoprotein subfractions measured by nuclear magnetic resonance spectroscopy (all Pinteractions < 0.0001). The differential effects were strongest for very large TG-rich lipoprotein.

CONCLUSIONS: Our results support the original findings and suggest that obese individuals may be more susceptible to aggregated genetic risk associated with common TG-raising alleles, with effects accentuated in the large TG-rich lipoprotein subfraction.

National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-144095 (URN)10.1373/clinchem.2017.280545 (DOI)000419121500031 ()29097515 (PubMedID)
Available from: 2018-01-30 Created: 2018-01-30 Last updated: 2018-06-09Bibliographically approved
Kroeger, J., Meidtner, K., Stefan, N., Guevara, M., Kerrison, N. D., Ardanaz, E., . . . Wareham, N. J. (2018). Circulating Fetuin-A and Risk of Type 2 Diabetes: A Mendelian Randomization Analysis. Diabetes, 67(6), 1200-1205
Open this publication in new window or tab >>Circulating Fetuin-A and Risk of Type 2 Diabetes: A Mendelian Randomization Analysis
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2018 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 67, no 6, p. 1200-1205Article in journal (Refereed) Published
Abstract [en]

Fetuin-A, a hepatic-origin protein, is strongly positively associated with risk of type 2 diabetes in human observational studies, but it is unknown whether this association is causal. Weaimed to study the potential causal relation of circulating fetuin-A to risk of type 2 diabetes in a Mendelian randomization study with single nucleotide polymorphisms located in the fetuin-A-encoding AHSG gene. We used data from eight European countries of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study including 10,020 incident cases. Plasma fetuin-A concentration was measured in a subset of 965 subcohort participants and 654 case subjects. A genetic score of the AHSG single nucleotide polymorphisms was strongly associated with fetuin-A (28% explained variation). Using the genetic score as instrumental variable of fetuin-A, we observed no significant association of a 50 mu g/mL higher fetuin-A concentration with diabetes risk (hazard ratio 1.02 [95% CI 0.97, 1.07]). Combining our results with those from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (12,171 case subjects) also did not suggest a clear significant relation of fetuin-A with diabetes risk. In conclusion, although there is mechanistic evidence for an effect of fetuin-A on insulin sensitivity and secretion, this study does not support a strong, relevant relationship between circulating fetuin-A and diabetes risk in the general population.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-150390 (URN)10.2337/db17-1268 (DOI)000438781600018 ()29523632 (PubMedID)2-s2.0-85047763125 (Scopus ID)
Available from: 2018-08-06 Created: 2018-08-06 Last updated: 2018-08-06Bibliographically approved
Huang, T., Ding, M., Bergholdt, H. K. M., Wang, T., Heianza, Y., Sun, D.-j., . . . Qi, L. (2018). Dairy Consumption and Body Mass Index Among Adults: Mendelian Randomization Analysis of 184802 Individuals from 25 Studies. Clinical Chemistry, 64(1), 183-191
Open this publication in new window or tab >>Dairy Consumption and Body Mass Index Among Adults: Mendelian Randomization Analysis of 184802 Individuals from 25 Studies
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2018 (English)In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 64, no 1, p. 183-191Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Associations between dairy intake and body mass index (BMI) have been inconsistently observed in epidemiological studies, and the causal relationship remains ill defined.

METHODS: We performed Mendelian randomization (MR) analysis using an established dairy intake-associated genetic polymorphism located upstream of the lactase gene (LCT-13910 C/T, rs4988235) as an instrumental variable (IV). Linear regression models were fitted to analyze associations between (a) dairy intake and BMI, (b) rs4988235 and dairy intake, and (c) rs4988235 and BMI in each study. The causal effect of dairy intake on BMI was quantified by IV estimators among 184802 participants from 25 studies.

RESULTS: Higher dairy intake was associated with higher BMI (β = 0.03 kg/m2 per serving/day; 95% CI, 0.00–0.06; P = 0.04), whereas the LCT genotype with 1 or 2 T allele was significantly associated with 0.20 (95% CI, 0.14–0.25) serving/day higher dairy intake (P = 3.15 × 10−12) and 0.12 (95% CI, 0.06–0.17) kg/m2 higher BMI (P = 2.11 × 10−5). MR analysis showed that the genetically determined higher dairy intake was significantly associated with higher BMI (β = 0.60 kg/m2 per serving/day; 95% CI, 0.27–0.92; P = 3.0 × 10−4).

CONCLUSIONS: The present study provides strong evidence to support a causal effect of higher dairy intake on increased BMI among adults.

National Category
Nutrition and Dietetics
Identifiers
urn:nbn:se:umu:diva-144092 (URN)10.1373/clinchem.2017.280701 (DOI)000419121500026 ()29187356 (PubMedID)
Available from: 2018-01-26 Created: 2018-01-26 Last updated: 2018-06-09Bibliographically approved
Bennet, L., Franks, P. W., Zöller, B. & Groop, L. (2018). Family history of diabetes and its relationship with insulin secretion and insulin sensitivity in Iraqi immigrants and native Swedes: a population-based cohort study. Acta Diabetologica, 55(3), 233-242
Open this publication in new window or tab >>Family history of diabetes and its relationship with insulin secretion and insulin sensitivity in Iraqi immigrants and native Swedes: a population-based cohort study
2018 (English)In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 55, no 3, p. 233-242Article in journal (Refereed) Published
Abstract [en]

Aims Middle Eastern immigrants to western countries are at high risk of developing type 2 diabetes. However, the heritability and impact of rst-degree family history (FH) of type 2 diabetes on insulin secretion and action have not been adequately described. Methods Citizens of Malmö, Sweden, aged 30–75 years born in Iraq or Sweden were invited to participate in this population- based study. Insulin secretion (corrected insulin response and oral disposition index) and action (insulin sensitivity index) were assessed by oral glucose tolerance tests.

Results In total, 45.7% of Iraqis (616/1348) and 27.4% of native Swedes (201/733) had FH in parent(s), sibling(s) or single parent and sibling, i.e., FH+. Approximately 8% of Iraqis and 0.7% of Swedes had ≥ 3 sibling(s) and parent(s) with diabetes, i.e., FH++. Irrespective of family size, prediabetes and diabetes increased with family burden (FH− 29.4%; FH+ 38.8%; FH++ 61.7%) without signi cant di erences across ethnicities. With increasing level of family burden, insulin secretion rather than insulin action decreased. Individuals with a combination of ≥ 3 siblings and parents with diabetes presented with the lowest levels of insulin secretion.

Conclusions The Iraqi immigrant population often present with a strong familial burden of type 2 diabetes with the worst glycemic control and highest diabetes risk in individuals with ≥ 3 siblings and parents with diabetes. Our data show that in a population still free from diabetes familial burden in uences insulin secretion to a higher degree than insulin action and may be a logical target for intervention. 

Place, publisher, year, edition, pages
Springer Milan, 2018
Keywords
Family history of diabetes, Insulin action, Insulin secretion, Middle East, Type 2 diabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-146160 (URN)10.1007/s00592-017-1088-5 (DOI)000426308200004 ()29274011 (PubMedID)
Available from: 2018-05-15 Created: 2018-05-15 Last updated: 2018-06-09Bibliographically approved
Corbin, L. J., Tan, V. Y., Hughes, D. A., Wade, K. H., Paul, D. S., Tansey, K. E., . . . Timpson, N. J. (2018). Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference. Nature Communications, 9, Article ID 711.
Open this publication in new window or tab >>Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference
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2018 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 711Article, review/survey (Refereed) Published
Abstract [en]

Detailed phenotyping is required to deepen our understanding of the biological mechanisms behind genetic associations. In addition, the impact of potentially modifiable risk factors on disease requires analytical frameworks that allow causal inference. Here, we discuss the characteristics of Recall-by-Genotype (RbG) as a study design aimed at addressing both these needs. We describe two broad scenarios for the application of RbG: studies using single variants and those using multiple variants. We consider the efficacy and practicality of the RbG approach, provide a catalogue of UK-based resources for such studies and present an online RbG study planner.

National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-145586 (URN)10.1038/s41467-018-03109-y (DOI)000425382800003 ()29459775 (PubMedID)
Available from: 2018-03-28 Created: 2018-03-28 Last updated: 2018-06-09Bibliographically approved
Franks, P. W. & Merino, J. (2018). Gene-lifestyle interplay in type 2 diabetes. Current Opinion in Genetics and Development, 50, 35-40
Open this publication in new window or tab >>Gene-lifestyle interplay in type 2 diabetes
2018 (English)In: Current Opinion in Genetics and Development, ISSN 0959-437X, E-ISSN 1879-0380, Vol. 50, p. 35-40Article, review/survey (Refereed) Published
Abstract [en]

Type 2 diabetes (T2D) is widespread, affecting the health of hundreds of millions worldwide. The disease results from the complex interplay of lifestyle factors acting on a backdrop of inherited DNA risk variants. Detecting and understanding biomarkers, whether genotypes or other downstream biological features that dictate a person's phenotypic response to different lifestyle exposures, may have tremendous utility in the prevention of T2D. Here, we explore (i) evidence of how human genetic adaptation to diverse local environments might interact with lifestyle factors in T2D, (ii) the key challenges facing the research area of gene x lifestyle interactions in T2D, and (iii) the solutions that might be pursued in future studies. Overall, many preliminary examples of such interactions exist, but none is sufficient to have a major impact on clinical decision making. Future studies, integrating genetics and other biological markers into regulatory networks, are likely to be necessary to facilitate the integration of genomics into lifestyle medicine in T2D.

Place, publisher, year, edition, pages
CURRENT BIOLOGY LTD, 2018
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-151074 (URN)10.1016/j.gde.2018.02.001 (DOI)000441150400006 ()29459268 (PubMedID)2-s2.0-85042100153 (Scopus ID)
Available from: 2018-08-24 Created: 2018-08-24 Last updated: 2018-08-24Bibliographically approved
Meidtner, K., Podmore, C., Kroger, J., van der Schouw, Y. T., Bendinelli, B., Agnoli, C., . . . Wareham, N. J. (2018). Interaction of Dietary and Genetic Factors Influencing Body Iron Status and Risk of Type 2 Diabetes Within the EPIC-InterAct Study. Diabetes Care, 41(2), 277-285
Open this publication in new window or tab >>Interaction of Dietary and Genetic Factors Influencing Body Iron Status and Risk of Type 2 Diabetes Within the EPIC-InterAct Study
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2018 (English)In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 41, no 2, p. 277-285Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Meat intake has been consistently shown to be positively associated with incident type 2 diabetes. Part of that association may be mediated by body iron status, which is influenced by genetic factors. We aimed to test for interactions of genetic and dietary factors influencing body iron status in relation to the risk of incident type 2 diabetes.

RESEARCH DESIGN AND METHODS: The case-cohort comprised 9,347 case subjects and 12,301 subcohort participants from eight European countries. Single nucleotide polymorphisms (SNPs) were selected from genome-wide association studies on iron status biomarkers and candidate gene studies. A ferritin-related gene score was constructed. Multiplicative and additive interactions of heme iron and SNPs as well as the gene score were evaluated using Cox proportional hazards regression.

RESULTS: Higher heme iron intake (per 1 SD) was associated with higher ferritin levels (β = 0.113 [95% CI 0.082; 0.144]), but not with transferrin (−0.019 [−0.043; 0.006]) or transferrin saturation (0.016 [−0.006; 0.037]). Five SNPs located in four genes (rs1799945 [HFE H63D], rs1800562 [HFE C282Y], rs236918 [PCK7], rs744653 [SLC40A1], and rs855791 [TMPRSS6V736A]) were associated with ferritin. We did not detect an interaction of heme iron and the gene score on the risk of diabetes in the overall study population (Padd = 0.16, Pmult = 0.21) but did detect a trend toward a negative interaction in men (Padd = 0.04, Pmult = 0.03).

CONCLUSIONS: We found no convincing evidence that the interplay of dietary and genetic factors related to body iron status associates with type 2 diabetes risk above the level expected from the sum or product of the two individual exposures.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-147482 (URN)10.2337/dc17-1080 (DOI)000430455100017 ()29167213 (PubMedID)
Available from: 2018-05-07 Created: 2018-05-07 Last updated: 2018-06-09Bibliographically approved
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